Genetics Flashcards
Classification of genetic diseases
1. Single gene disorders: Mendelian: (4 types) Non Mendelian: Germ line mosaicism Trinucleotide repeat mutation Genomic imprinting Mitochondrial inheritance 2. Chromosomal disorders: Structural and Numerical 3. Multifactorial
Sperm mitochondrial DNA is eliminated. How
Ova eliminates all sperm mitochondrial DNA by ubiquitin proteasome pathway
The organs usually affected by mitochondrial inheritance are
Brain
Skeletal muscle
Eye, as they contain more amounts of mitochondria
Heteroplasmy
Presence of normal and mutant mitochondrial DNA in the same person
Examples of diseases of mitochondrial inheritance
K. Kearns Sayre syndrome L. Leigh syndrome, Leber Hereditary optic neuropathy M. MELAS N. NARP syndrome O. CPEO P. Pearson syndrome
Most common disease inherited through mitochondrial inheritance
MELAS
Mitochondrial Encephalopathy
Lactic Acidosis and
Stroke like episodes
Most common mitochondrial myopathy
CPEO
Chronic Progressive
External Ophthalmoplegia
Diseases due to trinucleotide repeat mutations in the coding region
Huntington’s disease CAG
Spinocerebellar ataxia CAG
Diseases due to trinucleotide repeat mutations in the non coding region
Fragile X syndrome CGG
Friedreich’s ataxia GAA
Myotonic dystrophy CTG
Cause of fragile X syndrome
Mutation in FMR1 gene ➡️ increased CGG repeats 5-40 CGG- normal 55-200 repeats- premutation 200-4000 repeats- full mutation
Anticipation/ Sherman’s paradox
CGG repeats increases with each generation
Increased CGG repeats causes fragile X syndrome
Why is fragile X syndrome called the way it is
When cells are cultured in a folate deficient media, constriction is seen in the X chromosome as if the X chromosome is broken
Clinical presentation of fragile X syndrome
- 2nd most common genetic cause of mental retardation
- Large head, everted ears, mandible
- Large testis/ macrorchidism- most distinctive feature
Fragile X tremor syndrome
Gene affected- FMR1
Gain of function mutation ➡️ intentional tremor
(Opposite effect of fragile X syndrome)
Gonadal mosaicism
Type of autosomal dominant disorder
Even if both parents are normal, child may be affected
Post zygotic mutation ➡️ mutation only in gametes, not in somatic cells
Examples of gonadal mosaicism
Tuberous sclerosis
Osteogenesis imperfecta
Genomic imprinting
Gene silencing/ inactivation
Either paternal/ maternal allele is inactivated ➡️ only one allele is functional
Normal phenomenon
Due to epigenetics
Epigenetics
Heritable modifications in DNA/ histone like DNA methylation or histone deacetylation ➡️ loss of expression of genes
Prader Willi syndrome
Cause
Maternal allele of chromosome 15q is usually silent, then
Paternal deletion: cause
Loss of function of SNORP gene
Features of Prader Willi syndrome
Short stature Hypotonia Hypogonadism Hyperphagy (increased ghrelin)➡️ obesity Mental retardation
Causes of Angelman syndrome/ Happy Puppet syndrome
Paternal allele was silenced
The functional maternal is deleted then Angelman syndrome
Defect in ubiquitin ligase gene (UBE3A)
Features of Happy Puppet syndrome/ Angelman syndrome
Inappropriate laughter Ataxia Seizures Mental retardation Hypotonia
Uniparental disomy
If both alleles come from same parent
Prader Willi syndrome: paternal deletion/ maternal disomy
Angelman syndrome: the opp
Autosomal dominant disorder characteristics
Usually have adult onset
Does not skip generations
Usually due to structural protein defects
1. Incomplete penetrance
2. Variable expressivity
Most common Mendelian mode of inheritance
Examples of autosomal dominant disorders
He has a very dominant father H. Huntington’s disease H. Hereditary spherocytosis A. APKD V. VWF, VHL D. Dystrophia myotonica O. Osteogenesis imperfecta M. Marfan’s syndrome I. Intermittent porphyria N. NF-1 A. Achondroplasia N. NF-2 T. Tuberous sclerosis F. FAP, Familial hypercholesterolemia
Marfan’s syndrome
Cause
Autosomal dominant
Defect in FBN-1 gene encoding for fibrillin-1
(defect in FBN-2 gene encoding for fibrillin-2 leads to congenital contractural arachnodactyly)
Clinical presentation of Marfan’s syndrome
