Medical Genetics Flashcards
Describe the molecular genetic basis and clinical aspects of Huntington’s Disease
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
State the genetic conditions tested for (and the tests used) during pregnancy
Down Syndrome: Combined Ultrasound (Nuchal Translucency Increases in DS) and Biochemical Screening (CUBS)
Describe the role of BRCA1/2 mutations in the contribution to cancer
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
Briefly describe Sanger DNA Sequencing
i.e. Fluorescent Dideoxynucleotide Sequencing
Used in detection of point mutations
Analyses a single gene at a time
Describe X-Linked Dominant Inheritance
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
Describe the basis of next generation DNA sequencing
i.e. Massively Parallel Sequencing
Of many or all genes
Used to find small mutations somewhere in the exome
Describe the difference between Tumour Suppressor Genes, Proto-Oncogenes and Oncogenes
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
Describe the features of autosomal dominant inheritance
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
Define ‘Cascade Screening’
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)
State the genetic conditions tested for (and the test method) during the neonatal period
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)
Describe the clinical aspects and molecular genetic basis of Duchenne Muscular Dystrophy
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
Describe the concept of ‘modifier genes’
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
Describe the clinical aspects and molecular genetic basis of Cystic Fibrosis
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
Briefly describe the main autosomal trisomies
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
Describe the concept of ‘variable expression’ in Mendelian Inheritance
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
Describe the concept of Genetic Anticipation
The phenomenon where symptoms of an inherited condition become more marked and become apparent at an earlier age in subsequent generations
Describe Pre-Implantation Diagnosis and state its advantages and disadvantages
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
State some of the genetic conditions screened for in specific adult populations
Tay Sachs Disease - Screened for in Jewish people, e.g. Pre-Pregnancy
Thalassaemia - Population Carrier Screening
State some important aspects of clinical history and examination that are especially helpful in clinical genetics
Hx: Age of Onset, Progression
FHx: Consanguinity, Miscarriages, Stillbirths
O/E: Dysmorphic Features (Head Shape/Size, Eyes, Ears, Nose, Philtrum), Unusual Features (Polydactyly)
State the application of Array Comparative Genomic Hybridisation in DNA Analysis
Detection of sub-microscopic duplications and deletions
Describe the concept of ‘incomplete penetrance’ in Mendelian Inheritance
Complete/Incomplete Penetrance: One may inherit the mutation but this would not be enough to develop the disease (i.e. incomplete penetrance)
Describe the ‘Two-Hit Hypothesis’
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
Describe the clinical and genetic consequences of Fragile X Syndrome
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
Describe the clinical aspect and molecular genetic basis of Myotonic Dystrophy
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
Describe the features of autosomal recessive inheritance
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
Describe the concept of ‘gonadal mosaicism’ in Atypical Mendelian Inheritance
Presence of more than one cell line in the gonads (but NOT in somatic cells) due to a mutation in a gamete precursor cell
Describe Gain and Loss of Function mutations
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
Describe X-Linked Recessive Inheritance
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
