1. 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

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
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

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)