Chromosomes and Chromosomal Abnormalities: Maria Descartes, Bruce R. Korf, and Fady M. Mikhail

35 Chromosomes and Chromosomal Abnormalities
Maria Descartes, Bruce R. Korf, and Fady M. Mikhail
The development and maintenance of the human body is METHODS OF CHROMOSOME ANALYSIS
directed by an estimated 20,000 genes, consisting of some 3
billion base pairs (bp) of DNA. These genes encode the struc- Chromosome Preparation
ture of proteins and noncoding RNAs, which together are The history of clinical cytogenetics can be characterized as a
responsible for the orderly unfolding of human development, series of technical advances, each of which has led to the rec-
beginning with the fertilized egg (zygote), and for the main- ognition of new clinical syndromes resulting from chromo-
tenance of body structure and function. The entire pool of somal abnormalities. The modern era in human cytogenetics
genetic information must be replicated with each cell division began with the discovery of methods to permit individual
and a complete set of information apportioned to the two chromosomes to be identified in dividing cells. The key break-
daughter cells. In addition, the full complement of genes must through was the use of hypotonic treatment to spread the
be transmitted from generation to generation through the chromosomes apart, thereby avoiding overlaps. This advance
germ cells. led, in 1956, to the discovery that the normal human chromo-
Genes do not exist as isolated entities within the cell some number is 46, rather than 48, as had been previously
nucleus, but rather are arranged on structural units called thought. The second major advance was the discovery that
chromosomes. Each chromosome contains hundreds or thou- phytohemagglutinin, a kidney-bean extract, can stimulate
sands of genes arranged in a linear order. This order is repro- lymphocytes to divide in culture, providing an easily obtained
ducible from cell to cell within an individual organism, and source of dividing cells for analysis. The first golden age of
from individual to individual in the population. The normal discovery of chromosomal abnormalities began with the rec-
human chromosome complement consists of 46 chromo- ognition of trisomy 21 in persons with Down syndrome in
somes, including 22 pairs of nonsex chromosomes (auto- 1959 and continued through the early 1960s with the identi-
somes) and either two X chromosomes in females or an X and fication of other aneuploidy syndromes.
a Y in males. Each of these chromosomes has a characteristic Chromosome structure is most easily appreciated during
structure and includes a specific set of genes arranged in a mitosis, when the chromatin fiber is condensed and coiled
specific order. The chromosomes are units that ensure the into a characteristic structure. Spontaneously dividing cells are
orderly distribution of a complete set of genetic information rarely available, except in tumors or chorionic villus tissue
during cell division. used in prenatal diagnosis. Rather, cells are grown in short-
Chromosome number and structure are tightly regulated, term culture. For routine analysis, peripheral blood lympho-
and deviations from the norm usually are associated with cytes most commonly are used, although skin fibroblasts also
clinical problems. Multiple genes are simultaneously dis- may be cultured and analyzed. Phytohemagglutinin-stimulated
rupted as a consequence of chromosomal abnormalities; peripheral blood usually is grown in culture for 3 days. Block-
accordingly, the phenotypic consequences usually are complex. ing the mitotic spindle with a drug such as colchicine leads to
Because of the complexity of the nervous system and its accumulation of dividing cells, which then are induced to
dependence on multiple genes, neurologic problems accom- swell by treatment with hypotonic saline, fixed, and spread on
pany most of the chromosomal disorders. to a microscope slide.
Chromosomal abnormalities were among the first genetic
disorders to be studied in the laboratory. From the late 1950s
onward, with the advent of reliable techniques for chromo-
somal analysis, a set of syndromes resulting from changes in
Chromosome Banding
chromosome number or structure was described. Initially, Until the 1970s chromosomes were identified on the basis of
these were syndromes associated with loss or gain of entire their size and the position of the centromeres. This allowed
chromosomes or large chromosome segments, such as Down chromosomes to be classified into groups labeled A to G (A:
syndrome, resulting from trisomy 21. Refinements in analytic chromosomes 1-3, B: chromosomes 4-5, C: chromosomes
technology have gradually improved the resolution of chro- 6-12 and X, D: chromosomes 13-15, E: chromosomes 16-18,
mosomal analysis, permitting progressively smaller changes to F: chromosomes 19-20, G: chromosomes 21-22 and Y), but
be detected. Current techniques are bridging the gap between not unambiguously identified. The introduction of banding
chromosomal anomalies visible with the light microscope and techniques finally allowed each chromosome to be identified
changes in individual genes at a submicroscopic level. At the and permitted the identification of chromosome regions,
same time, techniques have been developed that permit chro- bands, and subbands. Most laboratories use Giemsa stain
mosomal analysis in nondividing cells and in various tissues banding (G-banding), which involves treatment of the meta-
that can be sampled prenatally. phase chromosomes with a protease (i.e., trypsin), followed
This chapter focuses on the approach to chromosomal by Giemsa staining for routine analysis. The advent of chro-
disorders in pediatric neurology. The various methods of mosome banding stimulated a second wave of discovery of
chromosomal analyses are considered first, followed by a structural chromosomal abnormalities during the 1970s.
description of the various types of chromosomal abnormali- Chromosomes are displayed as a karyotype (Figure 35-1),
ties. This discussion is followed by an overview of the clinical which is prepared by arranging homologous chromosomes in
approach to chromosomal abnormalities and then a brief an orderly fashion, starting from chromosome 1 and ending
clinical description of chromosomal syndromes relevant to with chromosome 22 and including the sex chromosomes.
the practice of pediatric neurology. The chapter closes with a Subsequent developments in laboratory cytogenetics have
look at the future of cytogenetic analysis (see also Chapter 34). gradually improved the resolution of chromosomal analysis.
e644
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Chromosomes and Chromosomal Abnormalities e645
35
Figure 35-1. Normal male human karyotype (46,XY).
As the cell proceeds through mitosis, the chromosome gradu- specific for a particular single locus. They are especially useful
ally contracts, until anaphase, when the chromatids separate. for identifying subtle submicroscopic deletions and duplica-
If cells are collected during early metaphase (i.e., prometa- tions (Figure 35-2). Centromeric probes are specific for unique
phase), chromosomes are highly extended, revealing a fine, repetitive DNA sequences (e.g., alpha-satellite sequences) in
highly detailed banding pattern. This banding pattern has the centromere of a specific chromosome. They are suitable for
facilitated recognition of subtle chromosome rearrangements making a rapid diagnosis of one of the common aneuploidy
involving small chromosome segments. Even with this syndromes (trisomies 13, 18, and 21, and sex chromosome
approach, however, the resolution is limited to 3–5 to million aneuploidies) using nondividing interphase nuclei. This is
bp (Mb) of DNA, which may include dozens of genes. particularly useful in a prenatal setting using amniotic fluid
or chorionic villi sampling (CVS). Whole-chromosome paint
probes consist of a cocktail of probes obtained from differ-
Molecular Cytogenetics ent regions of a particular chromosome. When this cocktail
The gap between light microscope resolution of chromosome mixture is used in a single hybridization, the entire relevant
structure and the gene was bridged by the introduction of chromosome fluoresces (is “painted”). Whole-chromosome
several molecular cytogenetic techniques. Fluorescence in paints are useful for characterizing complex chromosomal
situ hybridization (FISH) involves hybridizing a fluorescently rearrangements and for identifying the origin of addi-
labeled single-stranded DNA probe to denatured chromo- tional chromosomal material, such as small marker or ring
somal DNA on a microscope slide preparation of metaphase chromosomes.
chromosomes and/or interphase nuclei prepared from the FISH using locus-specific probes has been extremely useful
patient’s sample. After overnight hybridization, the slide is in the detection of microdeletion syndromes resulting from
washed and counterstained with a nucleic acid dye (e.g., DAPI, deletions of multiple contiguous genes. These are subtle sub-
or 4′,6-diamidino-2-phenylindole), allowing the region where microscopic deletions that are below the resolution of the
hybridization has occurred to be visualized using a fluores- routine G-banded chromosome analysis. Also, two-color and
cence microscope. FISH is now widely used for clinical diag- three-color FISH applications are routinely used to diagnose
nostic purposes. There are different types of FISH probes, specific deletions, duplications, or other rearrangements, both
including locus-specific probes, centromeric probes, and in metaphase chromosomes and in interphase nuclei. Use of
whole-chromosome paint probes. Locus-specific probes are FISH usually requires that the patient either exhibits features
e646 PART VI Genetic, Metabolic and Neurocutaneous Disorders
15
−4 −2 −1 0 +1 +2 +4
q12
q13.2
Figure 35-2. Fluorescence in situ hybridization (FISH) analysis

using the DiGeorge/velocardiofacial syndrome probe. Note the q14
deleted Tuple1 (22q11.2) red probe on one chromosome 22 (arrow).
The ARSA (22q13.3) green probe is included as an internal control. q15.2
consistent with a well-defined syndrome with known chromo-

