Medical Genetics

Question 1

Describe the molecular genetic basis and clinical aspects of Huntington’s Disease

Answer 1

Onset typically between 30-50 years

Characterised by progressive chorea (involuntary movements), dementia and psychiatric symptoms

Autosomal Dominant with Genetic Anticipation

Unstable length mutation in the HTT gene

Number of CAG repeats increased from 10-35 to 36-120

This repeat encodes a polyglutamine tract

Expansion of tract causes insoluble protein aggregates and neurotoxicity

Question 2

State the genetic conditions tested for (and the tests used) during pregnancy

Answer 2

Down Syndrome: Combined Ultrasound (Nuchal Translucency Increases in DS) and Biochemical Screening (CUBS)

Question 3

Describe the role of BRCA1/2 mutations in the contribution to cancer

Answer 3

BRCA1/2 proteins are large nuclear proteins and with roles including DNA repair, transcriptional regulation of other genes and cell-cycle regulation

They promote double-stranded DNA repair by homologous recombination

Question 4

Briefly describe Sanger DNA Sequencing

Answer 4

i.e. Fluorescent Dideoxynucleotide Sequencing

Used in detection of point mutations

Analyses a single gene at a time

Question 5

Describe X-Linked Dominant Inheritance

Answer 5

e.g. Vitamin D Resistant Rickets

No male to male transmission

Vertical pattern of inheritance

Male-Female Transmission = All Daughters Affected

Female-Female Transmission = 50% of Daughters Affected

F:M = 2:1

Question 6

Describe the basis of next generation DNA sequencing

Answer 6

i.e. Massively Parallel Sequencing

Of many or all genes

Used to find small mutations somewhere in the exome

Question 7

Describe the difference between Tumour Suppressor Genes, Proto-Oncogenes and Oncogenes

Answer 7

TSG: Normally inhibit progression through cell cycle and cell prilferation, promote apoptosis or act as stability genes

Mutation Results in Loss of Function

Requires 2 Mutated Copies to Become Tumourigenic

Proto-Oncogenes: Normally stimulate cell cycle or promote cell division/growth

Activation by mutation results in Oncogenes with Gain of Function in protein

Only needs one mutated copy for tumourigenic effect

Question 8

Describe the features of autosomal dominant inheritance

Answer 8

e.g. Achondroplasia

Affects every generation

Males and Females equally affected

Vertical pattern of inheritance

50% chance of child being affected if a parent is heterozygous

Disease = Aa or AA, Healthy = aa

Question 9

Define ‘Cascade Screening’

Answer 9

Systematic identification and testing of members of the family of a proband with a particular disease of interest

(aka testing the family of a patient diagnosed with a disease such as CF)

Question 10

State the genetic conditions tested for (and the test method) during the neonatal period

Answer 10

Heel Spot on Guthrie Card

Phenylketonuria and Medium-Chain Acyl-CoA Dehydrogenase Deficiency (Mass Spectrometry)

Congenital Hypothyroidism and Cystic Fibrosis (Immuno-Assay)

Sickle Cell Disorder (High-Performance Liquid Chromatography)

Question 11

Describe the clinical aspects and molecular genetic basis of Duchenne Muscular Dystrophy

Answer 11

Onset at 3yrs, Wheelchair by 12yrs

X-Linked Recessive Inheritance

Serum Creatine Kinase leaks from damaged muscle fibres into serum

Out-Of-Frame Deletion Mutations

Question 12

Describe the concept of ‘modifier genes’

Answer 12

Genetic variants that can affect the manifestation of a disease by altering indirectly influencing expression of another gene

This may help explain the variable expressivity seen in some mutations, and may affect the age of onset, rate of disease progression and severity of symptoms

Question 13

Describe the clinical aspects and molecular genetic basis of Cystic Fibrosis

Answer 13

Characterised by recurrent lung infections and exocrine pancreatic insufficiency

CFTR mutation results in defective chloride ion channels and increased thickness of secretions

Most common mutation is F508del (in-frame deletion of one codon resulting in loss of phenylalanine ‘F’ at position 508 )

