Vitamin-D resistant rickets
X-linked dominant trait;
affects both male and female;
in males the condition is uniform in severity but in females the heterozygote is variably affected because of X-inactivation
Turner’s syndrome
aneuploidy–45XO
- female
- webbed neck
- short stature
- infertile
Klinefelter’s syndrome
aneuploidy–47XXY
- male
- tall and thin
- gynaecomastia (with cancer risk)
- infertile
- mild learning impairment
Red-green colorblindness
X-linked recessive
Duchenne muscular dystrophy
- X-linked recessive -mutation in Dystrophin gene (X-linked)
- the encoded protein normally is cytosolic and connects the cytoskeleton of muscle fibre to the ECM through the cell membrane; this provides cell stability
- in DMD there’s progressive muscle weakness, degeneration and lethality
Haemophilia
- X-linked recessive
- a rare bleeding disorder where coagulation is compromised due to deficiency in clotting factors
- haemophilia A–> lack of clotting factor VIII
- haemophilia B–> lack of clotting factor IX
(A is more common)
Rett syndrome
- X-linked dominant
- neurological disorder
-there are no affected males as the condition is early lethal; female survive due to X-inactivation
Prader willi syndrome
- affects multiple system, but primarily a neurological disorder
- caused by loss of function of genes in a particular region of chromosome 15
- some genes are only expressed on the copy that is inherited from the father (genomic imprinting)
For this syndrome:
- most cases-> a segment of paternal chromosome is deleted in each cell; missing critical genes (as, paternal=deleted; maternal=turned off)
- some others-> both copies of chromosome 15 inherited from mother (maternal uniparental disomy)
- rarely-> a mutation, translocation or other defect that inactivates the genes on paternal chromosomes
Angelman syndrome
- primarily affects nervous system
- loss of function of a gene; In certain areas of the brain, only maternal copy of this gene is active (genomic imprinting)
For this syndrome:
- most cases-> segment of maternal chromosome 15 that contains this gene is deleted
- some cases-> there’s a mutation in the maternal copy of the gene
- rarely-> both copies of chromosome 15 are from father (uniparental disomy)
Beckwith-Wiedemann syndrome
-on chromosome 11, for some genes, only the paternal inherited copy is expressed (genomic imprinting)
For this syndrome:
- (most cases)–> mutations in imprinting centres of chromosome 11 result in disrupted regulation as a result of abnormal methylation
- (some cases)–> paternal uniparental disomy results in two active copies of the paternally expressed genes and missing genes that are normally active on the maternal copy [often also accompanied by mosaicism]
(there are other causes but not needed)
in the disorder: there's either increased dosage of IGF2 (growth factor) or no expression of CDKN1C (a CDK inhibitor; i.e. a cell cycle repressor) - foetal overgrowth -multi-organ hyperplasia -increased childhood tumours
DIDMOAD
- mitochondrially inherited condition
- Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness- mitochondrial form
Kearns-Sayre syndrome
- mitochondrial inheritance
- mtDNA deletion–> multiple genes lost
- chronic progressive external ophthalmoplegia with myopathy
LHON
- mitochondrial inheritance
- mutation in NADH dehydrogenase
- leber hereditary optic neuropathy
MELAS
- mitochondrial inheritance
- tRNA (leu) mutation
- Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes
MERRF
- mitochondrial inheritance
- tRNA (lys) mutation
- Myoclonic Epilepsy associated with Ragged-Red Fibres
Pearson marrow/pancreas syndrome
- mitochondrial inheritance
- pancytopenia, lactic acidosis and exocrine pancreatic insufficiency
Down’s syndrome
-de novo mutation disease
-trisomy 21
-increased dosage of about 243 genes
-variable expressivity
–(more than 90% of times the additional copy is from mother;
this follows with the fact that in germline variants cytogenetic variants mostly arise in maternal germline)
BRCA1
-breast cancer type 1 susceptibility protein
(breast and ovarian cancer susceptibility)
- tumour suppressor gene
-the normal gene product is involved in homologous recombination mechanism of DNA repair; if HR is absent then cells rely on NHEJ, which is less accurate– therefore cells more likely to acquire mutations
-indel mutation of BRCA1 allele
( example of genetic drift– present in ashkenazi population)
-females carrying one copy of mutated allele have 80% risk of developing of developing breast/ovarian cancer by 90yrs
- it’s INCOMPLETELY penetrant
Ellis-van creveld syndrome
- Autosomal recessive
- splice site mutation
- short limb dwarfism, polydactyly etc.
- due to founder effect –common in amish population
apert syndrome
- de novo mutation disease
- missense mutation on FGFR2 (Ser-> Trp)
- prolonged signalling–> bone growth/ spermatogonial stem cell advantage (selfish positive selection)
22q11.2
-also called DiGeorge syndrome
-De novo disease
-‘q11.2’ on chromosome 22 is deleted due to NAHR
(removal of about 40 genes)
-cognitive and developmental problems; facial features(cleft palate); congenital heart defects
azospermia
- de novo mutation disease
- absence of sperms
- due to structural variants- in one of the 3 AZF regions
huntington’s disease
-autosomal dominant inheritance
-mutation is on hungtingtin gene on chr4
-number of CAG repeats are: (which codes for Glu)
<35 in normal
36-39 in maybe affected
40+ in affected
-age of onset is about 35-40yrs
polycystic kidney disease
- autosomal dominant inheritance
- can arise due to a variety of mutations in PKD1 and PKD2
- onset is 40-50 years