somal etiology or demonstrates an abnormal karyotype. The q21.1
reason for this is because single FISH probes reveal rearrange-
ments only of the segments being interrogated and do not
provide information about the rest of the genome. Another
limitation of FISH is the number of probes that can be applied q21.3
in a simultaneous assay. FISH techniques have been developed
utilizing pools of whole-chromosome paint probes for every
chromosome to provide a multicolor human karyotype in
q22.2
which each pair of homologous chromosomes can be identi-
fied on the basis of its unique color when studied using special q22.32
computer-based image analysis software (spectral karyotyping
and multicolor or M-FISH).1
One type of FISH that has the potential to reveal chromo- q23
somal imbalances across the genome is comparative genomic
hybridization (CGH). In CGH, DNA specimens from the
q24.2
patient and a normal control are differentially labeled with
two different fluorescent dyes and hybridized to normal meta-
phase chromosome spreads. Differences between the fluores- q25.1
cent intensities of the two dyes along the length of any given
chromosome will reveal gains and losses of genomic seg-
ments.2 The limitations of this technology include many of
the same limitations of G-banded chromosome analysis. q25.3
Thus, as with G bands, the resolution of CGH is limited to
that of metaphase chromosomes, which is approximately
5 Mb for most clinical applications.2
The latest addition to molecular cytogenetic techniques is
chromosomal microarray (CMA) technology, including array q26.2
CGH and single-nucleotide polymorphism (SNP) arrays.
Array CGH involves hybridizing a test sample of interest and
a control reference sample, each differentially labeled with
different colored fluorescent dyes, to an array slide contain- Figure 35-3. Array comparative genomic hybridization (array
ing thousands of DNA probes. Following hybridization and CGH) analysis using a whole-genome-coverage oligo-array. A
washing to remove unbound DNA, the array is scanned and chromosome 15 plot is shown with a one-copy loss (heterozygous
analyzed using computer software to measure the relative deletion) in the Prader–Willi/Angelman region at 15q11.2q13.1.
ratios of fluorescence of the two dyes, which detects gains/
losses of genomic regions represented on the array (Figure
35-3).3 High-density SNP arrays can also be used to detect computer software. The deviation from the expected fluores-
genomic copy-number gains/losses. In these experiments, the cent intensities of the two alleles of an SNP are compared
patient’s DNA is fluorescently labeled with a fluorescent dye with previously analyzed control samples spanning several
and hybridized to a high-density SNP array. Following hybrid- adjacent SNPs to detect genomic copy-number gains/losses.4,5
ization and washing, the array is scanned and analyzed using High-resolution CMAs can detect genomic copy-number
gains/losses bigger than 50 kb across the euchromatic portion Deletions and Duplications
of human genome. Also, clinically relevant haploinsufficient 35
genes have been targeted at a higher resolution on many CMA A deletion involves loss of part of a chromosome and results
platforms, allowing the detection of gains/losses as small as in monosomy for that segment of the chromosome, whereas
5 to 10 kb in these targeted regions. In the past few years, duplication represents the doubling of part of a chromosome,
high-resolution whole-genome-coverage CMA platforms have resulting in trisomy for that segment. The result is either
been increasingly used in clinical molecular cytogenetic labs. decrease (in a deletion) or increase (in a duplication) in gene
These provide a relatively quick method of scanning the entire dosage. In general, duplications appear to be less harmful than
genome for gains/losses with significantly higher resolution deletions. Very large deletions usually are incompatible with
and greater yield of clinical abnormalities than was previously survival to term. Deletions or duplications larger than approx-
possible. This has led to the identification of novel genomic imately 5 Mb in size can be visualized under the microscope
disorders in patients with autism spectrum disorders (ASDs), using G-banded chromosome analysis. Clinical syndromes
developmental delay (DD), intellectual disability (ID), and/ resulting from submicroscopic deletions or duplications (i.e.,
or multiple congenital anomalies (MCAs).6 microdeletions/microduplications) with a size less than 5 Mb
have been identified with the help of molecular cytogenetic
techniques, including FISH and CMA. In these syndromes,
CHROMOSOMAL ABNORMALITIES groups of contiguous genes are either deleted or duplicated,
Most chromosomal abnormalities exert their phenotypic resulting in a defined set of congenital anomalies. The mo
effects by increasing or decreasing the quantity of genetic lecular mechanisms responsible for these microdeletions/
material. Chromosomal abnormalities can be divided into microduplications have been extensively studied and are
numerical and structural abnormalities. well documented.7 Specific microdeletion/microduplication
syndromes of neurologic interest are described later in this
chapter.
Numerical Abnormalities
The most straightforward of chromosomal abnormalities are Translocations
alterations of chromosome number. Deviation from the Translocations involve the exchange of genetic material
normal diploid complement of 46 chromosomes is referred between chromosomes. In a balanced reciprocal translocation
to as aneuploidy; an extra chromosome results in trisomy, the exchange is equal, with no loss or gain of genetic material,
whereas a missing chromosome results in monosomy. Although although it is possible for a gene to be disrupted at one of the
all of the possible chromosomal trisomies have been observed breakpoints. More often, the carrier of a balanced transloca-
in spontaneous abortions, trisomies 13, 18, and 21 are the tion is free of clinical signs or symptoms but is at risk for
only autosomal trisomies to be observed in a nonmosaic state having offspring with unbalanced chromosomes. The risk for
in liveborn infants. All autosomal monosomies are lethal. The production of unbalanced gametes from a balanced transloca-
only viable monosomy involves the X chromosome (45,X tion carrier depends on the chromosomes involved, the spe-
resulting in Turner syndrome). cific breakpoints of the translocation, and the sex of the carrier.
Aneuploidy results from an error in cell division referred Empirical data are available for some specific translocations.8
to as nondisjunction, in which two copies of a chromosome go Risks include miscarriage and birth of a liveborn child with
to the same daughter cell during meiosis or mitosis. Nondis- congenital anomalies, resulting from chromosome imbalance.
junction occurs most often in the first meiotic division in the The phenotype usually is a complex mixture of the results of
maternal germline. Mitotic nondisjunction results in the pres- loss or gain of at least two chromosome segments and there-
ence of an aneuploid and a normal cell line, a condition fore can be difficult to predict.
referred to as mosaicism. The causes of nondisjunction are One specific type of translocation that is relatively common
unknown. The only well-documented risk factor is advanced is Robertsonian translocation. This results from a fusion of
maternal age. two acrocentric chromosomes (chromosomes 13, 14, 15, 21,
The term polyploidy refers to the presence of a complete or 22) at the centromere. Carriers of a Robertsonian transloca-
extra set of chromosomes; triploidy represents three sets with tion have 45 chromosomes and are clinically unaffected. The
69 chromosomes, whereas tetraploidy represents four sets with most common clinically significant outcome is trisomy 21, in
92 chromosomes. Rarely, a triploid fetus will be liveborn, but which a carrier for a Robertsonian translocation involving
in general polyploidy is lethal. In a few instances, however, chromosome 21 produces a gamete with both the transloca-
mosaicism for a diploid and a triploid cell line producing tion chromosome and a normal 21, resulting in trisomy 21
congenital anomalies has been compatible with long-term after fertilization.
survival.
Inversions
Structural Abnormalities Inversions occur when there are two breaks in a chromosome
Structural chromosomal rearrangements result from chromo- and the intervening material rotates 180 degrees. Inversions
some breakage, with subsequent reunion in a different con- that span the centromere are referred to as pericentric, whereas
figuration. They can be balanced or unbalanced. In balanced those that do not span the centromere are called paracentric.
rearrangements the chromosome complement is complete, Inversions generally do not result in added or lost genetic
with no loss or gain of genetic material. Consequently, bal- material and therefore usually are viewed as neutral changes.
anced rearrangements are generally harmless, with the excep- Disruption of a gene at one of the breakpoints, however, could
tion of rare cases in which one of the breakpoints disrupts change the function of that gene. Also, alteration of gene order
an important functional gene. Carriers of balanced rearrange- at the borders of the inversion could affect the function of
ments are often at risk of having children with an unbalanced blocks of genes that are coordinately regulated (position effect).
chromosome complement. When a chromosome rearrange- If a crossover occurs in the inverted segment of a pericentric
ment is unbalanced, the chromosome complement contains inversion during meiosis, two recombinant chromosomes
an incorrect amount of genetic material, usually with serious result, one with duplication of one end and deletion of the
clinical effects. other end, and the other having the opposite arrangement.
Such a crossover event in a paracentric inversion results in ous abortions. Approximately 50% of these spontaneous mis-
dicentric or acentric chromosomes that tend to be unstable. carriages have a chromosomal abnormality.11 By birth, the rate
of chromosomal abnormalities declines to approximately
Insertions 0.5% to 1% in liveborn infants, although the rate is much
higher (5% to 10%) in stillborn infants.12
An insertion occurs when a segment of one chromosome
becomes inserted into another chromosome. Because these
changes require three chromosomal breakpoints, they are rela- CLINICAL INDICATIONS FOR
tively rare. Abnormal segregation in a balanced insertion CYTOGENETIC ANALYSIS
carrier can produce offspring with either duplication or dele-
tion of the inserted segment, in addition to balanced carriers Chromosome analysis has been incorporated in the routine
and normal offspring. battery of tests available to the clinician. This section considers
some of the more common indications for chromosome
Marker and Ring Chromosomes analysis.
A marker chromosome is a rearranged chromosome whose
genetic origin is unknown based on its G-banded chromo- Multiple Congenital Anomalies
some morphology. Usually, these chromosomes are present in Genetic imbalance resulting from a chromosomal abnormal-
addition to the normal chromosome complement and are ity usually leads to aberrant embryonic development. Most
thus called supernumerary marker chromosomes (SMCs). The commonly, this abnormal development involves multiple
birth prevalence of SMCs is in the range of 2 to 7 per 10,000, tissues, including the brain. Many specific syndromes can be
and 30% to 50% originate from chromosome 15.9 Two-thirds recognized from a constellation of dysmorphic physical fea-
of de novo marker chromosomes can be associated with an tures and specific congenital anomalies. The clinician should
abnormal outcome, whereas inherited ones can be passed be familiar with the most common syndromes, especially
from generation to generation without apparent clinical those resulting from trisomies 13, 18, and 21, and the sex
effects. Larger markers with more genetically active material chromosome aneuploidies (47,XXX, 47,XXY, and 45,X). Phe-
are more likely to be of clinical significance. FISH and CMA notypes resulting from duplication or deletion of smaller
have proved very helpful in the precise identification of the amounts of genetic material can be more difficult to identify
genetic origin of SMCs. clinically. Some of the more important syndromes are
Ring chromosomes are formed when a chromosome under- described in the next section. Some clues to the occurrence of
goes two breaks and the broken ends reunite in a ring struc- a chromosomal abnormality are provided in Box 35-1. As a
ture. Rings encounter difficulties in mitosis and are unstable, rule, chromosomal studies should be performed in a patient
resulting in some cells that lose the ring and are therefore who exhibits congenital anomalies involving two or more
monosomic for the chromosome and others that have mul- tissues, in patients for whom a specific alternative diagnosis
tiple copies of the ring. cannot be established, and if the anomalies are not related to
one another as cause and effect (e.g., hydrocephalus resulting
Isochromosomes from spina bifida).
An isochromosome is a chromosome in which one arm is
missing and the other duplicated in a mirror-image fashion. Developmental Delay and/or
The most probable mechanism for the formation of an iso-
chromosome is the misdivision through the centromere in Intellectual Disability
meiosis II, wherein the centromere divides transversely rather In some chromosomal abnormalities, the phenotype is pri-
than longitudinally. The most commonly encountered iso- marily that of DD and/or ID, with few or no congenital anom-
chromosome is that which consists of two long arms of the X alies. Sometimes, minor dysmorphic features are present, but
chromosome. This accounts for approximately 15% of all these often are not noticed on routine examination. G-banded
cases of Turner syndrome.9
Cytogenetic Nomenclature BOX 35-1 Common Clues to the Need for

