Common Genetic

Disorders
Tsinuel Girma
Jimma university
March 2008
 Human genetics

Deals with variations among individuals

due to variations at DNA level
 CHROMOSOMES & GENES

• Eukaryotic DNA is
organized in
chromosomes.

• Genes have specific

places on
chromosomes.
 GENES
term coined by Wilhelm Johannsen in 1909

“The word ‘gene’ is completely free from any

hypothesis; it expresses only the evident
fact that, in any case, many characteristics
of the organism are specified in the
gametes by means of special conditions,
foundations, and determiners which are
present in unique, separate, and thereby
independent ways…”
 GENERAL CONCEPTS
• Humans have 23 pairs of chromosomes
• 22 pairs of autosomes and 1 pair of sex
chromosome (xx female and xy male)
• Somatic cells are diploid (46 chromosomes)
• Germ cells are haploid( 23 chromosomes)
• 50,000- 100,000 genes in one individual
• Genetic abnormalities account to 11-16% of patients
in teaching hospitals, USA
• Ethiopia ~ 4% ( extrapolation)
• 1% of NB have hereditary malformations and 0.5%
inborn errors of metabolism or sex chromosome
• Chromosomal anomalies in 0.4% of live births
 Genotype Vs. Phenotype

• Genotype refers to the alleles of a gene

that a person carries
 homozygous if same allele of a gene on both copies of
the chromosome
 heterozygous if the two alleles of a gene differ
• Phenotype refers to the physical
manifestations of the genotype and is
affected by environmental factors as well
as by other genes
 From genotype to phenotype

Transcription and translation

Central Dogma: DNA → RNA → Protein

 GENETIC VARIATION

There are two types of genetic variations:

1. Mutation: DNA gene is damaged or changed in such a way as to

alter the genetic message carried by that gene.

Only gremlin mutations , not somatic, are heritable

2. Polymorphism : No impact on health or function of the organism

Recombination: rearrangement of human genome between

generations and essential for diversity and evolution of species
 Types of Mutation

The sun was hot but the old man did not get his hat

1. Point mutation
The son was hot but the old man did not get his hat
2. Deletion
The was hot but the old man did not get his hat
3. Insertion
The sun was hot but the fat old man did not get his hat
4. Frame shift
T hes unw ash otb utt heo ldm and idn otg eth ish at
 CAUSES OF MUTATIONS

There are two ways in which DNA can become

mutated:

• Mutations can be inherited : mutation is passed to

children.
• Mutations can be acquired: , environmental agents
(MUTAGENS) damage DNA, or when mistakes occur
when a cell copies its DNA prior to cell division.
 PATTERNS OF INHERITANCE

Mendelian inheritance ,for single mutant gene

• Autosomal dominant
• Autosomal recessive
• X-linked recessive
• X-linked dominant, rare (VD-resistant rickets)
Multi-factorial
• Additive and interactive effects of one or more genes
plus environmental factors
PEDIGREE
 AUTOSOMAL RECESSIVE INHERITANCE

• Autosomal recessive disorders occur when a

mutation in both alleles of a gene on an
autosome (not on the X or Y chromosome) is
required for the disease to occur
• Males and females are affected equally
because the mutation is in a gene on an
autosome
• E.g. Cystic fibrosis
 Autosomal recessive characteristics

Risk of recurrence when both parents are

heterozygous carriers
• 25 percent of the couple's children will be
affected
• 75 percent normal (2/3 heterozygous carriers
and 1/3 homozygous normal)
Consanguinity — Autosomal recessive disorders
are more common when there is consanguinity
because the parents are likely to carry the same
mutation (marriage between second cousin and
lower)
 Autosomal Dominant Inheritance

• Autosomal dominant disorders occur when a

mutation in one allele of a gene causes disease.
• Males and females are equally affected, with
some exceptions
• The affected person has one normal and one
abnormal allele, and thus is heterozygous.
• Autosomal dominant disorders may result from
mutations that cause an increase or decrease in
function.
 Recurrence risk

• 50 percent of the parent's offspring will be

heterozygous for the defect and 50 percent will
be normal
• Vertical transmission :autosomal dominant
disorders are inherited through generations
because males and females are equally
affected, they are equally likely to have affected
children.
• Reduced penetrance :if not everyone who
carries the abnormal gene has the disease, the
penetrance is less than 100 percent. Either the
person has the disease or does not.
 X-linked recessive inheritance

• Only male offspring ,50%, are clinically affected

• All daughters of affected male are obligate
carriers
• Only 50% of female with carrier mother are
carriers
• Random inactivation of portion of x in each cells
protects the female from gene effect
• E.g., Hemophilia
 X-linked dominant

Extremely rare conditions !

