Clinical Genetics

Sachith MettanandaDept. of Paediatrics

Nucleus

46 Chromosomes

38 000 genes

Base pairs in nucleotides

Human cell

• Humans are 99.9% identical in their functional genes

• Genes code for proteins required for cellular function– Structural proteins, hormones, enzymes, etc.

Genetics Environment

Diseases

Genetic diseases

• Chromosomal anomalies• Single gene disorders• Mitochondrial inheritance• Multifactorial inheritance

Chromosomal anomalies

Numerical Structural

Trisomy

Monosomy

Occur in 0.4% of live births

Trisomy

• Presence of three copies of a single chromosome

• Causes– Nondisjunction at gametogenesis– Translocations

Down syndrome (Trisomy 21)

Protruding tongue

• Round face• Epicanthic folds• Small ears• Upward slanting

almond shape eyes• Flat nasal bridge• Microcephaly

Flat occiputSingle palmar crease (Simian crease) Short stubby

fingers

Causes for Downs

o Nondisjunction at gametogenesis - 95 % Error at meiosis Increases risk with increasing maternal age (over 35yrs) Independent of paternal age

o Translocations - 4 % Translocated on to a chromosome 14 rarely 15, 22 or 21 Robertsonian translocation

o Mosaicism Normal cells + trisomy 21 cells Occur after formation of zygote, by nondisjunction at

meiosis Phenotype milder

Down syndrome (Trisomy 21)

Nondisjunction

Translocations

Down syndrome Associated with

–Developmental delay & learning difficulties–Congenital heart lesions (AVSD, VSD, ASD)– Intestinal atresia (duodenal atresia)–Hypothyroidism (acquired)–Atlanto-axial subluxation–Alzheimers disease–Recurrent respiratory infections

Edward syndrome (Trisomy 18)

Rocker-bottom feet

Small chin, low set ears, short sternum, overlapping of fingers

• Associated with–Cardiac malformations – VSD, ASD–Renal anomalies

Patau syndrome (Trisomy 13)

One eye, bulbous nose

Small eyes (micropthalmia)

Polydactyly

• Associated with–Cerebral malformations–Cardiac anomalies

• Trisomy 21 – mortality high in first year, but many survive to adulthood

• Trisomy 13 – rarely survive for more than a few weeks

• Trisomy 18 - rarely survive for more than a few

Klinefelter syndrome (47, XXY)

• Infertility• Hypogonadism with

small testis• Gynaecomastia• Tall stature

Monosomy

• Presence of only one member of a chromosome pair

• Autosomal monosomies are lethal

Turner syndrome (45, X)

Neck webbing

Wide carrying angle (cubitus vulgus)

Short stature, widely spaced nipples, poorly developed 2ry sexual characteristics

Turner syndrome (45, X)

• Associated with–Failure of sexual maturation &

subfertility (due to ovarian dysgenesis)–Congenital heart diseases (Coarctation

of Aorta)–Renal anomalies (horse-shoe kidney)–Normal IQ

Chromosomal mosaicism

• Presence of two or more cell lines with different karyotypes in a person

eg: 46XX/ 47XX,+21

• Clinical features depend on the chromosome involved & proportion of normal to abnormal cells

Chromosomal anomalies

Numerical Structural

Trisomy

Monosomy

Structural anomalies • Deletions– Cri-du-chat (5p)– Prader-willi (15q)

• Duplications• Inversions• Translocations– Reciprocal translocations – Philadelphia

chromosome– Robertsonian translocations

• Fragile chromosomes

Prader-willy syndrome

• Obesity• Hypotonia• Hypogonadism• Developmental delay

Fragile X syndrome

• Prominent large everted ears (bat ears)

• Macrocephaly• Long face• Prominent mandible• Large testis• Mentally retarded

Diagnosis of chromasomal anomalies

• Karyotype

Genetic diseases

• Chromosomal anomalies• Single gene disorders• Mitochondrial inheritance• Multifactorial inheritance

Single gene disorders

• Autosomal dominant• Autosomal recessive• X-linked recessive• X-linked dominant• Y-linked

Autosomal dominant inheritance• Genotype/phenotype– AA – homozygous ; severely affected, usually

lethal– Aa – heterozygous ; affected– aa – normal

• Disorders associated with structural proteins

Aa aa50% 50%

Aa aa

• Pedigree– Vertical transmission

Autosomal dominant inheritance

• Achondroplasia• Ehlers-Danlos syndrome• Familial hypercholastaraemia• Marfan disease• Neurofibromatosis• Tuberous sclerosis• Huntington disease• Myotonic dystrophy• Osteogenesis imperfecta

Achondroplasia

Upper segment/lower segment Most of the time sporadic (due to mutations)

Multiple neurofibromatosis

Multiple neurofibromatosis

Cafe-au-lait patches

Tuberous sclerosis

Adenoma sebaceum

Tuberous sclerosis

Ash leaf shaped patches Palpable shagreen patch

Marfan syndrome

Tall stature, long thin limbs, arm span greater than the height, hyperextensible joints, lower segment > upper segment

Long thin digits (arachnodactyly)

Autosomal recessive inheritance• Genotype/phenotype– AA – homozygous; affected– Aa – heterozygous; carrier– aa – normal

• Disorders associated with functional proteins

AA aa

Aa100%

Aa Aa

AA Aa aa25% 50% 25%

• Pedigree– Horizontal inheritance– Consanguinity

Autosomal recessive inheritance

• Thallasaemia• Sickle cell anaemia• Phenylketonuria• Cystic fibrosis• Galactosaemia• Glycogen storage diseases

X-linked recessive inheritance• Genotype/phenotype– XX – homozygous female ; severely affected– Xy – male ; affected– Xx – heterozygous female ; carrier– xx, xy – normal

Xy xx

Xx xy 50% 50%

Xx xy

Xx xx Xy xy25% 25% 25% 25%

• Pedigree– Oblique inheritance– Common / only in males– ? affected females

X-linked recessive inheritence

• Haemophilia A & B • G6PD deficiency• Duchene muscular dystrophy • Becker muscular dystrophy• Red-green colour blindness• Fragile X syndrome

Duchene muscular dystrophy

Pseudohypertrophy of calf

Gover’s sign (proximal muscle weakness)

X-linked dominant inheritance• Genotype/phenotype– XX – homozygous female ; severely affected– Xy – male ; severely affected– Xx – heterozygous female ; affected– xx, xy – normal

Xx xy

Xx Xy xy xy 25% 25% 25% 25%

xx Xy

Xx xy50% 50%

• Pedigree– Similar to Autosomal dominant–More/only females

X-linked dominant inheritance

• Vitamin D resistant rickets• Rett syndrome• Incontinentia pigmenti

Y-linked inheritance

• Eg: hairy pinna

Diagnosis of single gene disorders

• Molecular genetic studies– Southern blot– Fluorescent in-situ hybridization (FISH)

Treatment of single gene disorders

• Gene therapy– Defined as introduction of nucleic acids into a

tissue to prevent, inhibit or reverse a pathological process

– Still mostly in the experimental stages

Mitochondrial inheritance

• Mitochondrial genome– Codes for 13 proteins

• Transmission–Maternal transmission

• Eg:– Leber heriditary optic neuropathy–MELAS

Multifactorial inheritance• Genes + Enviornment• Familial diseases• Eg: – Diabetes mellitus– Hypertension– Bronchial Asthma– Cleft palate– Neural tube defect– Hypospadias– Coronary heart disease