By convention, each chromosome arm is divided into regions, Chromosomal Analysis
and each region is subdivided into bands and subbands, num-
bered from the centromere outward. Cytogeneticists describe FAMILY HISTORY
findings of chromosomal analysis using a standardized system • Recurrent miscarriage
of nomenclature (International System for Human Cytoge- • Infertility
netic Nomenclature).10 Detailed description of this system is • Family history of developmental delay, intellectual disability,
beyond the scope of this chapter, but major terms with exam- and/or multiple congenital anomalies
ples are listed in Table 35-1. The normal male karyotype is • Family history of balanced chromosome rearrangement
designated 46,XY, and the normal female karyotype is 46,XX. CLINICAL FACTORS
Any chromosomal abnormality is described after the sex chro-
• Low birth weight, congenital microcephaly, and dysmorphic
mosome constitution.
features
• Multiple congenital anomalies
Incidence of Chromosomal Abnormalities • Hemihypertrophy and/or significant body asymmetry
• Pigmentary dysplasia (streaky hyperpigmentation/
Estimates of the incidence of chromosomal abnormalities vary hypopigmentation)
with the mode of ascertainment and the technology used for • Infertility and/or delayed puberty
chromosome analysis. In general, the incidence falls rapidly • Unexplained developmental delay, intellectual disability, or
from conception to birth. The highest rates have been observed autism spectrum disorder
among products of conception from first-trimester spontane-
TABLE 35-1 Abbreviations Used to Describe Chromosomes and Their Abnormalities, and Representative Examples
35
Abbreviation Meaning Example Interpretation
46,XX Normal female karyotype
46,XY Normal male karyotype
69,XXY Triploid karyotype with XXY sex chromosome complement
+ Additional chromosome 47,XX,+21 Female karyotype with trisomy 21
- Missing chromosome 45,XX,-22 Female karyotype with monosomy 22
add Additional material of 46,XX,add(19)(p13) Female karyotype with additional material of unknown origin
unknown origin attached to chromosome 19 at band p13
arr Chromosomal microarray arr 15q11.2q13.1(21,258, Chromosomal microarray analysis demonstrating an
345–26,194,049)x1 interstitial deletion on the long arm of chromosome 15
between linear genomic positions 21,258,345 and
26,194,049 bp in the Prader–Willi/Angelman region
del Deletion 46,XX,del(5)(p14) Female karyotype with a terminal deletion on the short arm
of chromosome 5, with breakpoint at band p14
der Derivative chromosome 46,XX,der(1)t(1;3)(p22;q13) Female karyotype with a “derivative” chromosome 1,
resulting from segregation of a balanced translocation
between chromosomes 1 and 3, with breakpoints at
bands 1p22 and 3q13, respectively
dup Duplication 46,XX,dup(1)(q22q25) Female karyotype with a duplication on the long arm of
chromosome 1, with breakpoints at bands q22 and q25
i Isochromosome 46,X,i(X)(q10) Female karyotype with one normal X chromosome and an
isochromosome for the long arm of X chromosome
ins Insertion 46,XY,ins(5;2)(p14;q22q32) Male karyotype with a segment of the long arm of
chromosome 2 between bands 2q22 and 2q32 inserted
into the short arm of chromosome 5 at band 5p14
inv Inversion 46,XY,inv(2)(p21q31) Male karyotype with an inversion on chromosome 2, with
breakpoints at band p21 on the short arm and band q31
on the long arm (pericentric inversion)
ish In situ hybridization 46,XX.ish del(22) Normal female karyotype by G-banded chromosome
(q11.2q11.2)(Tuple1–) analysis, but with microdeletion on chromosome 22 at
band q11.2 (DiGeorge region) detected by metaphase
FISH analysis using the Tuple1 probe
mar Marker chromosome 47,XY,+mar Male karyotype with an additional unidentified marker
chromosome
mos Mosaic karyotype mos 47,XY,+2112/46,XY18 Mosaic karyotype with trisomy 21 cell line in 12 cells and
normal male cell line in 18 cells
p Short arm of chromosome
q Long arm of chromosome
r Ring chromosome 46,XX,r(7)(p22q36) Female karyotype with a ring chromosome 7, with
breakpoints at band p22 on the short arm and band q36
on the long arm
rob Robertsonian translocation 45,XX,rob(13;21)(q10;q10) Female karyotype with a Robertsonian translocation
representing fusion of chromosomes 13 and 21;
balanced karyotype
4 6,XX,rob(13;21) Female karyotype with
(q10;q10),+21 a Robertsonian translocation but with additional
chromosome 21, resulting in trisomy 21
t Translocation 46,XY,t(2;5)(q21;q31) Male karyotype with a balanced reciprocal translocation
involving chromosomes 2 and 5, with breakpoints at
bands 2q21 and 5q31, respectively
Abbreviations summarized from Shaffer LG, McGowan-Jordan J, Schmid M, editors. An International System for Human Cytogenetic Nomenclature
(ISCN) 2013. Basel: S. Karger.
chromosome analysis and CMA testing therefore should be variations (CNVs), both gains and losses, ranging in size from
considered in the evaluation of a child with unexplained DD/ kb to Mb, and not recognized by high-resolution G-banded
ID. ID is a common condition that affects 1% to 3% of the chromosome analysis.15,16 CNVs have been proposed to be a
population, and the cause is established in only 50% of the major factor responsible for human diversity.17 Through
cases13,14 (also see Chapter 51). genomic rearrangement of rearrangement-prone regions as a
The use of CMA to analyze the genomes of normal humans result of the genomic architecture, CNVs can cause genomic
led to the discovery of extensive genomic copy-number disorders as a result of gains and/or losses of dosage-sensitive
gene(s), resulting in a clinical phenotype.18 Using CMA tech- to detect unbalanced chromosomes can be offered. The actual
nologies, clinically significant pathogenic CNVs have been risk of unbalanced chromosomes in the pregnancy depends
reported in up to 17% to 19% of patients with ASDs, DD, ID, on the nature of the rearrangement but generally is greater
and/or MCAs.6,18,19 Because of their high diagnostic yield, than 1%. The laboratory performing the prenatal testing must
CMAs were recommended in 2010 by the American College of be informed of the details of the rearrangement, to ensure that
Medical Genetics and Genomics (ACMG) as the preferred first- subtle changes are detected. The recurrence risk for future
tier clinical diagnostic test for individuals with unexplained trisomy for a couple who have had one pregnancy affected
DD, ID, and/or MCAs.19,20 with trisomy is approximately 1%.27 This risk is irrespective of
the particular chromosome involved in the trisomy. Pregnan-
cies are increasingly being monitored for fetal anomalies by
Fertility Problems ultrasound or maternal serum screening, with findings indica-
Chromosomal imbalance most often leads to miscarriage tive of increased risk followed up by prenatal diagnostic
rather than to live birth. Carriers of balanced rearrangements, testing.
including translocations or inversions, may therefore come
to attention through recurrent miscarriage.21,22 It is recom-
mended that couples who have experienced two or more unex- Malignancy
plained first-trimester miscarriages be offered chromosomal Genetic studies have revealed that cancer cells acquire their
analysis. Finding a balanced rearrangement permits genetic oncogenic properties through a series of changes in the genetic
counseling of the couple, including offering prenatal diagno- information. These changes include gene mutations and
sis for future pregnancies. Other members of the family also chromosome rearrangements. The chromosome rearrange-
may carry the balanced rearrangement and should be offered ments result in abnormal gene dosage because of deletion
counseling and testing. Unexplained infertility should prompt or duplication, or result in juxtapositions of genetic mate-
a request for chromosome studies, especially for women pre- rial that alter gene regulation. Consideration of the various
senting with primary amenorrhea and men presenting with genes that are involved in malignancy, many of which are
azoospermia. oncogenes and tumor-suppressor genes, is beyond the scope
of this chapter. In several instances, however, specific chromo-
Unexplained Stillbirth/Neonatal Death somal rearrangements have been associated with particular
cancers. Chromosomal analysis can be helpful in these dis-
Chromosome abnormalities account for approximately 5% to orders to provide diagnostic information, to assess appro-
10% of all stillbirths and neonatal deaths, and not all of these priate treatment and prognosis, and to follow response to
babies have multiple abnormalities that would immediately therapy.
suggest a chromosomal cause.
Prenatal Diagnosis SPECIFIC CYTOGENETIC SYNDROMES

Chromosomal analysis of a developing fetus can be achieved Polyploidy
through collection of fetal cells by CVS, amniocentesis, or
peripheral umbilical blood sampling (PUBS).23 CVS involves Cytogenetics
sampling part of the fetal placenta using a biopsy device either Tetraploidy is an infrequent chromosomal abnormality,
passed through the cervix or inserted by a needle through the although triploidy occurs fairly often. Most triploid embryos
mother’s abdomen.24,25 It is performed at 10 to 12 weeks of miscarry in the first trimester. In approximately 20% of first-
gestation. CVS offers the advantage of early testing. Amniocen- trimester spontaneous abortions, the conceptus is found to
tesis involves sampling amniotic fluid at 16 to 18 weeks of have a triploid karyotype. Liveborn infants with triploidy
gestation. Fetal cells in the fluid are cultured and can be used exhibit multiple congenital anomalies and rarely survive the
for chromosomal analysis. PUBS is offered after 20 weeks of newborn period. Those that do usually are mosaics for a
gestation and involves sampling fetal blood by nicking the diploid and a triploid cell line (sometimes referred to as mixo-
umbilical vein under ultrasound guidance.26 ploids because diploid and triploid cell lines may arise from
Indications for prenatal testing are listed in Box 35-2. separate fertilizations).
General practice is to offer prenatal testing for pregnancies in
which the risk of a chromosomal abnormality exceeds the risk
of a complication of the procedure. For couples in which one
Clinical Features
partner carries a chromosome rearrangement, prenatal testing The triploid phenotype is distinct and easily recognized. Poly-
hydramnios or preeclampsia may complicate the pregnancy.
The placenta may be large, and hydatidiform changes may be
seen. Birth weight is usually low. Syndactyly involving the
BOX 35-2 Common Indications for Prenatal third and fourth digits is characteristic. Craniofacial features
Cytogenetic Diagnosis include low-set, malformed ears, hypertelorism, and micro-
gnathia. Cardiac, renal, and central nervous system malforma-
• Parent is carrier of balanced chromosome rearrangement tions are common. Males may have dysplastic external
• Advanced maternal age (older than 35 years of age at time of genitalia. Studies of the parental origin of the three chromo-
delivery) some sets in triploidy have revealed that a majority of affected
• Abnormality on ultrasound examination persons have two maternal sets, perhaps because of more
• Congenital anomaly frequent survival to term of triploid fetuses with two maternal
• Short femur/thickened nuchal skin (indications of trisomy 21) sets of chromosomes (digynic triploids).28 Long-term survi-
• Echogenic bowel vors often are mosaics and may have less obvious phenotypic
• Maternal serum screen indicative of increased risk of trisomy features. Body asymmetry and pigmentary dysplasia may be
21 or 18 clues to chromosomal mosaicism in general, including, in
some cases, triploidy.29
Management aplasia) occur commonly. Limb anomalies include postaxial

