GEN: Clinical Genetics Flashcards
what are Mendel’s 2 Laws?
- laws of segregation → each individual has two alleles of each charateristic but only one transmitted to each offspring
- laws of independent assortment → genes at different loci segregate independently but not if they are closely linked
what are Mendelian disorders?
single gene mutations - pathogenic and heritable alteration affecting sturcutre/function of protein
what is hemizygous?
presence of single copy of chromosome or gene - X in XY (MEN)
what are autosomal genes?
genes located on autosomes → chromosomes 1-22 (not sex)
what are the 3 types of heterogeneity?
Recognise, understand and use standard pedigree symbols
what are autosomal dominant conditions?
- caused by mutations in single autosomal genes
- affecting males/females
- Heterozygous - one wild and one mutant copy
- equal chance of passing normal/mutant allele
- vertical inheritance
- key feature: MALE TO MALE TRANSMISSION
What is the inheritance pattern of Myotonic Dystrophy?
Two important characteristics of autosomal dominant
conditions to remember:
- Variable (reduced) penetrance
- Variable expression
what are 2 example of AUTOSOMAL DOMINANT disease with different manifestations?
cherubism → 100% in males, 50-75% in females, 2:1 male predominance = marked fullness of jaw
Marfan Syndrome, characterised via: tall stature, long limbs, chest abnormalities, scoliosis, arachnodactyly, dislocated lens, aortic aneurism
what are the mutation types in autosomal dominant diseases?
Inherited - from an affected parent
- from an apparently unaffected mosaic
parent
De novo - new mutation in a gamete (sporadic
event) or shortly after fertilisation
- during early development: mosaicism
what is germline mosaicism?
parent carrying small proportion of gametes harbouring same mutation
- exclude non-paternity
- 2 independent de novo mutations unlikely
what are 3 examples of germline mosaicism?
- achondroplasia with point mutation of FGFR3
- osteogenesis imperfecta
- duchenne musclar dystrophy
what are autosomal recessive conditions?
- males/females affected
- generally single sibship/cousins affected
- future subling of affected individual probability to be affected = 1 in 4
- future sibling carrier probability = 1 in 2
- probability of exisiting unaffected sibling being carrier = 2 in 3
what increases the risk of recessive disorders in offspring
Consanguinity (incest)
what is compound heterozygosity?
different mutations in same gene, example: CFTR
what is homozygosity
same allele on both chromosomes, example: sickle cell anaemia
what is X linked inheritance?
- males affected via female line
- asymptomatic women
- all daughters of affected males are carriers
- sons of affected males not affected
can females be affected via X-linked recessive disorders?
yes, due to non-random inactivation ⇒ chance expression in certain tissues. Turner syndrome 45,X
what maintains the inactivation on X chromosomes?
methylation
what does X-linked dominant mean?
- can be lethal to men
- 50% offspring risk to males and females of affected mothers
- all daughters of affected males inherit condition
- no sons of affected male inherit condition
are males or females affected in X-linked dominant disorders?
both, with females showing mosaic involvement pattern like skin
what is an example of an autosomal dominant disease?
Rett syndrome
what are some genetic tests for diagnosis?
- standard chromosome analysis
- fluroscent in situ hybridisation - molecular cytogenic technique using flurescent complimentary probes for specific targets
- comparative genomic hybridisation array
- single gene testing
- next generation sequencing
- methylation analysis
