Skewed X-chromosome Inactivation in Unsolved Neurodevelopmental Disease Cases Can Guide Re-evaluation for X-linked Genes

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Abstract Despite major technical and genetic advances, more than half of the neurodevelopmental disorders (NDDs) cases remain undiagnosed. We explored the frequency of non-random XCI in the mothers of male patients and in affected females from a clinically heterogeneous cohort of unsolved NDD cases, negative at FRAXA, chromosomal microarray analysis and Trio Exome Sequencing. We hypothesize that an unbalanced XCI could unmask previously discarded genetic variants on the X chromosome connected both to XCI and NDD. A multiplex fluorescent-PCR-based assay was used to screen the XCI pattern after methylation sensitive HhaI digestion. Trio-based ES re-analysis was performed in families with skewed XCI occurrence. Linkage analysis and RT-PCR were used to further study the X-chromosome inactive allele. X-drop was used to define the chromosome deletion boundaries. We found a skewed XCI (>90%) in 16/186 mothers of affected NDD males (8.6%) and 12/90 female patients (13.3%), far beyond the expected XCI in normal population (3.6%, OR=4.10; OR=2.51). Reanalyzing ES and clinical data, we solved 7/28 cases (25%). These included variants in the KDM5C, PDZD4, PHF6, TAF1, OTUD5, and ZMYM3, and a genomic deletion spanning exons 3-4 of the ATRX gene. The identification of a skewed XCI is an easy assay that can help selecting a subgroup of patients for the re-evaluation of X-linked variants, improving the diagnostic yield in NDD patients, and allowing the identification of new X-linked disorders.

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