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Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.

Incontinentia pigmenti (IP) is an X-linked, dominant genodermatosis usually fatal in utero in males. In rare circumstances, survival is possible due to abnormal karyotype or somatic mosaicism. In this report, the mechanism and significance of loss of detectable mutation in peripheral blood leukocytes of a somatic mosaic male is discussed and an alternative approach to achieving molecular diagnosis presented. A male patient is reported, who initially presented at 2 days of age with a rash and seizure. Clinical assessment and histology of a skin biopsy were consistent with a diagnosis of IP. He was subsequently found to have bilateral retinal detachments. Screening for the common deletion in IKBKG was negative. A novel nonsense variant, c.937C>T (p.Gln313*) in IKBKG was identified at an approximate level of 15% in a blood sample taken at 10 days of age, but was undetectable in a sample taken at 3 years most likely due to selective apoptosis of mutant cells. Samples taken from the patient when he was 5-6 years of age identified the mutation at a low level in hair root and urine but not in blood or buccal cells. The detection of the mutation in cells derived from all germ layers indicates a de novo event at an early stage of embryogenesis. This is the first report of a nonsense mutation in a male IP patient.

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