Outline the patterns of inheritance associated with X-linked genes Outline the patterns of inheritance associated with X-linked genes. Where possible give a molecular explanation for the pattern. Vikki Moye, November 2007

X-linked inheritance When a gene for particular disease/trait lies on the X chromosome it is X-linked Males = XY (X from mother, Y from father) Females = XX (1 X from mother, 1 X from father) X-linked genes are NEVER passed from father to son In an affected family affected females must have an affected father Males are hemizygous for x-linked traits Males are never carriers A single dose of mutant allele in a male will produce a mutant phenotype regardless of whether it is dominant or recessive

Dominant or recessive? X-linked inheritance can be described theoretically as either : dominant recessive However: Random / non random x-inactivation blurs the distinction between dominant and recessive

X-inactivation Unfavourable skewing can cause female carriers to be affected X-inactivation causes dosage of X-linked genes to be equalised between XX and XY Inactivation is presumed to be permanent Skewed x-inactivation defined as >80% of X chromosomes showing preferential inactivation of one chromosome After 55 years level of skewing increases in peripheral blood cells Consistent relationship between pattern of X-inactivation and clinical phenotype has been difficult to demonstrate Peripheral blood cells are not representative of affected tissue

X-linked recessive diseases X-inactivation Hemizygosity Examples include: Duchenne and Becker Muscular Dystrophy Haemophilia A+B XL-Emery Dreifuss Muscular Dystrophy XL-Adrenoleukodystrophy XL-adrenal hypoplasia congenita

X-linked recessive diseases Disease is typically passed from an affected grandfather through carrier daughters to half of his grandsons Males are much more likely to be affected Due to male hemizygosity (no backup copy of the gene on the second X chromosome) Females are mosaics for mutant and normal X chromosomes. Normally show an intermediate phenotype which is clinically unaffected or very mildly affected but biochemically abnormal Females can be severely affected when there is heavily skewed X-inactivation inactivating the majority of the normal X chromosomes

Examples of presentation XL recessive diseases in males versus females XL-EDMD Joint contracture, muscle wasting and cardiac involvement Asymptomatic / Cardiac involvement DMD Progressive muscle wasting, proximal weakness (wheelchair bound by 12), cardiomyopathy Cardiomyopathy Haemophilia B Spontaneous joint bleeding, prolonged bleeding after injuries 10% show mild bleeding abnormalities

X-linked dominant inheritance X inactivation Male lethality Male sparing Metabolic interference Examples include: Rett Syndrome Incontinentia Pigmenti Coffin Lowry syndrome Epilepsy with mental retardation (EFMR)

Autosomal or XL dominant Examine the offspring of an affected male and normal female…. If affected male has an unaffected son and…. all of his daughters are affected …. The disease is X-linked

X-linked dominant All daughters of an affected male and normal female are affected One X chromosome has to come from the father All sons of an affected male and normal female are unaffected Father contributes the Y chromosome 50% of the offspring of an affected female and unaffected male will be affected In the general population females are more likely to be affected than males (2:1) Females have 2 X chromosomes either of which could carry the mutant allele

X-inactivation involvement In XL dominant disorders males are generally more severely affected than females. For example Coffin-Lowry syndrome manifests as severe to profound mental retardation in males Carrier females can manifest as normal or profoundly mentally retarded X-inactivation determines this: If X inactivation is severely skewed so that the majority of normal chromosomes are inactivated the phenotype will be more severe

Male lethality Some X-linked dominant disorders are so severe that male survival is rare Incontinentia pigmenti Majority of males spontaneously abort after the first trimester Live born males are generally XXY or have somatic mosaicism Retts syndrome Males who inherit the MECP2 mutation suffer severe neonatal encephalopathy or if they survive will have severe mental retardation syndrome (more severe than Retts)

Male sparing Some XL-dominant diseases show male sparing transmission though unaffected or very mildly affected males. Examples include craniofrontonasal dysplasia (CFND) and epilepsy with mental retardation (EFMR) No risk to males from transmitting males Males contribute a Y chromosome to males Female offspring of transmitting males are at almost 100% risk of being affected 1 X chromosome will have to come from the father From affected females there is a 50% risk that female offspring will affected and male offspring will be an unaffected transmitting male A mother will pass either one of her X chromosomes to a daughter or son Male sparing is possibly caused by metabolic interference or cellular interference

Metabolic and cellular interference Metabolic interference: Two alleles A and A’, code for slightly different subunits of a protein Homozygotes / hemizygotes for A and A’ have normal phenotype Heterozygotes AA’ affected phenotype, The different protein products from A and A’ are thought to interact to produce a harmful effect Cellular interference Dominant negative mutations Product of mutant allele interferes with the function or product of the wildtype allele Possibly leads to the formation of an abnormal multimeric protein

Pseudoautosomal inheritance The X and Y chromosomes have a region of homology (2.6 Mb) on the tips of their short arms The pseudoautosomal region Genes in this region: have homologous copies on the X and Y chromosomes Are not subject to X-inactivation (as expected) Do not show usual X or Y linked patterns of inheritance but segregate like autosomal alleles SHOX-related haploinsufficiency disorders range from Leri-Weill dyschondrosteosis (LWD) at the more severe end of the spectrum to SHOX-related short stature at the mild end of spectrum Caused by deletion / point mutation or other chromosomal disruption of one of the SHOX genes on either the X or Y chromosome Inheritance of this group of disorders follows classic autosomal dominant inheritance.

Some final caveats that affect patterns of X-linked inheritance Many X-linked diseases can be caused by de-novo mutations or germline mosaicism in a parent 99.5% of Rett syndrome cases are caused by de novo mutations or germline mosaicism 33% of DMD cases are due to de novo mutations / germline mosaicism Biological fitness to reproduce: When the disease is so severe that affected females do not reproduce it is difficult to conclude that a disease is X-linked Male lethality UP

Some final caveats that affect patterns of X-linked inheritance Many X-linked diseases can be caused by de-novo mutations or germline mosaicism in a parent 99.5% of Rett syndrome cases are caused by de novo mutations or germline mosaicism 33% of DMD cases are due to de novo mutations / germline mosaicism Biological fitness to reproduce: When the disease is so severe that affected females do not reproduce it is difficult to conclude that a disease is X-linked Male lethality UPD of XY (both from father) will show male-male transmission of x-linked disorder There are rare reports of male-male transmission of Haemophilia

References: Most of the information in this presentation has been obtained from : GeneReviews and OMIN websites Human Molecular Genetics 3 (Strachan and Read) Introduction to Risk Calculation in Genetic Counselling (Ian Young)