X-linked inheritance Oliver Quarrell

Lecture Plan Lyon hypothesis X linked recessive males do not reproduce X linked recessive males reproduce X linked dominant 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 X-chromosome There are some rare mechanisms which result in non-random X-inactivation

X-Linked Inheritance X X X Y

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 x-linked 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

www.neuro.wustl.edu/.../ pathol/dmdpath.htm

www.neuro.wustl.edu/.../ pathol/dmdpath.htm

www.mja.com.au/.../ byr10494_fm.html

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?

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

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 mutations If mother not a carrier cannot exclude gonadal mosaicism Residual risk to daughter

May be gonadal mosaicism No need to test sister 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

Mother is a carrier have to offer to test mother and sister Deletion present 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 Deletion present Deletion present

Options for a carrier female Not have any children Accept the risk and have children Have a blood sample at 7-9 weeks for free fetal DNA 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 less than 1%

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

www.neuro.wustl.edu/.../ pathol/dmdpath.htm

X-Linked Inheritance X X X Y 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 Fragile X Affected females Intellectual impairment DMD Most carriers Normal 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.