a brief discussion on the mode of inheritance of common genetic disorders

1. GENETIC DISORDER,
MUTATIONS, CYTOGENETIC
DISORDERS
Dr Tamil Nila

2. Concepts
• Genetics is the study of genes
• 23 pairs of chromosomes
• 22 pairs – Autosomal
• One pair – sex chromosome
• 20000 – 30000 genes
• Every gene has 2 alleles – one paternal + one maternal
• Exon – Coding region of DNA (1.5%)
• Intron – Non coding region of DNA (98.5%)

3. Definitions
• Heterozygous
• Homozygous
• Dominant inheritance
• Recessive
• Co-dominant
• Pleiotropy
• Incomplete penetrance
• Variable expressivity
• Anticipation

4. Mutation
Point
mutation
Silent
Missense
Non sense
Frame shift
mutation

5. Chromosomal abnormalities
• Structural
• Deletion
• Insertion
• Translocation
• Ring chromosome
• Iso chromosome
• Inversion
• Numerical
• Aneuploidy
• Monosomy
• Trisomy

6. Epigenetics
• Hereditary chemical modification in DNA/ Chromatin/ Histone at a
functional level
• No change in nucleotide sequence
• Decreased gene expression
• Processes
• DNA methylation
• Histone deacetylation

7. Diagnosis of genetic disorders
• Cytogenetics
• Karyotyping
• FISH
• Molecular genetics
• MLPA (Multiple ligation probe amplification)
• PCR
• Microarray
• Sequencing

8. Human Genetic disorders
Mutations in single
gene with large effects
Chromosomal
disorders
Complex multigenic
disorders

9. Mendelian disorders
Autosomal
Dominant Recessive
X linked
Dominant Recessive

10. Autosomal dominant
• Male = Female
• Expressed in heterozygous states
• One parent is affected
• Manifests in adulthood
• No skip generations
• Defect in structural proteins

11. Autosomal disorders
• Huntington’s chorea
• Hereditary spherocytosis
• Adult onset Polycystic kidney
disease
• Von Hipple Lindau disease
Von Willebrand disease
• Dystrophia myotonica
• Osteogenesis imperfecta
• Marfan’s syndrome
• Intermittent porphyria
• Neurofibromatosis 1
• Achondroplasia
• NF -2
• Tuberous sclerosis
• Familial adenomatous polyposis
Familial hypercholestrolemia
He Has A Very DOMINANT Father

12. Autosomal recessive disorders
• Male = Female
• Homozygous state
• When heterozygous – Carriers
• Manifests in childhood/ infancy
• Due to enzyme deficiency

13. Autosomal recessive disorders
• Alpha -1- antitrypsin
Ataxia telangiectasia
Alkaptonuria
• Beta-thalassemia
• Cystic fibrosis
Congenital Adrenal hyperplasia
• Deafness
• Emphysema
• Friedrich’s Ataxia
• Gaucher’s ataxia
Glycogen storage disorder
Galactosemia
• Hemochromatosis
Homocystinuria
• Inborn errors of metabolism
ABCDE…

14. X linked recessive disorders
• Male >> Female
• Females – Carriers
• Females are affected when random
X inactivation occurs
• When Mother is a carrier
• 50% sons are affected
• 50% daughters are carriers
• When Father is affected
• All sons are normal
• Al daughters are carriers
Criss – Cross
inheritance

15. X – Linked recessive diseases
• Lesch Nyhan syndrome
• Hemophilia A & B
Hunter’s disease
• Color blindness
• G6PD deficiency
• Duchenne muscular dystrophy
• Chronic granulomatous disease
• Agammaglobulinemia
• Fabry’s disease
Fragile X syndrome
• Wiscott Aldrich syndrome
Lady Harding College
Girls Don’t Care About
Foolish Words

16. X linked Dominant disorders
• Mother is affected
• Both sons and daughters are affected
• Father is affected
• Only daughters are affected

