Inheritance Flashcards
X-linked dominant inheritance
Dominant trait on the X chromosome. Condition is expressed in heterozygote females as well as males. Female carriers have 50% risk of passing it on, male carriers have 100% risk of passing it on to daughters but none of his sons will be affected.
How can you tell X-linked dominant inheritance from autosomal dominant inheritance?
If descendants of affected males are considered, all sons will be healthy and all daughters will be affected. An excess of heterozygote females may also be an indication.
X linked dominance with male lethality
Disorder caused by a dominant mutation in a gene on the X chromosome which is observed almost exclusively in females because it is almost always lethal in males (Klinefelters an example of an exception). There will be a history of miscarriage in the family since 50% of males carrying the abn X will die. Results in a skewed ratio of females in the family. Females will pass on the abn X to 50% of their daughters.
X-linked hypophosphatemia (XLH)
aka victim D resistant rickets. Caused by mutations in the PHEX gene, which stimulates expression of FGF-23 (inhibits kidneys ability to reabsorb phosphate into the bloodstream).
X-linked Alport syndrome
1:50,000. Characterised by kidney disease, sensorineural hearing loss, eye abns and renal disease. Mutation in COL4A5 gene which plays an important role in kidneys, vision, hearing. COL4A3 and 4 are autosomal forms.
Intercontinentia pigmentia (X linked dominant)
IP affects skin, nails, teeth, eyes and CNS. Infants have blistering rash that develops to wart like skin growths. Adults have blaschko lines. Generally lethal in males (either XXY or mosaic in known male patients). Caused by deletion in IRBKG gene at Xq28.
Rett syndrome (X linked dominant, male lethal)
Neurodevelopmental disorder almost exclusively affecting females. 1:10,000 female births. Caused by MECP2 mutation in 80% but also FOXG1 and CDKL5 (all X linked). 8 common missense and nonsense mutations.
- Repetitive stereotyped hand movements, such as wringing
- gastrointestinal disorders
- seizures
- no verbal skills
- 50% of affected individuals do not walk.
- Scoliosis, growth failure, and constipation are also common
Oral-facial-digital syndrome type 1 (X linked dominant)
Malformations of the face, oral cavity, and digits with polycystic kidney disease. Mutation in OFD1 at Xp22.3 - p22.2. Almost exclusively seen in females. Affected females have 1/3 unaffected daughters, 1/3 affected daughters, 1/3 unaffected sons. When an unaffected mother has an affected child, she has a 1% recurrence risk due to germline mosaicism.
Why are X linked dominant disorders often less severe in females?
Skewed X inactivation can attenuate the severity and symptoms. However skewed inactivation can also result in heterozygous females manifesting X linked recessive diseases only seen in males eg haemophilia.
Example of an X-linked dominant male unaffected syndrome
Craniofrontonasal syndrome (CFNS)
How are genes in the PAR inherited?
As autosomal dominant or recessive - these escape X inactivation and both males and females have two copies.
How can you recognise X-linked recessive inheritance?
- mainly males will be affected by the disorder
- female carriers will pass on the disorder to affected sons
- all daughters of an affected male will have the mutation (obligate carriers)
- women who are carriers will have a 50% chance of having affected sons and 50% chance of having carrier daughters.
- affected homozygous females are exceptionally rare.
- affected males are usually born to unaffected parents, usually inherited from a heterozygous unaffected mother (who may have affected male relatives).
- absence of male to male transmission in the pedigree.
- the apparent male to male transmission is due to the father being affected and the mother being a carrier (often generations down in a consanguineous family)
How can a female be affected by an X-linked recessive disorder?
- skewed X inactivation
- a deletion involving the other X chromosome
- X rearrangement or lack of second X ie Turners
- female with two pathogenic sequence changes e.g. compound heterozygote
- UPD of X chromosome
Examples of X linked recessive disorders
- dystrophinopathies e.g.
a) duchenne muscular dystrophy (DMD)
b) becker muscular dystrophy (BMD)
c) DMD associated dilated cardiomyopathy (DCM) - Hereditary haemophilia A and B.
- X linked retinitis pigmentosa (XLRP)
- red/green colour blindness
Duchenne muscular dystrophy
- affects 1 in 3500 male births
- characterised by progressive muscle weakness
- age of onset 2-5yrs, first signs are impaired motor development and delayed milestones (sitting, standing)
- 50% lower IQ than siblings
- DMD is rapidly progressive, with affected children in a wheelchair by age 13.
- common cause of death is cardiomyopathy or respiratory complications in 30s.
Caused by pathogenic variants in the DMD gene on Xp21
Becker muscular dystrophy
- milder form to DMD
- later onset, 20s.
- heart failure is most common cause of death
- mean age of death is 40s
- female heterozygotes are at increased risk of DMD associated cardiomyopathy (DCM)
DMD associated dilated cardiomyopathy
- Severe end of spectrum disease
- dilated cardiomyopathy with congestive heart failure but no skeletal involvement.
- males present between 20-40yrs; female carriers later in life with slower disease progression
How do dystrophinopathies arise?
- caused by pathogenic variant in dystrophin gene at Xp21
- the protein dystrophin is a rod shaped cytoskeletal protein which is essential for sarcolemmal stability in muscle.
- in DMD the protein is virtually absent, whereas in BMD the protein can vary from 20% to virtually normal
- DMD associated cardiomyopathy is caused by mutations in the DMD gene that affect the first exon only, that produce dystrophin in cardiac muscle, however the other promotors for skeletal muscle remain intact.
Dystrophinopathy hotspots
- central regions (exons 44-53) - 80% of deletions occur here
- 5’ regions (exons 2-20) - 20% of deletions occur here
- duplications lead to frameshifts which account for 5-10%
- point mutations, which can occur throughout the entire gene.
What is spinal and bulbar atrophy (SBMA) also known as and what is it?
Kennedy disease
Late onset neuromuscular disease in which degeneration of motor neurons leads to muscle weakness and wasting.
Caused by CAG repeat expansion in exon 1 of androgen receptor gene (affected range >35 repeats, complete penetrance at >38) More repeats, more severe and earlier onset.
Mainly seen in males
Explain the two types of Androgen insensitivity syndrome (AIS) and how its caused.
Pathogenic sequence variations in the androgen receptor gene on Xq11-12
Complete AIS (CAIS)
- complete insensitivity to androgens
- child inherits genitals that are entirely female and are therefore raised as girls
Partial AIS (PAIS) - partial sensitivity to androgens. Level of sensitivity will determine how the genitalia develop
Genetics of hereditary haemophilia A and haemophilia B
Bleeding disorders caused by changes in:
1) coagulation factor VIII (F8) in haemophilia A.
- large gene composed on 26 exons.
- changes include single base substitutions to large insertions and deletions.
- inversions in intron 22 are most common, accounting for 45% of cases.
2) coagulation factor IX (F9) in haemophilia B
- 8 exons
- 90% of cases are based on single base substitution
- pathogenic variants are scattered through the gene
Prevalence of haemophilia A and B
A: 1 in 4000 - 5000 births
B: in in 20,000 births