polydactyly in two-thirds of patients and rocker-bottom feet. 35
Most triploid fetuses are spontaneously aborted or are still- Congenital heart defects, especially ventricular septal defect
born. Most liveborn infants with full triploidy die in the early (VSD), are common, as are renal anomalies, including cystic
days of life. Survivors require supportive care for their con- dysplasia. The phenotype overlaps to some degree with that
genital anomalies and developmental impairment. of Meckel–Gruber syndrome (encephalocele, polydactyly,
polycystic kidney), inherited as an autosomal-recessive trait
Aneuploidy resulting from mutation of the MKS1 gene. This overlap
underlines the importance of confirming the clinical diagnosis
Only a minority of aneuploid embryos survive to term; the of trisomy 13 by chromosomal analysis.
rest result in miscarriage, usually in the first trimester. Only
the most common trisomy and monosomy syndromes com- Management
patible with live birth are considered in the following
discussion. Few infants with trisomy 13 survive beyond the newborn
period, with apnea being the most common cause of death.32
Often the anomalies are too numerous and too severe to
Trisomy 13 (Patau Syndrome) be corrected. In the absence of life-threatening malformations,
Cytogenetics however, long-term survival has been well documented,
albeit usually with severely impaired cognitive function.
Trisomy 13 occurs in approximately 1 in 7000 live births.30 A Baty and colleagues documented the natural history of this
majority of affected persons have 47 chromosomes, with an disorder.33,34
extra copy of chromosome 13. Approximately 5% to 10% of
these individuals have a trisomy because of translocation
between 13 and another acrocentric chromosome, usually Trisomy 18 (Edwards’ Syndrome)
chromosome 14 (Robertsonian translocation). Mosaicism
occurs in a small proportion of cases, and when it does, it may
Cytogenetics
ameliorate the phenotype. Duplication of part of chromo- Trisomy 18 affects approximately 1 in 4000 live births. It is
some 13 resulting from unbalanced translocation can result virtually always associated with a 47-chromosome karyotype,
in abnormal phenotypic features, although not necessarily although a small proportion of affected newborns have a
similar to those seen in full trisomy 13. Advanced maternal mosaic karyotype. Segregation of a parental balanced translo-
age has been shown to be a factor in the occurrence of this cation may result in trisomy for part of the short or long
aneuploidy syndrome. arm of chromosome 18. Molecular analysis has revealed that
most nondisjunction events that lead to trisomy 18 occur
Clinical Features in maternal meiosis, which is most likely to occur at older
maternal age.
Trisomy 13 is associated with congenital anomalies involving
most major organ systems (Figure 35-4). Holoprosencephaly
is the hallmark central nervous system anomaly,31 occurring in
Clinical Features
about 80% of cases. Infants with trisomy 13 who demonstrate Infants with trisomy 18 have low birth weight and micro-
holoprosencephaly usually have accompanying craniofacial cephaly. Other common features include a prominent occiput,
anomalies. The eyes may be set closely together (hypotelorism) low-set “simple” ears, and a small mouth (Figure 35-5). Hands
or even fused in a single orbit (cyclopia). Other ocular anoma- usually are tightly clenched in a characteristic configuration,
lies include microphthalmia, iris colobomata, cataracts, and with the fourth and fifth fingers overlapping the first and
retinal dysplasia. Premaxillary agenesis and cleft lip or palate second. Terminal phalanges often are hypoplastic, and rocker-
also may be present. Ulcer-like defects in scalp skin (cutis bottom feet may be present. Congenital heart defects and
Figure 35-4. A newborn with trisomy 13. (Karyotype courtesy of M Rochon, Sherbrooke, Quebec, Canada.)
Figure 35-5. A patient with trisomy 18 at 7 years of age. (Karyotype courtesy of M Rochon, Sherbrooke, Quebec, Canada.)
renal anomalies also are common. Brain malformations Clinical Features

include heterotopias, agenesis of the corpus callosum, Dandy–
Walker malformation, and Arnold–Chiari malformation. Down syndrome consists of a set of characteristic physical
Infants commonly are jittery and hypertonic and have apnea features and developmental impairment (Figure 35-6). Short
and seizures. stature and brachycephaly are characteristic, and mild micro-
cephaly may be noted. Down syndrome growth charts are
Management available and should be used to monitor growth in affected
children.36 Craniofacial features include upslanted palpebral
No definitive treatment exists for trisomy 18. Most affected fissures, epicanthal folds, flat facial profile, and small, low-set
infants die in the neonatal period.32,35 Long-term survivors ears with narrow ear canals. White speckles (Brushfield spots)
have developmental impairment and require supportive care. may be seen on the iris. A common finding is redundant folds
of nuchal skin, which is one of the markers used for prenatal
diagnosis by ultrasound examination.37 Fingers are short, with
Trisomy 21 (Down Syndrome) incurving of the fifth finger (clinodactyly) and, often, a single
transverse palmar crease. A wide space between the first and
Cytogenetics second toes is a frequent finding. The hallmark neurologic
Trisomy 21 is the most common and widely recognized of the feature of Down syndrome is hypotonia. No gross central
autosomal trisomy syndromes. It occurs in approximately 1 in nervous system malformation is consistently seen, although
800 live births, with a striking increase in frequency with lack of normal growth of the brain is typical. Microscopic
advanced maternal age. The frequency of Down syndrome at analysis has revealed impaired myelination, reduced density
birth may be lower in areas in which prenatal screening and of neurons, malformed dendritic trees and spines, defective
testing are offered. Full trisomy 21 occurs in about 95% of lamination of the cortex, and abnormality of synaptic density.38
cases. Translocation, usually between chromosome 21 and Impaired neurologic development is a universal feature39 but
another acrocentric chromosome, most often chromosome the degree of impairment varies widely. Children with Down
14, is identified in approximately 4%. A parent who carries syndrome benefit from early intervention, 40,41 physical therapy,
such a translocation may be at risk for recurrence of Down and being reared in a family setting. An increased frequency
syndrome. Rarely, patients with clinical Down syndrome have of psychiatric problems, such as depression and behavioral
only a partial trisomy of 21. The remaining 1% of affected problems, including hyperactivity, disruptive behaviors, and
persons have a mosaic karyotype. The pathogenesis of the repetitive behaviors, has been documented,42,43 as have sleep
features of Down syndrome is attributed to increased dosage problems.44 Linguistic ability may be impaired out of propor-
of genes on chromosome 21. The levels of gene expression are tion to cognitive impairment. Seizures, including infantile
tightly regulated, with increased levels of expression leading spasms, may be seen with increased frequency.45 An increased
to aberrant development. Efforts are under way to identify frequency of dementia, associated with pathologic changes of
specific genes responsible for specific components of the Alzheimer’s disease, has been described in patients with Down
Down syndrome phenotype. syndrome.46–48 Congenital anomalies commonly associated
35
Figure 35-6. Patients with trisomy 21 (Down syndrome). A, A newborn with trisomy 21 (Down syndrome). B, A boy with Down syndrome at
12 years of age. (Karyotype courtesy of M Rochon, Sherbrooke, Quebec, Canada.)
with Down syndrome include heart and gastrointestinal Trisomy 8 (Warkany’s Syndrome)
defects. The most typical heart defect is common atrioventricu-
lar (AV) canal, although other anomalies, such as VSD or The only other autosomal trisomy compatible with live birth
tetralogy of Fallot, may be seen. Gastrointestinal malforma- is trisomy 8. This trisomy is lethal in utero, except as a mosaic
tions include duodenal atresia and Hirschsprung disease. karyotype. Phenotypic features include hypertelorism; camp-
todactyly and other joint contractures; long, slender habitus;
Management absence of patellae; and deep creases of the palms and soles
(Figure 35-7). Asymmetric growth, presumably resulting from
The American Academy of Pediatrics has published guidelines chromosomal mosaicism, also may be a feature.
for management of children with Down syndrome.49 Children
with Down syndrome frequently require surgery for correction
of congenital anomalies, such as heart defects or gastro-
Turner Syndrome
intestinal malformations. They have a markedly increased risk Cytogenetics
of respiratory infection and sleep-related upper airway obstruc-
Turner syndrome is associated with a 45,X karyotype, with a
tion, often requiring antibiotic treatment. The frequency of
single X chromosome. Mosaicism is not uncommon, however,
leukemia is increased in children with Down syndrome. Tran-
with a separate cell line containing either a normal 46,XX or
sient leukemoid reactions also may occur.
XY karyotype, or 46 chromosomes including a structurally
Children with Down syndrome are at risk for atlantoax-
rearranged X or Y.51 Turner syndrome occurs in about 1 in
ial dislocation. Whether screening for dislocation should be
4000 female live births worldwide but it is much more
offered for children with Down syndrome, particularly those
common in stillbirths and miscarriages. Unlike other aneu-
who will participate in sports activities, has been the subject
ploidy syndromes, the frequency of Turner syndrome does not
of controversy.50 All children with Down syndrome should
increase with advancing maternal age.
be monitored for neurologic signs of cervical cord compres-
sion. Parents of children with Down syndrome should be
counseled regarding the natural history of the disorder, oppor-
Clinical Features
tunities for intervention, and genetic recurrence risks, and Patients with Turner syndrome typically have a female
should be provided emotional support. Life expectancy for phenotype, although those with a cell line including a Y
persons with Down syndrome has improved with advances chromosome may have some degree of virilization, often
in surgery and medical treatment of complications of the with ambiguous genitalia. At birth, infants may manifest
disorder. pedal edema or diffuse edema (Figure 35-8). Facial features
A B C
Figure 35-7. A patient with mosaic trisomy 8. A and B, At 18 months of age. C, The same patient with trisomy 8 at 18 years of age. Note
the deep palmar and plantar creases that are commonly seen in these patients. (Karyotype courtesy of M Rochon, Sherbrooke, Quebec, Canada.)
A B
C
Figure 35-8. A girl with Turner syndrome. A, At 9 years of age. B, At 1 month of age. C, At birth. (Courtesy of K Khoury; karyotype courtesy
of M Rochon, Sherbrooke, Quebec, Canada.)
include small mandible, narrow maxilla, and epicanthal folds.