1. Skeletal defect: Tall stature Hyperextensible joints Dolicocephalic head 2. Ocular defects: Ectopia lentis Superotemporal dislocation 3. CVS: MV Prolapse (like Klinefelter’s) Aortic dissection
Most common cause of death in Marfan’s syndrome
CVS defect like aortic dissection
Diagnosis of Marfan’s syndrome
Revised Ghent’s criteria
- Family history
- Clinical signs and symptoms
- Fibrillin-1 gene mutation
NF-1 or von Recklinghausen’s disease
Gene on chromosome 17 (letters)
Encode for neurofibromin
Can be associated with juvenile myelo monocytic leukaemia (JMML)
Presentations:
1. Cafe au lait spots (>6 spots)
2. Lisch nodules: (pigmented iris hamartomas)
3. Neurofibromas: (meningeomas, pheochromocytoma)
NF-2
Gene on chromosome-22
Encodes for Merlin
Associated with bilateral acoustic neuroma/ Schwannomas)
Ehler Danlos syndrome basics
AD and AR (type 6,7) Type 3 collagen mostly affected Most common : 3 Least common: 7 Most dangerous type of EDS: Type 4 (vascular)
AD types of Ehler Danlos syndrome
1. Classical: Diaphragmatic hernia Mitral valve prolapse 3. Common, hypermotility: Loose skin (Rubberman syndrome) Thin skin (cigarette paper skin) 4. Vascular: Aorta may rupture
AR types of Ehler Danlos syndrome
6. Kyphoscoliosis Defect in lysyl hydroxylase enzyme 7. a,b: arthrochalasia: Joint, bone defects c: Dermatosparaxis: Severe skin fragility
Autosomal recessive disorders
Young/ early onset usually
Complete penetrance
Usually due to enzyme deficiency
Uniparental disomy (both alleles from a single parent) can also be seen
Examples of autosomal recessive disorders
A. Alkeptonuria, Ataxia, Albinism B. Beta thalassemia, sickle cell anaemia C. Cystic fibrosis, congenital adrenal hyperplasia D. Deafness E. Emphysema (α1 antitrypsin deficiency) F. Friedrich’s ataxia G. GSDs, Galactosemia H. Hemachromatosis, homocystinuria I. Inborn error of metabolism
All lysosomal storage disorders are autosomal dominant except
Fabry’s disease
Hunter’s disease
Autosomal recessive
Tay Sachs disease mnemonic
T. Tay Sachs A. Ashkenazi Jews Y. Young S. Spot- cherry red in macula A. AR C. CNS defects H. Hexosaminidase α defect (GM2 increases) S. Symptoms of motor neuron and mental retardation
Histopathology of Tay Sachs disease
Neuron: Ballooned Vacuolation (distended with lysosomes) Electron microscopy: Onion skin appearance
Onion skin appearance
X-ray: Ewing’s sarcoma e- microscopy: Tay Sachs disease Nerve biopsy: CIPD H and E: malignant hypertension, 1° sclerosing cholangitis Gross: spleen in SLE
Niemann Pick’s disease
Types
Defect in sphingomyelinase ➡️ accumulation of sphingomyelin Type A: Neuronal involvement Severe, early mortality Type B: Neuronal involvement absent Better prognosis Type C: most common, intermediate
Gaucher’s cell
Wrinkled/ crumpled tissue paper appearance
PAS +
Oil red O+
Perl’s +
Pseudo Gaucher’s cell
Seen in CML
Perl’s stain -ve
Types of Gaucher’s disease
1. Non neuropathic: Adulthood Most common Bone involvement, pathological fractures Hepatosplenomegaly 2. Neuropathic: Infants Less common More severe CNS involvement 3. Intermediate
X-linked recessive disease examples
Lady. Lesch Nyhan syndrome Hardinge. Haemophilia A and B, Hunter’s disease College. Colour blindness Girls. G6PD deficiency Don’t. Duchenne muscular dystrophy Care. Chronic granulomatous disease About. Agammaglobulinemia Foolish. Fabry’s disease, Fragile X syndrome Words. Wiscott Aldrich syndrome
X-linked dominant disorders example
R. Rett’s syndrome
A. Alport syndrome
V. Vit D resistant rickets
I. Incontinentia pigmenti
X-linked dominant properties
Mother: can give diseases to both sons and daughters
Father: affects only daughters
Types of chromosomes
Metacentric: 1 Submetacentric: X Acrocentric: 13,14,15,,21,22,23Y Telocentric: does not exist in humans
Chromosomal disorders
1. Structural: Deletion Insertion Translocation Ring chromosome Iso chromosome Inversion 2. Numerical: Aneuploidy; monosomy and trisomy
Reasons for aneuploidy
- Meiotic non dysjunction
2. Anaphase lag
Ring chromosome
Type of structural chromosomal abnormality
Break at both ends
Fusion of damaged ends
Can be seen in Turner’s syndrome
Robertsonian translocation
Translocation between 2 acrocentric chromosomes (13,14,15,21,22,Y)
t(14:21) Down’s syndrome
Isochromosome