 Multifactorial inheritance

• 2-10% rate recurrence among first degree

relatives
• Rate increase with incidence of the disease,
number of family members affected, and severity
of the disease
• Sex predilection
• Concordance for identical twins is 20-60 %
 Chromosomal abnormalities

• either abnormal number or structure of

the somatic or sex chromosomes
• Important cause of mental retardation
and malformations
• Trisomies are the most common number
abnormalities
1. Down (trisomy 21)
2. Patau,( trisomy 13)
3. Edwards (trisomy 18)
 Down syndrome ( trisomy 21)
• Advanced maternal age increases the risk
• It can be translocation or non-disjunction
type
• Both types are identical phenotypes
• Translocation carriers have higher chance
of transmission indicating the importance
of cytogenetic study for all Downs
 Physical appearance
Head and neck
• Upslanting palpebral fissures
• Epicanthic folds
• Flat nasal bridge
• Small and low -set ears
• Protruding tongue
• Furrowed tongue
• Narrow palate
• Abnormal teeth
• Short neck
• Excessive skin at nape of the neck
Extremities
• Short broad hands
• Hypoplastic mid phalanx and incurved fifth finger
• Transverse palmar crease
• Wide space between the first and second toes (sandal gap deformity)
• Hyperflexibility of joints and hypotonia
 Malformations/malfunctions

• Atrioventricular septal defect (also called endocardial

cushion defect) with or without other lesions — 45
percent
• Duodenal atresia or stenosis - 2.5 percent
• Hirschsprung's disease
• Refractive errors (myopia, hyperopia, astigmatism) — 35
to 76 percent
• Strabismus — 25 to 57 percent
• Short stature
• Hearing impairment - 38 to 78
• leukemia in DS is 1 to 1.5 percent
• variety of immunologic impairments resulting in
increased susceptibility to infection, autoimmune
disorders, and malignancies
• Mental retardation
 SCREENING MARKERS
• Maternal age
• Ultrasound – nuchal translucency
• Fetal chromosome –amniocentesis or
chorionic villi sampling (CVS)
• Quadruple serum testing
1. Alph fetoprotien (AFP — either ng/mL or
IU/mL)
2. Unconjugated estriol(uE3 — ng/mL)
3. hCG - beta subunit( mIU/mL or IU/mL)
4. Inhibin A (inhA — pg/mL)
 Sex chromosome anomalies

• Turner syndrome (45,x)

• Klinefelter syndrome (47,xxy)
• Fragile x syndrome
Turner syndrome( gonadal dysgenesis)

• most common sex-chromosome abnormality in

female conceptions
• affects 3 percent of all females conceived but
only 1 in 1000 embryos with a 45,X karyotype
survives to term
• incidence varies from 1:2000 to 1:5000 in live-
born phenotypic females
• the maternal X is retained in two thirds of
patients and the paternal X in the remaining one
third
 CLINICAL MANIFESTATIONS

• Neonates: congenital lymphedema and two or more of

the following dysmorphic features: webbed neck, nail
dysplasia, high palate, and short fourth metacarpal
• Many patients are short and stocky and have a
squarely shaped chest (use growth curves specific for
Turner )
• in older patients primary hypogonadism occurring either
before or after puberty (gonadal dysgenesis)
• Primary amenorrhea ,short stature and delayed puberty ,
autoimmune diseases (including chronic autoimmune
thyroiditis),
Cognitive function is normal, but may have
neurodevelopmental abnormalities.
 Associated diseases

• Renal anomalies: 30 to 50 percent have a renal

malformation, most commonly horseshoe
kidney, followed by abnormal vascular supply.
Idiopathic hypertension is common.
• Cardiovascular disease :coarctation and AS
• Osteoporosis
• Celiac disease
• Hypothyrodism
• Ocular abnormalities
 Klinefelter syndrome (47,XXY)

• most common sex chromosome abnormality

causing primary hypogonadism.
• results from non-disjunction of the sex
chromosomes and is associated with advanced
parental age
• Most cases are diagnosed during evaluation for
infertility or gynecomastia, and it is likely that a
significant proportion of affected males are not
identified.
 major clinical manifestations
• Male newborns with the 47,XXY karyotype are
phenotypically normal with normal male external
genitalia and no apparent dysmorphism
• tall stature; small testes; and infertility
(azoospermia) become noticeable during
adolescence and adulthood.
• While most 47,XXY boys have IQ scores in the
average range, their IQs are approximately 10
points lower than their siblings' scores
• Delayed secondary sex development
Thank you