In older children and adults with Turner syndrome, short
Management
stature and webbing of the neck are commonly seen. The Recommendations for diagnosis and management of Turner
thorax is broad, with increased distance between the nipples. syndrome have been published.54,55 Newborns should be eval-
Congenital anomalies include abnormalities of the lymphatic uated for renal and cardiac defects and monitored if these are
system; cardiac defects, especially coarctation of the aorta and found. An increased risk for dissection of the aorta has been
bicuspid aortic valve; and renal anomalies, such as horseshoe reported in affected adults.56 Thyroid autoimmunity may be a
kidney. feature, so monitoring of thyroid function is recommended.
Although ID is rare, delays in both gross and fine motor Although not all children with Turner syndrome are growth-
development are common in females with Turner syndrome.52 hormone deficient, significant growth-hormone-induced im
Some patients display cognitive problems, but difficulties with provement has been demonstrated in affected individuals.
visuospatial perception are most common.53 Hearing impair- Turner syndrome typically is associated with the presence
ment occurs frequently, and children should be monitored for of a streak gonad, lack of secondary sexual development,
deficits or progression of impairment. and infertility. Referral to an endocrinologist for hormonal
induction of puberty should be done at an appropriate age. Management

Intraabdominal gonads in patients with Turner syndrome 35
who have a Y chromosome are at risk of transformation into Children with Klinefelter syndrome, particularly those with
gonadoblastoma and therefore should be removed. more than two X chromosomes, require support at home and
school for learning and behavioral problems. Testosterone is
administered, beginning in adolescence, to improve secondary
Klinefelter Syndrome sexual development.
Cytogenetics
Klinefelter syndrome occurs in about 1 in 1000 males and Other Sex Chromosome Aneuploidies
is associated with a 47,XXY karyotype. The incidence increases Two other major sex chromosome aneuploidies are 47,XXX
as a function of maternal age in half of the cases. Rare and 47,XYY. XXX females have tall stature, and usually other
patients may have multiple X chromosomes (e.g., 48,XXXY major physical stigmata are absent. XYY is associated with a
or 49,XXXXY). The presence of multiple X chromosomes in male phenotype and tall stature but no other physical features.
such persons is associated with more severe cognitive Learning disabilities and neuromotor impairment occur com-
impairment. monly in 47,XXX females.59 The behavioral phenotype of XYY
syndrome has been a source of some controversy because of
Clinical Features reports associating the karyotype with criminal behavior. The
The diagnosis of Klinefelter syndrome usually is not suspected frequency of learning disabilities and behavioral problems is
at birth. Affected males tend to be tall, with long limbs (Figure increased among affected males, although widely ranging cog-
35-9). They display hypogonadism, and virilization may nitive outcomes have been reported.58
be incomplete at puberty; gynecomastia develops in some
patients. Azoospermia and infertility are characteristic. Breast
cancer is 20 times more common in Klinefelter syndrome
Structural Abnormalities
than in the normal male population. As in Turner syndrome, Structural abnormalities of chromosomes cause phenotypic
ID is not a typical feature of Klinefelter syndrome. Learn- effects resulting from loss and/or gain of genetic material. In
ing disabilities, language delay, and behavior problems are some cases, these occur sporadically as a result of de novo
reported.57,58 chromosome rearrangements, whereas in others, they may be
Figure 35-9. A boy with Klinefelter’s syndrome at age 13 years. (Courtesy of K Khoury; karyotype courtesy of M Rochon, Sherbrooke,
Quebec, Canada.)
inherited as a consequence of segregation of a familial bal- CNV) is sufficient to reach a threshold just enough to cause
anced chromosomal rearrangement. Some deletion or dupli- some form of neuropsychiatric disease, whereas a second hit
cation syndromes are fairly well characterized in terms of (e.g., second CNV) pushes that individual toward a more
phenotypic effects and may be recognized clinically. Clinical severe phenotype with DD and ID. It is worth mentioning that
diagnosis often is complicated, however, by a number of these two hits involve different regions/genes in the human
factors. First, most of these syndromes are much less common genome as opposed to the two-hit model reported in cancer,
than the trisomy syndromes. Second, the exact extent of which involves both alleles of a tumor-suppressor gene. The
deleted or duplicated material may differ from one affected two-hit model was initially proposed to explain the variable
child to another, leading to subtle but important variation in expressivity in the 16p12.1 microdeletion.63 Further examina-
clinical manifestations. Third, many of these syndromes are tion of other recurrent CNVs associated with either syndromic
seen as a consequence of malsegregation of a familial bal- or variable phenotypes clearly showed evidence of clustering
anced chromosomal rearrangement. The usual consequence is of two hits in the CNVs with variable phenotypes compared
imbalance of two or more distinct chromosome regions, with the syndromic forms. Also, a strong correlation was
resulting in a set of anomalies that combine the phenotypic observed between the proportion of inherited first CNV and
effects of both segments. the frequency of the second CNV.60 This implies that variable-
For many years, genomic disorders resulting from micro- expressivity CNVs are much more likely to be inherited from
deletions and microduplications that are clinically recogniz- less severely affected parents, which suggests that they are by
able by their typical constellation of clinical features were themselves insufficient to determine the disease outcome.61,64
tested for by FISH using DNA probes specific to these genomic Although the two-hit model was initially applied to large
regions. The advances in CMA technologies over the past CNVs, it has been proposed that the second hit could also be
decade have allowed their widespread use not only in a a smaller CNV or an SNP involving a related gene or a risk
research setting but also as a clinically diagnostic modality in allele inherited from a parent.
a wide variety of human diseases. CMA analysis has been very Table 35-2 lists the microdeletion/microduplication syn-
useful in the study of CNVs, which can be broadly classified dromes that have been reported to date, as shown in the
as either benign polymorphic CNVs or pathogenic disease- DECIPHER database (https://decipher.sanger.ac.uk/disorders
causing CNVs. Between these two ends of the spectrum, many #syndromes/overview).65 In the following section, some of the
CNVs have uncertain clinical significance, and some of these syndromic microdeletions and microduplications that are
could potentially be risk factors for human disease. clinically relevant to the practice of pediatric neurology are
High-resolution CMA analysis allows the detection of clini- discussed.
cally relevant CNVs in 17% to 19% of patients with DD, ID,
and/or MCAs who had a normal G-banded chromosome 22q11.2 Deletion Syndrome
analysis.19 Clinically relevant CNVs can be either recurrent,
The 22q11.2 deletion syndrome includes the phenotypes pre-
with a common size and breakpoint clustering in the flanking
viously called DiGeorge syndrome (DGS), velocardiofacial
segmental duplications, or nonrecurrent, with different sizes
syndrome (VCFS, Shprintzen’s syndrome), conotruncal
and variable breakpoints for each CNV. These nonrecurrent
anomaly face syndrome, many cases of autosomal-dominant
CNVs typically share a common genomic region of overlap
Opitz G/BBB syndrome, and Cayler’s cardiofacial syndrome
that encompasses the gene(s) associated with the observed
(asymmetric crying facies).66 The condition is clinically hetero-
phenotype.7 These nonrecurrent rearrangements occur at a
geneous. Congenital heart defects are present in most affected
relatively lower frequency at the individual locus level, but
individuals (74%), particularly conotruncal malformation.
collectively they are as common as recurrent CNVs. Clinically
Additional findings include palatal abnormalities and velo-
relevant CNVs can encompass multiple contiguous genes,
pharyngeal incompetence (VPI), learning disabilities, immune
including dosage-sensitive genes, with each contributing to
deficiencies, hypocalcemia, and characteristic facies. Also
the phenotype independently. Others encompass a single gene
reported are hearing loss, seizures without hypocalcemia,
or just few genes.
speech delays, and behavioral difficulties. The 22q11.2 dele-
Two types of microdeletions and microduplications have
tion affects an estimated 1 : 2000 to 1 : 4000 live births. The
been distinguished: the syndromic forms in which the pheno-
deletion occurs in 2% of patients with isolated conotruncal
typic features are relatively consistent, and those in which the
heart defects and in 5% to 8% of individuals with isolated
same CNV can be associated with a diverse set of diagnoses.60
cleft palate. Most cases are de novo, but inherited deletions
The syndromic forms of CNVs were originally described as
have been reported in 6% to 28% of patients with the syn-
relatively large microdeletions or microduplications that are
drome.67 The inheritance is autosomal dominant. Some cases
highly penetrant, almost always de novo in origin, and usually
with deletion 10p13p14 have a phenotype similar to that of
identified in individuals with ID or MCAs. These are clinically
deletion 22q11.2. The phenotype of the reciprocal microdu-
recognizable syndromes that were described well before their
plication of the 22q11.2 region is mild and highly variable,
genetic causes were known. Examples include DiGeorge/
with familial transmission frequently observed.
velocardiofacial syndrome (Online Mendelian Inheritance in
Man [OMIM] database numbers 188400 and 192430),
Williams–Beuren syndrome (OMIM 194050), and Smith–
Prader–Willi and Angelman Syndromes
Magenis syndrome (OMIM 182290). On the contrary, the The recognition of the phenomenon of genomic imprinting
more recently described nonsyndromic recurrent CNVs have has led to the discovery of a new class of genetic disorders
been reported to have incomplete penetrance and variable associated with aberrations of imprinted genes. The prototype
expressivity (e.g., 1q21.1, 15q13.3, 16p11.2, 16p12.1, and disorders are Prader–Willi and Angelman’s syndromes (Figure
16p13.11 microdeletions and microduplications). These have 35-10 and Figure 35-11).68 The features of these syndromes
been associated with, but not limited to, DD, ID, autism, are described in Table 35-3. Prader–Willi syndrome (PWS) is
seizures, schizophrenia, cardiac and renal anomalies, and characterized by hypotonia and feeding difficulties in early
other congenital anomalies.60–62 Recently it was observed that life, hyperphagia and obesity in later life, short stature, hypo-
more than one CNV (the “two-hit” model) can explain the gonadism, and acromicria. Behavior problems are common,
phenotypic variability associated with the nonsyndromic and psychomotor development is mildly affected. PWS affects
recurrent CNVs. Therefore it was proposed that one hit (first 1 : 5000 to 1 : 10,000 individuals. Approximately 70% to 75%
TABLE 35-2 Microdeletion/Microduplication Syndromes Listed in the DECIPHER Database