17. X – Linked Dominant
• Rett’s syndrome
• Alport syndrome
• Vitamin D resistant rickets
• Incontinentia pigmenti
RAVI

18. Marfan’s Syndrome
Defect in fibrillin 1 (FBN 1) and
fibrillin 2 (FBN 2) gene
Excess of TGf - β
Elastin destroyed
Hyperelasticity of skin
Congenital contractural
arachnodactyly

19. Clinical presentations
Skeletal
defects
Tall stature
Hyper extensible
joints
Dolicocephalic head
Ocular
defects
Ectopia lentis
Superotemporal
dislocation of lens
CVS
defects
MV prolapse
Aortic dissection

20. Diagnosis & treatment
• Revised Ghent’s criteria
• Family history
• Signs & symptoms
• Fibrillin 1 gene mutation
• Treatment
• TGF – β blocker - Losartan

21. Ehlers – Danlos syndrome
• Defects in collagen synthesis or
assembly
• Clinical features
• Fragile & hyperextensible skin
• Hypermobile joints
• Ruptures on colon, cornea or large
arteries
• Poor wound healing

23. Familial hypercholestrelemia
• Autosomal dominant
• Mutations in the gene encoding
for
• LDL receptor
• ApoB protein
• Activating mutations of PCSK 9
• Clinical features
• Elevated serum cholesterol
• Atherosclerosis
• Coronary artery disease
• Xanthoma

24. Lysosomal storage diseases
Disorders Enzyme deficiency
Sphingolipidoses
Gaucher’s disease Glucocerebrosidase
Tay sach’s disease Hexosaminidase A
Fabry disease Alpha galactosidase
Krabbe disease Galactocerebrosidase
Niemann pick disease Sphingomyelinase
Mucopolysaccharidoses
Hurler syndrome Alpha L iduronidase
Hunter Syndrome Iduronate 2 sulphatase

25. Glycogen storage diseases
Type Deficient enzyme
I – Von Gierke Glucose – 6 – Phosphate
II – Pompe Lysosomal α 1,4 glycosidase
III – Cori Debranching enzyme
IV – Anderson Branching Enzyme
V - McArdle Muscle glycogen phosphorylase
VI – Hers Hepatic Glycogen phosphorylase

26. Down syndrome – Trisomy 21
• Most common chromosomal disorder
• Most common genetic cause of mental
retardation
• Pathogenesis
• Meiotic non disjunction
• Robertsonian translocation
• mosaics
• Complications
• CVS – Endocardial cushion defect, VSD
• GIT – duodenal atresia, Hirschsprung disease
• Acute leukemia
• Hypothyroidism
• Premature Alzheimer’s disease

27. Klinefelter syndrome
• Most common cause of male
hypogonadism
• More the X chromosome, more
the mental retardation
• Pathogenesis
• Meiotic non dysjunction
• Testicular biopsy
• Leydig cell hyperplasia
• Increased FSH, LH
• Decreased testosterone

28. Turner syndrome
• Most common cause of female
hypogonadism
• Pathogenesis
• Meiotic non – dysjunction
• Anaphase lag
• Ring chromosome
• Isochromosome
• mosaics

29. Fragile X syndrome
• X linked recessive disorder
• Loss of function mutation in
FMR 1 gene leading to increased
CGG repeats
• Most common inherited cause of
mental retardation
• Macro-orchidism

30. Prader – Willi syndrome
• Maternal allele is silenced
• Paternal allele – normal
• Clinical features
• Small bird like head
• Mentally retarded
• Respiratory problems
• Obesity
• Short lifespan
• Hyperphagia
• Hypogonadism
• hypotonia

31. Angelman syndrome
• Paternal gene is silenced
• Maternal gene – normal
• Clinical features
• Inappropriate laughter
• Stiff/ ataxic movements
• Microcephaly
• Seizures
• Mental retardation