The contribution of X-linked coding variation to severe developmental disorders.

Area of Science:

• Genetics
• Developmental Biology
• Medical Genetics

Background:

• Over 130 X-linked genes are associated with developmental disorders.
• X-linked genetic causes are hypothesized to explain higher developmental disorder rates in males.
• The contribution of X-linked variation to developmental disorders requires further investigation.

Purpose of the Study:

• To evaluate the burden of X-linked coding variation in a large cohort of developmental disorder patients.
• To determine if X-linked variants account for the male bias in developmental disorder prevalence.
• To refine strategies for detecting X-linked developmental disorders and assess variant pathogenicity.

Main Methods:

• Analysis of X-linked coding variation in 11,044 developmental disorder patients.
• Development of an improved strategy for detecting X-linked developmental disorders.
• Estimation of the pathogenicity of inherited rare missense variants in known developmental disorder-associated genes.

Main Results:

• Similar rates of X-linked causes were found in male (6.0%) and female (6.9%) patients, not explaining the male bias.
• An improved detection strategy identified 23 significant X-linked genes, all previously known.
• Only an estimated 13% of inherited rare missense variants in known X-linked developmental disorder genes are likely pathogenic in male probands.

Conclusions:

• X-linked variants do not explain the higher prevalence of developmental disorders in males.
• The majority of the X-linked genetic burden for developmental disorders resides within known associated genes.
• Statistical analysis of large datasets can enhance understanding of inheritance patterns for X-linked disorders.