When division of chromosome occurs transversely instead of longitudinally
Two short or two long arms
Most common isochromosome: iXq
Most common isochromosome in:
Cancer
Testicular tumour
In cancer: il7q
In testicular tumour: i21p
Down’s syndrome pathogenesis
Most common chromosomal disorder Most common genetic cause of mental retardation 1. Meiotic non dysjunction: 95% Occurs in oogenesis in meiosis-I 2. Robertsonian translocation: 4% t(14:21) 3. Mosaics: 1%
Down’s syndrome screening tests for mothers
Triple test: AFP βBCG Unconjugated estradiol Quadruple test: Triple test + inhibin
Clinical features of Down’s syndrome
- Most common cause of mental retardation
- Face: mongoloid idiocy
- Eyes: Brush field spots
- Palm: (single) Simian crease, clinodactyly
- Foot: Sandle gap/ saddle toe
Mongoloid idiocy
Facial features of Down’s syndrome
- Flat facial profile
- Upslanting/ oblique palpebral fissure
- Prominent epicanthal folds
- Flat occiput
- Flat nasal bridge
- Low set ears
Complications of Down’s syndrome
- Acute leukaemia
- Cardiovascular defect:
M/C endocardial cushion defect, VSD - GIT:
Annular pancreas
Duodenal atresia
Hirschsprung disease - Hypothyroidism
- Premature Alzheimer’s disease (gene for the disease on chromosome 21)
Acute leukaemia and Down’s syndrome
M/C leukaemia- ALL
M/C in children <3 years- AML
M/C type of AML- AML M7
Common features of Patau’s syndrome and Edward’s syndrome
- Mental retardation
- CVS defect
- Rocker bottom feet
- Prominent occiput
Patau syndrome specific characteristics
Microcephaly Micro ophthalmia Umbilical hernia Polydactyly Left lip and palate
Meiotic non dysjunction occurs in meiosis-I
13 chromosome trisomy
Edward’s syndrome specific characteristics
Micrognathia Short neck Renal malformation Limited hip abduction Overlapping fingers
Meiotic non dysjunction occurs in meiosis-II (unlike others)
18 chromosome trisomy
Cat eye syndrome
Trisomy 22
Multiple colobomas in the eye
Cat cry syndrome or Cri du chat syndrome
del 5p (short arm)
Cat-like cry
Behavioural abnormalities
Developmental delay
Lyon’s hypothesis
Only one X chromosome of genetically active
Other X, paternal or maternal, randomly becomes inactivated
Inactivated X chromosome- Barr body of buccal mucosa having drumstick appearance
(21 % of Xp and 3% of Xq escape inactivation)
Syndromes associated with advanced maternal age
Down’s syndrome
XXX syndrome
Syndromes associated with advanced paternal age
Marfan’s syndrome
Osteogenesis imperfecta
Achondroplasia
Klinefelter’s syndrome
Associated with both advanced maternal and paternal age
Expected hormonal changes
M/C cause of male hypogonadism
M/C cancer: breast cancer
M/C germ cell tumour: extragonadal GCT (teratoma)
Biopsy test for Klinefelter’s syndrome
Atrophy of seminiferous lobules
Hyalinisation of lobules
Leydig cell hyperplasia
Features of Klinefelter’s syndrome
- Tall stature
- Eunuchoid body habitus
- Long extremities
- Reduced 2° sexual characteristics
- Gynecomastia
- Frontal baldness absent
- Poor muscle tone
- Testicular atrophy- infertility
Turner’s syndrome basics
Most common female hypogonadism
Only monosomy compatible with life
Most common cause of primary amenorrhea
M/C monosomy- monosomy 16
Pathology of Turner’s syndrome
- Deletion of X chromosome
- Ring chromosome
- ISO chromosome
Common features of Turner’s syndrome
Mneumonic
C. Cardiac abnormalities, cubitis valgus, cystic hygroma
L. Lymphadema
O. streaked ovaries
W. Webbed neck
N. Normal intelligence, nipples widely spaced
S. Short stature, short 4th metacarpal
CVS abnormalities of Turner’s syndrome
M/C CVS defect: bicuspid aortic valve
M/C cause of death: preductal coarctation of aorta
M/C cause of 1° amenorrhea
Increased risk of developing gonadoblastoma
Noonan’s syndrome
Clinical features of Turner’s syndrome
Normal karyotype
Mutation in chromosome 12
Karyogram
Arrangement of chromosomes in descending order of length followed by sex chromosomes
Samples used for karyotyping
- Amniotic fluid
- Chorionic villi sampling
- Skin fibroblasts
- Peripheral blood lymphocytes
Arrested the cell in metaphase using colchicine
Staining/ banding for karyotyping
- Mc giemsa banding
2. Q- banding (quinalrine)
