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
what is teratogen exposure?
exposures during pregnancy/breastfeeding that harm developing baby
what are 2 teratogen examples
foetal alcohol syndrome, foetal anticonvulsant syndrome
what are number and structure chromosomal rearrangements?
number: aneuploidies (not divisible by 23), polyploidies (multiple sets of 23)
structure: balanced translocations or unbalanced (deletions, duplications, inversions, translocations and often associated with problems)
what is an example of sex aneuploidy?
Turner syndrome - 45X
- peripheral oedema at birth
- short stature
- primary amenorrhoea
- normal intelligence
- neck webbing
what is DiGeorge syndrome?
what is comparative genomic hybridisation array good for?
identification of small genomic imbalances affecting individuals health/development conferring increased susceptibility to autism, psychiatric disease or congenial abnormalities
what is single gene testing good for?
diagnosis/confirmation of genetic disorders as they facilitate management and accurate recurrence risk
what are the reproductive options fir single gene testing?
- prenantal diagnosis
- pre-implanation genetic diagnosis
can changes in the same gene lead to different conditions?
yes - Duchenne and Becker MD
Duchenne is shorter life expectancy and has early onset
what is an example of a condition with variable expression?
neurofibromatosis type 1 NF1 - various phenotypic abnormalities characterising condition
what do allele frequencies add up to?
1 = p + q
what do genotype frequencies sum up to?
p2 + 2pq + q2 = 1
what is p?
wild type
what is q?
recessive
