Vikki Moye, November 2007

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

2. 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

3. 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

4. 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

5. 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

6. 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

7. Examples of presentation XL recessive diseases in males versus females

8. 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)

9. 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

10. 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

11. 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

12. 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)

13. 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

14. 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

15. 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.

16. 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

17. 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

18. 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)