35
Syndrome OMIM Number Syndrome OMIM Number
12p13.33 microdeletion syndrome — 9q subtelomeric deletion syndrome 610253
12q14 microdeletion syndrome 166700 ATR-16 syndrome 141750
15q13.3 microdeletion syndrome 612001 AZF a, b, and c 415000
15q24 recurrent microdeletion syndrome — Adult-onset autosomal-dominant leukodystrophy 169500
(ADLD)
15q26 overgrowth syndrome —
Angelman’s syndrome (types 1 and 2) 105830
16p11.2 recurrent microdeletion and 611913
microduplication Cat-eye syndrome (type I) 115470
16p11.2p12.2 microdeletion syndrome — Charcot–Marie–Tooth syndrome type 1A (CMT1A) 118220
16p13.11 recurrent microdeletion and — Cri du chat syndrome (5p deletion) 123450
microduplication
Early-onset Alzheimer’s disease with cerebral 605714
17q21.3 recurrent microdeletion syndrome 610443 amyloid angiopathy
1p36 microdeletion syndrome 607872 Familial adenomatous polyposis 175100
1q21.1 recurrent microdeletion (susceptibility locus 612474 Hereditary liability to pressure palsies (HNPP) 162500
for neurodevelopmental disorders)
Leri–Weill dyschondrosteosis (LWD)—SHOX deletion 127300
1q21.1 recurrent microduplication (possible 612475
Miller–Dieker syndrome (MDS) 247200
susceptibility locus for neurodevelopmental
disorders) NF1-microdeletion syndrome 162200
1q21.1 susceptibility locus for thrombocytopenia- 274000 Pelizaeus–Merzbacher disease 312080
absent radius (TAR) syndrome
Potocki–Lupski syndrome (17p11.2 duplication 610883
22q11.2 deletion syndrome (velocardiofacial/ 192430, 188400 syndrome)
DiGeorge syndrome)
Potocki–Shaffer syndrome 601224
22q11.2 duplication syndrome 608363
Prader–Willi syndrome (types 1 and 2) 176270
22q11.2 distal deletion syndrome 611867
Renal cysts and diabetes (RCAD) 137920
22q13 deletion syndrome (Phelan–McDermid 606232
syndrome) Rubinstein–Taybi syndrome 180849
2p15p16.1 microdeletion syndrome 612513 Smith–Magenis syndrome 182290
2p21 microdeletion syndrome — Sotos’ syndrome 117550
2q33.1 deletion syndrome — Split hand/foot malformation 1 (SHFM1) 183600
2q37 monosomy 600430 Steroid sulphatase deficiency (STS) 300747
3q29 microdeletion syndrome 609425 WAGR 11p13 deletion syndrome 194072
3q29 microduplication syndrome 611936 Williams–Beuren syndrome (WBS) 194050
6p deletion syndrome 612582 Wolf–Hirschhorn syndrome 194190
7q11.23 duplication syndrome 609757 Xp11.22-linked intellectual disability —
8p23.1 microdeletion syndrome 222400 Xp11.22p11.23 microduplication —
8p23.1 microduplication syndrome — Xq28 (MECP2) duplication 300260
8q21.11 microdeletion syndrome —

ATR, alpha-thalassemia/mental retardation syndrome; AZF, azoospermic factors; WAGR, Wilms tumor, aniridia, genitourinary dysplasia, and mental
retardation.
of the individuals with PWS have a deletion of the paternally Either mechanism—deletion or uniparental disomy—leads to
contributed 15q11.2q13.1 region, whereas in Angelman’s deficiency of a gene or genes on chromosome 15 that are
syndrome (AS), 70% of affected individuals have a deletion expressed in the paternal but not the maternal homolog.
of the maternally contributed region. The AS phenotype is Paternal uniparental disomy accounts for a low percentage
completely different and it is characterized by severe ID, of cases of AS. Mutations in the UBE3A gene (a ubiquitin
absent speech, autistic behavior, unique behavior (inappropri- ligase gene involved in early brain development), located
ate happy demeanor), gait ataxia, epilepsy, electroencephalo- at 15q11.2, have been found in some patients with AS.69
gram (EEG) abnormalities (2- to 3-Hz, large-amplitude This gene is imprinted in the brain70,71 and is the gene respon-
slow-wave bursts), microcephaly, and dysmorphic features. sible for the AS phenotype. Deletion of a group of small
The EEG may be abnormal even in the absence of seizures. nucleolar RNA (snoRNA) genes, known as the SNORD116
However; a normal EEG and/or absence of seizures do not cluster, is thought to play a major role in causing the signs
exclude the diagnosis. Approximately 1 : 40,000 children are and symptoms of PWS.72 A small proportion of patients with
affected with AS. Most patients with PWS who do not have PWS or AS may have a small deletion or other mutation that
the 15q11.2q13.1 deletions have uniparental disomy for chro- leads to aberrant imprinting of the region.73 These findings
mosome 15, with two maternal copies and no paternal copies. have led to major advances in genetic diagnosis of PWS and
A B
Figure 35-10. A boy with Prader–Willi syndrome. A, At 7 months of age. B, At 6 years of age. (Karyotype courtesy of MG Mattei, Marseilles,
France.)
AS. Chromosome 15 deletions usually are submicroscopic but William–Beuren Syndrome

are easily detected by FISH and/or CMA. Defects in imprinting
or uniparental disomy can be identified by studies of patterns William–Beuren syndrome (WBS) is a microdeletion syn-
of DNA methylation in the region. One particular cloned drome of chromosome 7 at band q11.23 and occurs in
segment of DNA is methylated in the maternal, but not the 1 : 10,000 live births.75 Cardiovascular disease is present in
paternal, genome. Failure to identify the methylated or non- 80% of affected individuals, mostly in the form of supraval-
methylated copy of the sequence is indicative of deletion, vular aortic stenosis (SVAS), peripheral pulmonary stenosis,
uniparental disomy, or a mutation that alters the imprinting elastin arteriopathy, and hypertension. The 7q11.23 micro
mechanism. deletion encompasses the elastin gene (ELN), which is
Imprinted genes are expressed only from one of the two also mutated in isolated SVAS. Characteristic facial features
parental alleles (gene pair). In mammals, genomic imprinting include periorbital fullness, long philtrum, wide mouth,
is an event in which particular genes are expressed differen- full lips, full cheeks, and small, wide-spaced teeth. Affected
tially, depending on the parent of origin. Genomic imprints individuals have mild to moderate ID, specific cognitive
are reversible and lead to differential expression in the course profile/learning disabilities, and unique or distinctive
of development. Genomic imprinting is an epigenetic behavior/personality characteristics. Growth and endocrine
process that involves methylation and histone modifications abnormalities (hypercalcemia, hypothyroidism, hypercalci-
to achieve monoallelic gene expression without altering uria) and feeding difficulties in infancy are also common.
the genetic sequence. Genome-wide research for imprinted
genes in the human genome has identified over 150 candi
date imprinted genes.74 Other examples of human disorders
1p36 Deletion Syndrome
of genomic imprinting include Silver–Russell syndrome, Of the subtelomeric microdeletion syndromes, 1p36 deletion
Beckwith–Wiedemann syndrome, Albright hereditary osteo- syndrome is considered to be the most common, with an
dystrophy, and uniparental disomy 14 (maternal and paternal estimated incidence of 1 in 5000 to 1 in 10,000. It accounts
forms). for 0.5% to 1.2% of idiopathic ID.76 Clinical findings include
35
Figure 35-11. A boy with Angelman’s syndrome at 6 years of age. (Karyotype courtesy of M Rochon, Sherbrooke, Quebec, Canada.)
a characteristic craniofacial appearance: microbrachycephaly, ID ranges from mild to severe. Other birth defects have been
large and late-closing anterior fontanel, straight eyebrows, reported in individuals with WHS. One-third of the patients
deep-set eyes, epicanthal folds, broad nasal bridge, midface have structural central nervous system defects, and seizures
hypoplasia, abnormally formed low-set ears, and limb and occur in 50% to 100% of affected children. In 75% of patients
skeletal defects. DD and ID with absent/poor expressive lan- with WHS, the deletion is de novo; in about 13% of patients,
guage are constant features. Affected individuals often face the deletion results from the unbalanced segregation of a
serious physical disabilities that include congenital heart parental balanced translocation. It is now recognized that
defects (70%), cardiomyopathy (25%), brain abnormalities WHS and Pitt–Rogers–Danks syndrome (PRDS) represent the
(88%), seizures (44%), and EEG abnormalities (100%). clinical spectrum associated with a single syndrome.78
Ocular malformations or vision problems and hearing loss are
observed in approximately 50% of affected individuals. Cri du Chat Syndrome
Cri du chat syndrome is a genetic syndrome resulting from a
Wolf–Hirschhorn Syndrome variable-sized deletion on the terminal end of the short arm
Wolf–Hirschhorn syndrome (WHS) results from a variable- of chromosome 5. The first description was made by Lejeune
sized deletion on the terminal end of the short arm of chro- et al. in 1964.79 The incidence ranges from 1 : 15,000 to
mosome 4.77 It is characterized by distinctive facial appearance, 1 : 50,000. A high-pitched, cat-like cry is among the main clini-
growth delay, psychomotor retardation, and seizures, and is cal features in the newborn period; hence the name of the
confirmed by detection of a deletion of the Wolf–Hirschhorn syndrome. Other frequently described features are microceph-
critical region (WHCR) (chromosome 4p16.3). The syndrome aly, broad nasal bridge, epicanthal folds, micrognathia,
has clinical and cytogenetic variability. In some, the deletion impaired growth, and severe psychomotor and ID. The syn-
is visible by G-banded chromosome analysis; in others, it is drome has significant clinical and cytogenetic variability. Clin-
cryptic, and molecular cytogenetic analysis is required to make ical analysis of affected individuals and detailed molecular
the diagnosis. Characteristic facial features include the “Greek cytogenetic analysis suggest the existence of two critical
warrior helmet” appearance of the nose (the broad bridge of regions, one on 5p15.2 for facial dysmorphism, microcephaly,
the nose continuing to the forehead), microcephaly, high fore- and ID, and another on 5p15.3 for the typical cry.80 In affected
head with prominent glabella, ocular hypertelorism, epican- individuals, 80% of cases are the result of a de novo deletion,
thus, highly arched eyebrows, short philtrum, downturned and 10% are the result of the unbalanced segregation of a
mouth, micrognathia, and poorly formed ears with pits/tags. parental balanced translocation.
TABLE 35-3 Comparison of Features of Prader–Willi and Angelman’s Syndromes

