Genetics in Clinical Practice 2 Flashcards by Annabel Mensah-Djan

What are the 2 types of genetic consultation?

Diagnostic

2. Pre-symptomatic testing (Predictive)

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What does diagnostic genetic consultation involve?

Clinical assessment, investigations, counselling, implications for affected person and family members

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Who is predictive testing for?

Indiv at risk based on family history, usually for adult onset cond

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What is genetic counselling?

Comm of nature of genetic disorder

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Why is genetic counselling important?

Discuss risks of transmission/inheritance/penetrance of future pregnancies on basis of family history and support in making informed decisions

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What is clinical diagnosis based on?

Clinical (dysmorphic) features

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List the genetic tests

Standard chr analysis
FISH
Array CGH
Single gene testing
Next Gen Sequencing
Methylation analysis (imprinting disorders)

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What are the indications for genetic tests?

Multiple problems (structural abn, dev delay)

- Often unusual combo, unless recognised syndrome

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What have basic genetic tests been replaced by?

Array CGH

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What is VACTERL association?

Non-random association of birth defects that affects multiple body systems

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What does VACTERL association stand for?

Vertebral
Anal Atresia
Cardiac
Tracheo-oEsophageal atresia/phistula
Renal abnormalities
Limb (radial ray defect)

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What does Array CGH identify?

V. small genomic imbalances which may have effect on indiv’s health + dev/inc susceptibility to certain cond e.g. ASD, psychiatric disease, congenital abnormalities

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What disorders can deletion of chr 16 lead to?

Learning diff
Bipolar
Obesity in young adults
Lower IQ

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What is single gene testing used for and why?

Diagnosis/conformation of genetic disorders
Test (carrier/pre-symp) for at risk relatives
Can facilitate management + get accurate recurrence risk

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What rep options can be considered from results of single gene testing?

Prenatal diagnosis

- Pre-implantation genetic diagnosis

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What are the recurrence risks for achondroplasia for affected and unaffected parents?

Unaffected - 1%

Affected - 50%

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What is Next Generation Sequencing?

Test whole genome for no. of genes that may be rel to phenotype

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What does genetic diagnosis allow?

Confirm clinical diagnosis
Dec need for other investigations to get diagnosis
Only diagnostic in some cases
May help prognostication
Gene based therapies (rare)
RR assessment
Informed choice in future pregnancies
Pre-symptomatic testing

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Why are chr rearrangement tests needed?

Need tests to detect rearrangements at diff level res

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What are aneuploidies and 3 e.g.s?

Chr no. not div by 23

E.g. Down’s (trisomy 21), Patau (13), Edwards (18)

What are polyploidies?

Multiple sets of 23 chr

What are balanced chr structure (translocations)?

2 chr break + swap places without losing gen material/interfering with gene at specific break point

Name e.g.s of unbalanced chr structure

Deletions
Duplications
Inversions
Translocations

Define Deletions

Part of chr missing

E.g. Cri du Chat (chr 5 missing)

Define Duplications

Part of chr duplicated/present in 2 copies

Define Inversions

Chr breaks + rearranges itself so segment is reversed

Define Translocations

- 2 types: 1) Reciprocal = 2 diff chr exchanged segments 2) Roberstonian = entire chr attaches at centromere to another chr

What are the complications of Turner Syndrome?

- Peripheral oedema at birth - Short stature - 1 degree amenorrhoea (streak ovaries) - Normal intelligence

What is a risk figure needed for?

Adult onset cond | Offspring and family member risk

What does accurate estimation of risk require?

Confirmation of diagnosis | Accurate family tree

What do genetic tests help to do?

Refine risk Give options Management

What is risk to offspring (RR) of autsomal dom cond of affected M + unaffected F?

- 1 in 2 with equal probab from carrier parent

What is neurofibromatosis 1 an e.g. of?

A cond where various phenotype which abnormalities characterise cond are v. variable

How is risk of affected child calc for autosomal dom cond with incomplete penetrance?

Probab of inheriting mutant allele x penetrance

In e.g. of retinoblastoma (dom) with penetrance: 0.8/80% (meaning 80% dev cond), what is risk of affected child?

1/2 x 0.8(4/5) = 0.4 (4/10)

What is risk of affected sons, daughters being carriers, and unaffected sons of X-linked cond with normal M + carrier F parents?

- 1 in 4 affected sons - 1 in 2 daughters carriers - 1 in 2 sons unaffected

Why are only M affected in X-linked inheritance?

M don't have spare X

What is risk of affected offspring and carrier risk of unaffected siblings of autosomal rec cond and why?

- affected: 1 in 4 | - carrier risk is 1 in 2 at conception but becomes 2 in 3 if siblings of rec cond clinically unaffected

What does the Hardy-Weinberg equation help to explain?

Gene freq in pop + useful for calc risks of autosomal rec disorders

What does p + q mean in HWE?

p = freq of wild type allele q = freq of rec allele - rep prop of chr which have allele not no. of people who carry allele

If we have 2 alleles A + a, what are the ratios of the diff genotypes and their freq?

AA - p2 Aa - 2pq (2 bc there are 2 offspring with Aa in punnet square) aa - q2

What does allele freq at a locus add up to and the equation?

1 | p + q = 1

What does genotype freq sum to and the equation?

1 | p2 + 2pq + q2

How do you calc allele freq for rec allele?

disease incidence = q2 | freq of rec allele = square root of q2 = q

What does carrier freq (2pq) not equal and when does it change?

Rec allele freq (q) but approx to 2q when q small (most cases

Calc risk of CF to couple's offspring (e.g. from lecture) | CF incidence: 1 in 2500

q2 = 1 in 2500 q = square root 1/2500 = 1/50 carrier freq = 2pq so 2 x 1/50 - 1/25 (only use q as it is small) Offspring risk = prob both parents carriers x risk of affected offspring 2/3 (carrier risk of unaffected sibling of affected) x 1/25 (if no family history, use pop carrier risk) x 1/4 = 2/30 = 1/150

What does calc using HWE allow?

prenatal diagnosis + cascade testing - testing rel at risk for common genetic disorders esp if pop screening available

What is risk of offspring affected by X-linked cond of unaffected parents? (using diagram from lecture)

Carrier risk of consultant = 1/2 Risk of passing on gene = 1/2 Prob of having M offspring = 1/2 1/2 x 1/2 x 1/2 = 1/8