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 :

1. dominant

2. 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

• Examples include:

1. Duchenne and Becker Muscular Dystrophy

2. Haemophilia A+B

3. XL-Emery Dreifuss Muscular Dystrophy

4. XL-Adrenoleukodystrophy

5. XL-adrenal hypoplasia congenita

• X-inactivation

•Hemizygosity

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

Disease Male Female

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

• Examples include:

1. Rett Syndrome

2. Incontinentia Pigmenti

3. Coffin Lowry syndrome

4. Epilepsy with mental retardation (EFMR)

•X inactivation

•Male lethality

•Male sparing

•Metabolic interference

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 :

1. GeneReviews and OMIN websites

2. Human Molecular Genetics 3 (Strachan and Read)

3. Introduction to Risk Calculation in Genetic Counselling (Ian Young)