Residency/Diploma (Genetics)

Dr.Md.Sultanul Arephin
MBBS, BCS, MD(Resident), Cardiology

Part I & II
Mendelian disorder

1. Autosomal dominant.
2. Autosomal recessive.
3. Sex-linked dominant.
4. Sex-linked recessive.

Autosomal dominant

 At least 1 parent affected/trait

 Male/female equally affected & transmit disease

 Consecutive generations affected

 No carrier

 Heterozygotes are phenotypically affected

 Half of offsprings are affected

 Father to son transmission occurs

 1 mutate gene = disease (Single copy mutation affects)

 Unaffecteds cannot transmit disease

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 Variable expressivity

 Reduced/incomplete penetrance

 Exhibit anticipation

 Less severe condition

 Structural abnormality associated

 High mutation rate

 Vertical transmission

 Trait can involve receptor & structural protein

 Can transmit every generation

Variable expressivity refers to the degree in which a genotype is

phenotypically expressed. For example, multiple people with the same
disease can have the same genotype but one may express more severe
symptoms, while another may appear normal

An example of an autosomal dominant condition showing incomplete

penetrance is familial breast cancer due to mutations in
the BRCA1 gene. Females with a mutation in this gene have an 80%
lifetime risk of developing breast cancer. The penetrance of the
condition is therefore 80%.

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Autosomal recessive

 Parents can be unaffected healthy carrier

 Both sex equally affected

 Manifestation only in homozygous (Both copies of allele are mutated)

 Heterozygous are phenotypically unaffected

 Complete penetration

 Uniform expression

 Usually one generation affected

 Early onset & high mortality

 Metabolic types disorder

 Horizontal transmission

 Consanguinity maybe present

 Carrier exists

 If carrier marries normal -->50% normal & 50% carrier

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 If carrier marriage -->

A.25% homozygous & affected
B.25% normal
C.50% carrier

Sex linked recessive

 Males & homozygous state female affected

 Never transmit directly from father to son

 Only female can be carrier

 Father with normal gene; mother a carrier.

a 25% (one in four) daughter carrier
a 25% son with hemophilia
a 50% chance of having normal child (boy or girl)

Man who has hemophilia and a woman who is a carrier have:

a 25% (one in four) son with hemophilia
a 25% normal son
a 25% daughter carrier
a 25% daughter hemophilia

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Autosomal dominant examples

 Von Marfan is an imperfect but New(2) Poly(2) Family Hunter

 Here is my tube men(2)

Autosomal recessive

 Ataxia
 Atrophy (NMA, SMA)
 Nuria (Phe, Hom, Alka)
 Semia (Galac, Thala)
 Nemia (Sickle cell a-nemia)
 Wilson
 Storage (Glycogen, Lysosome)
 CF, Ehler danlos,Hemochromatosis, CAH
 Hurler syndrome (mucopolysaccharidosis )

X linked recessive

Hemophilia A, B
G6PD
Duchene muscular dystrophy
Becker muscular dystrophy
Agamma-globulinemia

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X linked dominant

 vitamin D resistant rickets

 Rett's syndrome
 Fragile X syndrome

Prenatal Dx

Indication
1.Advanced maternal age
2.High risk serum screening
3.Abnormal antenatal scan
4.Parent/child e genetic disease
5.Previous child e chromosomal abnormality
6.Parent e chromosomal abnormality

Methods
USG (1st trimester onward )
Chorionic villous biopsy (from 11 weeks)
Amniocentesis (from 19 weeks)
Fetal cord blood

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Turner syndrome

 Ovarian dysgenesis
 45XO
 Incomplete /partial monosomy of X chromosome
 Causes : Non dysjunction, Mosaicism

 C/F :
1.Phenotypic female
2.Short stature
3.Wide carrying angle
4.Webbed neck
5.Wide spaced nipples
6.Scanty pubic/axillary hair
7.Shield chest,low hairline, streak ovary, lack of breast development
8.High gonadotropin
9.Low estrogen
10.Primary amenorrhea
11.Usually mental condition normal --> Rare mental
12.Coarctatiom of aorta
13.Renal abnormality
14.Horseshoe kidney

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Klinefelter syndrome

 Seminiferous tubules dysgenesis

 47XXY
 46Xy / 47XXy mosaicism
 Leydig cell function impaired
 Hypogonadism
 Phenotypic male
 Barr body in male (1)

 C/F
1.Tall, obese
2.Infertile
3.Small azoospermic testes
4.Bilateral gynaecomastia (Not all)
5.High urinary gonadotropin

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Down syndrome

 Causes : Non dysjunction, mosaicism(2%), translocation

 C/F
1.Mentally retard
2.Hypotonia
3.Short stature
4.Craniofacial (Oval face, flat occiput,macroglossia,epicanthic fold)
5.Simian palmar crease

6.Anomaly
(ASD, VSD, PDA,
Fallot's tretalogy,
Tracheoesophageal fistula,
Duodenal atresia,
Hypothyroidism,
Endocardial cushion anomaly)

7.Increase gap between 1st & 2nd toe

8.Associated e inceeased age of mother

9.Can be dx by amniocentesis more accurately

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