Week 1 - Medical Genetics Flashcards
What is an allele?
A variant of a gene that occupies the same locus on a chromosome.
List the typical Mandelian inheritance.
- autosomal dominant
- autosomal recessive
- x-linked dominant
- x-linked recessive
What is autosomal dominant inheritance?
A copy of the allele of one of the autosomal chromosomes is sufficient for a phenotypic expression.
Features of autosomal dominant inheritance?
- equal chances among male and female offsprings
- vertical mode of transmission
- incomplete penetrance ( not everyone with mutation will show the clinical features. Eg: BRCA2 mutation indicates only risk of Breast cancer ; needs FGFR2 mutation)
- variable expression ( different manifestation although mutation is present )
What is a modifier gene?
A gene that affects the phenotypic expression of another gene.
Eg: FGFR2 and BRCA2
Examples of autosomal dominant inheritance?
- Achondroplasia (FBGF3 constant activation)
- Hungtington’s disease
- Myotonic dystrophy
- Inherited breast, colorectal cancer
- Hypertrophic cardiomyopathy
- Long QT syndrome
- Adult polycystic kidney disease
- Marfan’s syndrome
- Familial hypercholesterolnaemia
Define autosomal recessive inheritance.
A mode of inheritance which the phenotypic expression is present when both copies of the alleles are identical (homozygousity).
Features of autosomal recessive inheritance.
- equal chances of male and female offsprings being affected
- horizontal pattern
- consanguinity in the family
- both parents must be carriers for an offspring to be affected
What is compound heterozygousity?
A condition when 2 heterogenous recessive alleles are present and causes a disease
Examples of autosomal recessive inheritance?
- Sickle cell anaemia
- Congenital adrenal hyperplasia
- Cystic fibrosis
- Phenylketonuria
- Haemochromatosis
- Alpha 1 Antitrypsin deficiency
- Spinal muscular dystrophy
Define x-linked recessive inheritance.
Mutation of a gene on the X chromosome causes the phenotype to be expressed in males whom are hemizygous for the gene mutation and females whom are homozygous
Define lyonization/ x - inactivation
The process of turning off one of the 2 x chromosomes in females during early embryonic stage.
What is skewed x inactivation?
The process of turning off different amount of paternal and maternal x chromosomes.
What are Barr bodies?
Inactivated X chromosomes.
Features of X-linked recessive inheritance.
- No male-male transmission (knight’s move)
- Mothers are obligate carriers
- Sometimes carriers manifest the phenotype due to skewed x inactivation.
Example of x linked recessive inheritance.
Duchenne muscular dystrophy
What is x linked dominant inheritance?
Phenotypes that are expressed in heterozygous females.
Features of x linked dominant inheritance?
- Vertical pattern
- Males and females have equal chance of being affected.
- No male to male transmission
Examples of x linked dominant inheritance?
- Vitamin D resistant rickets/ x linked hyperphosphataemia (PHEX gene - affects bones, bowing of leg)
- Incontinentia pigmenti* - skin rash then pigmentation ( NEMO gene partial deletion)
- Rett’s syndrome* (MECP2 mutation - child development to stop at 6th - 18th months of age with regression)
- Male lethality - spontaneous abortion
What is Knight’s move?
Male in F1 to male in F3 transmission via a carrier daughter
Compare and contrast autosomal dominant and recessive transmission.
Similarity :
- Males and females have equal chances of being affected.
- Severity in males and females are equal.
Dissimilarities:
- AD: vertical pattern ; AR: horizontal pattern
- AD: heterozygous manifests disease; AR: homozygous / compound heterozygous manifest disease
- AD: offsprings have 50% chance of acquiring if one parent is affected; AR: offsprings have 25% chance of acquiring if one parent is a carrier
- AD: not related to consanguinity ; AR: associated with consanguinity
- AD: variable expression and incomplete penetrance; AR: expression is constant in family
Compare and contrast X linked recessive and X linked dominant inheritance.
Similarities:
- no M to M transmission
- uniform severity in males
Differences:
- Pedigree pattern : XR: knight’s move ; XD: vertical pattern
- Affected progeny : XR: all daughters are carriers; XD: all daughters are affected
- Sex ratio XR: M»_space; F; XD: F:M = 2:1
