Xlinked inheritance Oliver Quarrell Lecture Plan Lyon hypothesis

X-linked inheritance Oliver Quarrell

Lecture Plan • • • Lyon hypothesis X linked recessive males do not reproduce X linked recessive males reproduce X linked dominant lethal in males Main example will be Duchenne muscular dystrophy • Options for a female carrier

Sex-linked inheritance • Genes carried on the X chromosome. • More males than females affected. • Females are carriers. 50% sons affected. 50% daughters are carriers. • All daughters of affected males are carriers. • None of the offspring of affected males have the disorder. • Possibility of new mutations. • Gonadal mosaicism may occur. • Influenced by X inactivation.

Lyon hypothesis • • X-chromosome inactivation Occurs early in embryogenesis Random process Once occurred cells from subsequent cell divisions inactivate the same Xchromosome • There are some rare mechanisms which result in non-random X-inactivation

X-Linked Inheritance X Y X X

Muscular dystrophy • “please see this lady who has a relative affected by muscular dystrophy” • WHICH ONE • Beware of umbrella terms • In this lecture we are focusuing on the xlinked forms Duchenne and Becker • Comment on NHS choices website

Scenario • A lady presents to ante-natal clinic • Her brother had Duchenne muscular dystrophy • Her uncle died of muscular dystrophy age 21 he was in wheelchair. • Her mother must be a carrier

Summary of clinical problem

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Gower’s Sign • Proximal muscle weakness • Have to climb up legs

Duchenne Muscular dystrophy • • • Affects males May have delayed walking or running Progressive weakness – waddling gait Treatment steroids and later ventilatory support Wheelchair Die of respiratory failure Do not reproduce Raised creatine kinase muscle enzyme 70% deletion in dystrophin gene

What is the chance of an affected son?

1 in 2 chance she is a carrier

1 in 2 chance she is a carrier 1 in 4 chance of affected male

Management • Normal CK reduces chance of her being carrier but does not exclude it LYONISATION • Identify deletion in brother test pregnant lady • Look for point mutation • No deletion or point mutation found do a linkage analysis

New mutations • Males do not reproduce • To maintain prevalence in population need new mutations • In an isolated case 1/3 cases are new mutations • Consider an isolated case

Clinical Problem • May be a new mutation • Mother may be a carrier • May be gonadal mosaicism • Sister may or may not be a carrier • Daughter may or may not be a carrier

Management • • Normal CK of limited value 70% chance of identifying deletion in boy Rises to over 90% point muations If mother not a carrier cannot exclude gonadal mosaicism • Residual risk to daughter

Deletion absent Deletion present May be gonadal mosaicism No need to test sister But offer carrier test to daughter when she is 16 +

Primordial germ cell Egg

Deletion present Mother is a carrier have to offer to test mother and sister Offer carrier test to daughter when she is 16 +

New scenario daughter is a carrier. What are her options? Deletion present

Options for a carrier female • Not have any children • Accept the risk and have children • Have pre-natal diagnosis (PND) and consider TOP of affected male fetus • Consider pre-implantation genetic diagnosis PGD

Prenatal diagnosis • Option of free fetal DNA at 9 weeks • Some genetic material from the fetus circulates in the mother blood. • If Y chromosome material assume it is male • If no Y chromosome material assume it is female • Error rate 4 cases in 1000

Invasive test • • Chorion biopsy From 11 weeks Take sample from placental bed Risk of misc ~ 1 - 2% • Can do an amniocentesis but from 15 weeks and have to grow the cells • Risk misc ~1%

Chorion Biopsy

Success rate at outset 20% Success rate at embryo transfer ~30%

What happens if male can reproduce • Becker Muscular dystrophy • Haemophilia A or B

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X-Linked Inheritance X X Y X C C C

X-linked dominant • What happens to females if the condition is X-linked dominant?

What happens if the mutation is extremely deleterious • X-linked dominant lethal in males • Males die in utero • Females survive because they are mosaics

X chromosome and disease in females DMD Most carriers Normal Fragile X Affected females Intellectual impairment IP Retts Lethal in most males

Incontinentia Pigmenti • X-linked dominant lethal in males • Can see the Lyonisation

Sex-linked inheritance • Genes carried on the X chromosome. • More males than females affected. • Females are carriers. 50% sons affected. 50% daughters are carriers. • All daughters of affected males are carriers. • None of the offspring of affected males have the disorder. • Possibility of new mutations. • Gonadal mosaicism may occur. • Influenced by X inactivation.