Prader–Willi Syndrome* Angelman’s Syndrome†
Diagnostic criteria Major clinical criteria Consistent features (100%)
Neonatal hypotonia Developmental delay
Feeding problems in infancy Speech impairment
Rapid weight gain between 1 and 6 years of age Movement disorder (ataxia of gait, tremulous movement of limbs)
Characteristic facies Behavioral features: frequent laughter or smiling, hand flapping
Hypogonadism Frequent features (80%)
Developmental delay Acquired microcephaly
Hyperphagia Seizures (usually in patients younger than 3 years)
Minor criteria Abnormal EEG (high-amplitude 2- to 3-Hz spike-wave discharge)
Decreased fetal movement Associated features (20%–80%)
Characteristic behaviors Flat occiput, occipital groove
Sleep disturbances Protruding tongue
Short stature Prognathism
Small hands Wide mouth and widely spaced teeth
Narrow hands Drooling, chewing, mouthing movements
Esotropia/myopia Strabismus
Thick, viscous saliva Hypopigmentation
Speech articulation defects Brisk lower limb deep tendon reflexes
Skin picking Sleep disturbance
Supportive findings
High pain threshold
Decreased vomiting
Cytogenetics 70%–75% paternal 15q11.2q13.1 deletion 70% maternal 15q11.2q13.1 deletion
Uniparental disomy 20%–25% maternal disomy 2% paternal disomy
Imprinting defect 1%–3% 2%–5%
Gene mutation Unknown 5%–10% UBE3A gene mutation
EEG, electroencephalogram.
*Data from Holm VA, Cassidy SB, Butler MG, et al. Pediatrics 1993;91(8424017):398–402.
†
Data from Williams CA, Angelman H, Clayton-Smith J, et al. Am J Med Genet 1995;56(2):237–8.
(Mutation analysis data from Buiting K, Gross S, Lich C, et al. Am J Hum Genet 2003;72(12545427):571–7.; Jiang Y, Lev-Lehman E, Bressler J,
et al. Am J Hum Genet 1999;65(10364509):1–6.)
Deletions Involving Distal 6p Langer–Giedion Syndrome

Deletions involving distal 6p are relatively rare. These dele- Patients with the Langer–Giedion syndrome (LGS), also called
tions can be divided into two groups: interstitial with break- tricho-rhino-phalangeal syndrome type II (TRPSII), have a
points within the 6p22p24 region, and terminal deletions de novo deletion on chromosome 8 at band q24.11, compris-
with breakpoints within the 6p24pter region. The terminal ing a contiguous deletion of the TPRS and EXT1 genes.85
deletion of 6p results in a distinct phenotype, including hyper- This syndrome has autosomal-dominant inheritance and is
telorism, downslanting palpebral fissures, flat nasal bridge, characterized by short stature, sparse scalp hair, long nose
Dandy–Walker malformation, congenital heart defect, ante- with a bulbous tip, notched alae nasi, long and flat philtrum,
rior eye chamber abnormalities, hearing loss, and DD.81 thin lips, cone-shaped epiphyses, and multiple cartilaginous
Hydrocephalus has been seen in patients with terminal 6p exostoses.
deletions, but most cases have been associated with Dandy–
Walker malformation.82 WAGR 11p13 Deletion Syndrome
Chromosome 9q Subtelomeric Deletion The cardinal features of the WAGR 11p13 deletion syndrome
include Wilms tumor, aniridia, genitourinary abnormalities,
The chromosome 9q subtelomeric deletion represents one of growth delay, and ID. The size of the deletion varies but always
the most common subtelomeric deletions (6%).83 The syn- includes WT1 and PAX6 genes, which account for the onco-
drome can be caused either by a submicroscopic 9q34.3 dele- genic, ocular, and genitourinary features, respectively. Approx-
tion or by mutations in the EHMT1 gene, which is involved imately 30% of infants with sporadic aniridia will be positive
in histone methylation. Affected individuals invariably have for the characteristic deletion.86 The majority of patients have
severe hypotonia, with speech and gross motor delay. Facial ID, and more than 20% of patients also have features of
features include microcephaly/brachycephaly, hypertelorism, autism.87
synophrys, arched eyebrows, midface hypoplasia, short nose
with upturned nares, protruding tongue, everted lower lip, and
downturned corners of the mouth. Congenital heart defects
Jacobsen Syndrome
have been reported in approximately 50% of affected indi- Jacobsen syndrome is a contiguous-gene deletion syndrome
viduals. Epilepsy and behavior and sleep disturbances have caused by partial deletion of the long arm of chromosome
also been reported in some (10%–20%).84 11 (11q23.3qter). Typical features include DD, ID, short
stature, congenital heart defects, thrombocytopenia, and char- which results in severe lissencephaly with characteristic facial
acteristic dysmorphic facial features. Malformation of the changes, other more variable malformations, and severe neu- 35
heart, kidney, gastrointestinal tract, central nervous system, rologic and developmental abnormalities. The facial features
and skeleton is common. Some of the facial dysmorphism consist of high and prominent forehead, bitemporal hollow-
described includes skull deformities, hypertelorism, epican- ing, short nose with upturned nares, protuberant upper lip
thic folds, ptosis, broad nasal bridge, and small ears. The with downturned vermillion border, and small jaw.92 The
deletion is de novo in 85% of cases, and in the remaining reciprocal duplication results in DD, hypotonia, and facial
patients it results from the unbalanced segregation of a paren- dysmorphism. In contrast to patients with the deletion, those
tal balanced chromosome rearrangement.88 with the duplication have neither gross brain malformations
nor lissencephaly.93
Charcot–Marie–Tooth Neuropathy Type 1A
and Hereditary Neuropathy With Liability to Neurofibromatosis Type 1
Pressure Palsies Approximately 5% of patients with neurofibromatosis type 1
(NF1) have deletions of the entire NF1 gene and contiguous
Charcot–Marie–Tooth neuropathy type 1A (CMT1A) repre- genes at 17q11.2, resulting in the NF1 microdeletion syn-
sents 70% to 80% of all CMT1 and results from an approxi- drome. NF1 with large deletions is more likely to have dys-
mately 1.5-Mb duplication at 17p12, which encompasses the morphic features, cardiac anomalies, connective tissue
PMP22 gene (peripheral myelin protein 22).89 This protein is dysplasia, and ID.94 Patients with reciprocal microduplications
predominantly produced by Schwann cells and is a major have been reported.
component of the peripheral nervous system. Reciprocal dele-
tion of the same region results in the milder phenotype of Alagille Syndrome
hereditary neuropathy with liability to pressure palsies
(HNPP). The duplication is inherited in around two-thirds of Alagille syndrome (AGS) is a complex multisystem disorder
individuals and is de novo in the remaining third. Please see involving primarily the liver, heart, eyes, face, and skeleton.
Chapters 141 and 142 for more details. The clinical features are highly variable, even within families.
The major clinical manifestations of AGS are cholestasis, con-
genital cardiac defects, posterior embryotoxon in the eye,
Smith–Magenis Syndrome and typical facial features, and butterfly vertebrae. Renal and
Potocki–Lupski Syndrome central nervous abnormalities also occur. The two genes asso-
Approximately 90% of individuals with Smith–Magenis syn- ciated with AGS are JAG1 and NOTCH2.95,96 Sequence analysis
drome (SMS) have a deletion on chromosome 17 at band of JAG1 detects mutations in over 88% of individuals who
p11.2 that encompasses the RAI1 gene. The remaining 5% to meet clinical diagnostic criteria, whereas FISH and/or CMA
10% of cases carry a mutation in the RAI1 gene. Physical fea- analyses detect a microdeletion encompassing JAG1 at 20p12.2
tures include short stature, obesity, craniofacial dysmorphism, in approximately 7% of affected individuals.
and small hands and feet. Behavior disturbances, especially
sleep problems and self-injurious behavior, are frequently Potocki–Shaffer Syndrome
reported. The self-injurious behavior includes self-hitting, self- Potocki–Shaffer syndrome (PSS) is a contiguous-gene deletion
biting and/or skin picking, inserting foreign objects into body syndrome that results from a deletion of the 11p11.2p12
orifices (polyembolokoilamania), and pulling nails (onycho- region.97 The clinical features can include DD, ID, multiple
tillomania). Self-hug or spasmodic upper-body squeeze, hand exostoses, parietal foramina, enlarged anterior fontanel, minor
licking, and page flipping (“lick and flip”) constitute stereo- craniofacial anomalies, ophthalmologic anomalies, and
typic behavior that appears to be specific for SMS. All affected genital anomalies in males. Parietal foramina and multiple
individuals have mild to severe learning disabilities.90 The exostoses are the primary characteristic of this syndrome.
phenotypic features may be subtle in infancy and early child- Larger deletions of proximal 11p may result in features of PSS
hood. The facial appearance is characterized by a broad, and WAGR.
square-shaped face; brachycephaly; prominent forehead; syn-
ophrys; mildly upslanting palpebral fissures; deep-set eyes; X-Linked Ichthyosis Resulting From Steroid
broad nasal bridge; midfacial hypoplasia; short, full-tipped Sulphatase Enzyme Deficiency
nose; flat nasal bridge; micrognathia in infancy changing to
relative prognathia with age; and fleshy, everted upper lip. Males with X-linked ichthyosis resulting from steroid sulpha-
With progressing age, the facial appearance becomes more tase enzyme deficiency have generalized scaling that usually
distinctive and coarse. The reciprocal duplication of this starts shortly after birth. In 90% of cases, it is caused by a
17p11.2 region has been reported (Potocki–Lupski syndrome). microdeletion encompassing the STS gene (Xp22.31). In 5%
The most frequent features of this syndrome are hypotonia in of cases, the deletion is extensive enough to involve adjacent
infancy, DD, language and cognitive impairment, autistic fea- genes, resulting in learning disabilities, autism, and epilepsy
tures, poor feeding and failure to thrive in infancy, oral- in some of the affected boys.98
pharyngeal dysphagia, obstructive and central sleep apnea,
structural cardiovascular abnormalities, EEG abnormalities, Loss of Function of the MECP2 Gene/Duplication of
and hypermetropia. Most have short stature and mild to the MECP2 Region (Xq28)
normal facies.91 Variability in the phenotype is observed. It is
expected that persons with large duplications that encompass Loss-of-function mutations involving the MECP2 gene at
the more distal CMT1A region will have a more severe pheno- Xq28 result in Rett syndrome, a severe neurodevelopmental
type, including peripheral neuropathy. disorder that almost always occurs in females. Males with non-
Rett mutations in MECP2 demonstrate a wide variety of phe-
notypes, including X-linked ID with spasticity and other
Miller–Dieker Syndrome variable features. Males with Rett mutations in MECP2 have
Miller–Dieker syndrome represents a microdeletion syndrome neonatal severe encephalopathy that is usually lethal. Duplica-
spanning the PAFAH1B1 gene (also known as LIS1) at 17p13.3, tions at Xq28 that span the MECP2 gene in males are
associated with severe X-linked ID and progressive spasticity. Maternal Duplication of the 15q11.2q13.1 Region
These duplications usually also span the L1CAM gene.99
Chromosome 15q11.2q13.1 contains a cluster of imprinted
In the following section, some of the nonsyndromic microde- genes essential for normal development. Deficiencies in pater-
letions and microduplications that present with neurodevel- nal or maternal 15q11.2q13.1 result in PWS or AS, respec-
opmental problems are discussed. tively, as previously discussed. Maternal duplication of the
15q11.2q13.1 region leads to a distinct condition that often
Distal 1q21.1 Microdeletion and Microduplication includes autism. Despite incomplete penetrance of autism in
this syndrome, this duplication is the leading cytogenetic
The distal 1q21.1 microdeletion and its reciprocal microdupli- cause of autism.106 Recently the 15q11.2q13.1 duplication has
cation are newly described genomic disorders. They are been associated with a distinct pattern of mitochondrial
characterized by a spectrum of DD, ID, neuropsychiatric abnormalities that include a deficiency of complex III.107
abnormalities, nonspecific facial dysmorphism, head-size
abnormalities, and congenital malformations. The clinical 15q13.3 Microdeletion
manifestations have variable expressivity and incomplete pen-
etrance. They map immediately distal to the proximal 1q21.1 Manifestations of the 15q13.3 microdeletion include DD, ID,
microdeletion associated TAR (thrombocytopenia-absent ASD, seizures, and schizophrenia. Additional reported features
radius) syndrome.100 include mood disorders and ADHD.108 The condition has highly
variable intrafamilial and interfamilial phenotypic heterogene-
2p15p16.1 microdeletion ity, with some carriers having no clinical manifestations.109
Major congenital malformations are uncommon. The 15q13.3
The clinical phenotype of the 2p15p16.1 microdeletion microdeletion is often inherited. Patients with the reciprocal
includes moderate to severe ID, autistic features, poor motor duplication do not share a recognizable phenotype.110
and speech development, microcephaly, structural brain
anomalies, renal anomalies, digital anomalies, vision impair- 15q24 Microdeletion
ment, and a distinctive pattern of craniofacial features.101 The
reported structural brain anomalies include cortical dysplasia/ The 15q24 microdeletion syndrome has a distinct clinical
pachygyria. Dysmorphic craniofacial features include micro- phenotype with specific facial features, DD, microcephaly,
cephaly, bitemporal narrowing, wide inner canthal distance, and digital and genital anomalies. Global DD, speech prob-
short and downslanted palpebral fissures, epicanthal folds, lems, and ID are the most consistent features of the 15q24
prominent nasal tip, long and straight eyelashes, smooth phil- microdeletion. Reported facial features include long face
trum, and everted lower lip.101 with high anterior hairline, hypertelorism, epicanthal folds,
downslanting palpebral fissures, sparse and broad medial eye-
Terminal Deletions of the Long Arm of Chromosome brows, broad and/or depressed nasal bridge, small mouth,
long and smooth philtrum, and full lower lip.111 Other
2 (2q37 Microdeletion) common findings include growth retardation and failure to
Terminal deletions of the long arm of chromosome 2 at thrive; congenital malformations of the hands, feet, eyes, and
band 2q37 have a recognizable clinical phenotype, including genitalia; hypotonia; behavior problems; and joint laxity.112
ID (mild to severe), autistic features, seizure disorder, dysmor- Less common findings are conductive and sensorineural
phism, major malformations, and a pattern of findings hearing loss and seizures.113 The severity and extent of the
described as Albright hereditary osteodystrophy–like (AHO) clinical findings are variable among affected individuals.
metacarpal/metatarsal shortening. Other phenotypes associ- The 15q24 microdeletion is rare, and the exact prevalence
ated with 2q37 deletions include Wilms tumor, urogenital is unknown. All reported cases, so far, are the result of a de
anomalies, and eczema.102 novo deletion with autosomal-dominant inheritance.112
Several cases with the reciprocal duplication of the 15q24
3q29 Microdeletion region have been reported, but it remains unclear if the 15q24
duplications represent a separate clinical entity. In the cases
The 3q29 microdeletion is associated with a variable pheno- where inheritance was known, the duplications were inherited
type that includes neurodevelopmental features, microceph- from a normal or mildly affected parent.113
aly, and mild dysmorphic features. The neurodevelopmental
features included learning disabilities, autism, attention deficit
hyperactivity disorder (ADHD), schizophrenia, and bipolar
16p11.2 Microdeletion and Microduplication
disorder.103 Dysmorphic anomalies are nondistinct and include The 16p11.2 microdeletion and its reciprocal microdupli
elongated face, high nasal bridge, and short philtrum.103 Con- cation appear to be associated with approximately 1% of
genital malformations are rare. Most cases are de novo, but unexplained, idiopathic, and nonsyndromic autism.114 The
familial cases have been reported with or without ID in the wide spectrum of phenotypic/neurobehavioral abnormalities
parents.104 The phenotype of the reciprocal duplication is vari- associated with deletion and duplications of 16p11.2 includes
able, with few common features.104 DD, ID, ASD, ADHD, seizures, and schizophrenia. Dysmor-
phic features, congenital anomalies, and obesity have also
7q11.23 Microduplication been observed in affected individuals.115 They have inherited
and sporadic origin, and have also been identified in normal
The 7q11.23 microduplication is the exact reciprocal of the individuals. Compared with the 16p11.2 microduplication,
common WBS deletion, with an estimated incidence of the reciprocal microdeletion is more likely to be penetrant
1 : 13,000 to 1 : 20,000. The main clinical feature is variable and to be associated with nonspecific major or minor
speech/language delay with cognitive disabilities ranging from dysmorphism.115
normal to moderate ID. Autism has been reported in some
patients. Specific dysmorphic features noted include high and
broad nose, short philtrum, thin lips, and straight eyebrows.
16p11.2p12.2 Microdeletion
Triplications of this region have a similar phenotype but are The 16p11.2p12.2 microdeletion should be distinguished
more severe than that observed in patients with duplication from the 16p11.2 microdeletion. All reported patients with the
of the same region.105 16p11.2p12.2 microdeletion have a shared common distal
breakpoint at 16p12.2, but the proximal breakpoint varies.116,117 because any rearrangement large enough to be evident with
Common features of this microdeletion include DD, facial the light microscope could be seen. Nonetheless, the resolu- 35
dysmorphism, orofacial clefting, heart defects, frequent ear tion was very limited. FISH analysis increased the resolution,
infections, short stature, feeding difficulties, and hypotonia. but it was necessary to specify in advance the areas of interest
The facial features include flat face, deep and low-set eyes, and because it was not practical to explore all possible deletions
posteriorly rotated ears. or duplications, given that each required use of a different
DNA probe. CMA is moving us back toward a whole-genome
16p13.11 Microdeletion and Microduplication approach, with no need to know in advance where to look.
This is raising questions about whether CMA should be used
Deletions and reciprocal duplications of the 16p13.11 region
before a comprehensive dysmorphology evaluation because
have recently been reported in several cases of autism and ID.
many of the deletions or duplications detected are not associ-
Current clinical data indicate that deletions are likely to be
ated with well-delineated syndromes. A caution in use of this
pathogenic and are either de novo or inherited from clinically
approach, however, is that some gene-dosage changes are not
normal parents, whereas the clinical significance of the dupli-
known to be associated with an abnormal phenotype and are
cations is still uncertain.118
likely to be benign variants of no clinical significance. There-
fore correct interpretation of dosage changes still requires
17q21.31 Microdeletion a high level of sophistication and care in counseling the
The newly described 17q21.31 microdeletion has a clinical patient/family. The resolution of genomic analysis will con-
phenotype characterized by ID, hypotonia, and characteristic tinue to increase. Clinical whole-exome or whole-genome
facies, including long and hypotonic face, tubular nose with DNA sequencing is currently being used to uncover clinically
bulbous nasal tip, large and low-set ears, and blepharophimo- relevant gene mutations with a much higher power than
sis. Other associated features include epilepsy, congenital previously possible. Both CMA and whole-exome or whole-
heart defects (e.g., VSD and ASD), and renal and urologic genome sequencing will undoubtedly reveal an increasing
anomalies. The prevalence of this microdeletion has been esti- number of genomic changes that underlie neurologic dis
mated to be approximately 1 in 16,000. Reciprocal duplica- orders, leading to an increase in the power and precision of
tions of the same interval have been reported. Affected patients genetic diagnosis.
have autistic features and intellectual skills ranging from
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35 Chromosomes and Chromosomal Abnormalities