Prevents normal protein folding and insertion into the plasma membrane

Question 14

Briefly describe the main autosomal trisomies

Answer 14

Down’s: Trisomy 21, Learning Difficulties, Heart Defects, Hypothyroidism

Edwards’s: Trisomy 18, Small Chin, Clenched Hands, Malformation of Organs, Profound Learning Difficulties if Survive Past 1 Year

Patau: Trisomy 13, Congenital Heart Disease, 50% SR at 1/12, 10% at 1Yr, Profound Learning Difficulties

Question 15

Describe the concept of ‘variable expression’ in Mendelian Inheritance

Answer 15

Variable Expression: Two people in the same family, who have inherited the same mutation in the same gene, may have different disease severities or age of onset

Question 16

Describe the concept of Genetic Anticipation

Answer 16

The phenomenon where symptoms of an inherited condition become more marked and become apparent at an earlier age in subsequent generations

Question 17

Describe Pre-Implantation Diagnosis and state its advantages and disadvantages

Answer 17

One or Two cells are removed from an embryo to undergo PCR or FISH to check for a mutation and only unaffected embryos are transferred into the patient

Pros: Permits implantation of unaffected embryos

Cons: Possible long wait, Not available to all women, Difficulty with multiple visits and procedures, Take home baby rate usually <50% per cycle

Question 18

State some of the genetic conditions screened for in specific adult populations

Answer 18

Tay Sachs Disease - Screened for in Jewish people, e.g. Pre-Pregnancy

Thalassaemia - Population Carrier Screening

Question 19

State some important aspects of clinical history and examination that are especially helpful in clinical genetics

Answer 19

Hx: Age of Onset, Progression

FHx: Consanguinity, Miscarriages, Stillbirths

O/E: Dysmorphic Features (Head Shape/Size, Eyes, Ears, Nose, Philtrum), Unusual Features (Polydactyly)

Question 20

State the application of Array Comparative Genomic Hybridisation in DNA Analysis

Answer 20

Detection of sub-microscopic duplications and deletions

Question 21

Describe the concept of ‘incomplete penetrance’ in Mendelian Inheritance

Answer 21

Complete/Incomplete Penetrance: One may inherit the mutation but this would not be enough to develop the disease (i.e. incomplete penetrance)

Question 22

Describe the ‘Two-Hit Hypothesis’

Answer 22

The Two-Hit Hypothesis states that two mutated alleles are required for progression to cancer

The first may be inherited, meaning a second sporadic mutation is required to initiate tumourigenesis

Question 23

Describe the clinical and genetic consequences of Fragile X Syndrome

Answer 23

Significant Learning Disability

X-Linked Recessive Inheritance

With Genetic Anticipation

If Full Mutations: Phenotypes in males can be severe, some carrier females also affected more mildly

Question 24

Describe the clinical aspect and molecular genetic basis of Myotonic Dystrophy

Answer 24

Progressive muscle weakness in early childhood with myotonia and cataracts

Autosomal Dominant with Genetic Anticipation

Unstable length mutation of a CTG repeat

Affected if 50 or more repeats

Question 25

Describe the features of autosomal recessive inheritance

Answer 25

e.g. Sickle Cell, CF, PKU

Equal frequency and severity in males and females

Horizontal pedigree pattern

Disease expressed in homozygotes (two identical mutations) or compound heterozygotes (two different mutations in the same gene)

Low risk to offspring of affected individuals

Expressivity more constant in a family

May suggest consanguinity in the family

Question 26

Describe the concept of ‘gonadal mosaicism’ in Atypical Mendelian Inheritance

Answer 26

Presence of more than one cell line in the gonads (but NOT in somatic cells) due to a mutation in a gamete precursor cell

Question 27

Describe Gain and Loss of Function mutations

Answer 27

LOF: Mutation causes a reduction in the activity or amount of the encoded protein

GOF: Mutation results in a greater level of activity, a greater amount of protein or rarely, acquisition of a new function (e.g. BCR-ABL)

LOF mutations are more common

Question 28

Describe X-Linked Recessive Inheritance

Answer 28

e.g. Duchenne’s Muscular Dystrophy

No male to male transmission

‘Knights Move’ pattern of inheritance

Male-Female transmission = All Daughters are Carriers

Female-Female Transmission - 50% of Daughters are Carriers

M>>>F