GEN: Clinical Genetics

Question 1

what are Mendel’s 2 Laws?

Answer 1

1. laws of segregation → each individual has two alleles of each charateristic but only one transmitted to each offspring
2. laws of independent assortment → genes at different loci segregate independently but not if they are closely linked

Question 2

what are Mendelian disorders?

Answer 2

single gene mutations - pathogenic and heritable alteration affecting sturcutre/function of protein

Question 3

what is hemizygous?

Answer 3

presence of single copy of chromosome or gene - X in XY (MEN)

Question 4

what are autosomal genes?

Answer 4

genes located on autosomes → chromosomes 1-22 (not sex)

Question 5

what are the 3 types of heterogeneity?

Answer 5

Question 6

Recognise, understand and use standard pedigree symbols

Answer 6

Question 7

what are autosomal dominant conditions?

Answer 7

• 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

Question 8

What is the inheritance pattern of Myotonic Dystrophy?

Answer 8

Question 9

Two important characteristics of autosomal dominant
conditions to remember:

Answer 9

1. Variable (reduced) penetrance
2. Variable expression

Question 10

what are 2 example of AUTOSOMAL DOMINANT disease with different manifestations?

Answer 10

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

Question 11

what are the mutation types in autosomal dominant diseases?

Answer 11

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

Question 12

what is germline mosaicism?

Answer 12

parent carrying small proportion of gametes harbouring same mutation

• exclude non-paternity
• 2 independent de novo mutations unlikely

Question 13

what are 3 examples of germline mosaicism?

Answer 13

1. achondroplasia with point mutation of FGFR3
2. osteogenesis imperfecta
3. duchenne musclar dystrophy

Question 14

what are autosomal recessive conditions?

Answer 14

• 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

Question 15

what increases the risk of recessive disorders in offspring

Answer 15

Consanguinity (incest)

Question 16

what is compound heterozygosity?

Answer 16

different mutations in same gene, example: CFTR

Question 17

what is homozygosity

Answer 17

same allele on both chromosomes, example: sickle cell anaemia

Question 18

what is X linked inheritance?

Answer 18

• males affected via female line
• asymptomatic women
• all daughters of affected males are carriers
• sons of affected males not affected

Question 19

can females be affected via X-linked recessive disorders?

Answer 19

yes, due to non-random inactivation ⇒ chance expression in certain tissues. Turner syndrome 45,X

Question 20

what maintains the inactivation on X chromosomes?

Answer 20

methylation

Question 21

what does X-linked dominant mean?

Answer 21

• 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

Question 22

are males or females affected in X-linked dominant disorders?

Answer 22

both, with females showing mosaic involvement pattern like skin

Question 23

what is an example of an autosomal dominant disease?

Answer 23

Rett syndrome

Question 24

what are some genetic tests for diagnosis?

Answer 24

• 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

Question 25

what is teratogen exposure?

Answer 25

exposures during pregnancy/breastfeeding that harm developing baby

Question 26

what are 2 teratogen examples

Answer 26

foetal alcohol syndrome, foetal anticonvulsant syndrome

Question 27

what are number and structure chromosomal rearrangements?

Answer 27

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)

Question 28

what is an example of sex aneuploidy?

Answer 28

Turner syndrome - 45X

• peripheral oedema at birth
• short stature
• primary amenorrhoea
• normal intelligence
• neck webbing

Question 29

what is DiGeorge syndrome?

Answer 29

Question 30

what is comparative genomic hybridisation array good for?

Answer 30

identification of small genomic imbalances affecting individuals health/development conferring increased susceptibility to autism, psychiatric disease or congenial abnormalities

Question 31

what is single gene testing good for?

Answer 31

diagnosis/confirmation of genetic disorders as they facilitate management and accurate recurrence risk

Question 32

what are the reproductive options fir single gene testing?

Answer 32

• prenantal diagnosis
• pre-implanation genetic diagnosis

Question 33

can changes in the same gene lead to different conditions?

Answer 33

yes - Duchenne and Becker MD

Duchenne is shorter life expectancy and has early onset

Question 34

what is an example of a condition with variable expression?

Answer 34

neurofibromatosis type 1 NF1 - various phenotypic abnormalities characterising condition

Question 35

what do allele frequencies add up to?

Answer 35

1 = p + q

Question 36

what do genotype frequencies sum up to?

Answer 36

p2 + 2pq + q2 = 1

Question 37

what is p?

Answer 37

wild type

Question 38

what is q?

Answer 38

recessive