Maria Descartes, Bruce R. Korf, and Fady M. Mikhail

Figure 35-1. Normal male human karyotype (46,XY).

Figure 35-2. Fluorescence in situ hybridization (FISH) analysis

consistent with a well-defined syndrome with known chromo-

Cytogenetic Nomenclature BOX 35-1 Common Clues to the Need for

Prenatal Diagnosis SPECIFIC CYTOGENETIC SYNDROMES

Management aplasia) occur commonly. Limb anomalies include postaxial

renal anomalies also are common. Brain malformations Clinical Features

include small mandible, narrow maxilla, and epicanthal folds.

induction of puberty should be done at an appropriate age. Management

TABLE 35-2 Microdeletion/Microduplication Syndromes Listed in the DECIPHER Database

2p15p16.1 microdeletion syndrome 612513 Smith–Magenis syndrome 182290

2p21 microdeletion syndrome — Sotos’ syndrome 117550

2q33.1 deletion syndrome — Split hand/foot malformation 1 (SHFM1) 183600

2q37 monosomy 600430 Steroid sulphatase deficiency (STS) 300747

3q29 microdeletion syndrome 609425 WAGR 11p13 deletion syndrome 194072

3q29 microduplication syndrome 611936 Williams–Beuren syndrome (WBS) 194050

6p deletion syndrome 612582 Wolf–Hirschhorn syndrome 194190

7q11.23 duplication syndrome 609757 Xp11.22-linked intellectual disability —

8p23.1 microdeletion syndrome 222400 Xp11.22p11.23 microduplication —

8p23.1 microduplication syndrome — Xq28 (MECP2) duplication 300260

8q21.11 microdeletion syndrome —

AS. Chromosome 15 deletions usually are submicroscopic but William–Beuren Syndrome

TABLE 35-3 Comparison of Features of Prader–Willi and Angelman’s Syndromes

Deletions Involving Distal 6p Langer–Giedion Syndrome

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