Abstract
Families with multiple male children with intellectual disability (ID) are usually suspected of having disease due to a X-linked mode of inheritance and genetic studies focus on analysis of segregating variants in X-linked genes. However, the genetic cause of ID remains elusive in approximately 50% of affected individuals. Here, we report the analysis of next-generation sequencing data in 274 affected individuals from 135 families with a family history suggestive of X-linked ID. Genetic diagnoses were obtained for 19% (25/135) of the families, and 24% (33/135) had a variant of uncertain significance. In 12% of cases (16/135), the variants were not shared within the family, suggesting genetic heterogeneity and phenocopies are frequent. Of all the families with reportable variants (43%, 58/135), we observed that 55% (32/58) were in X-linked genes, but 38% (22/58) were in autosomal genes, while the remaining 7% (4/58) had multiple variants in genes with different modes on inheritance. This study highlights that in families with multiple affected males, X linkage should not be assumed, and both individuals should be considered, as different genetic etiologies are common in apparent familial cases.
Highlights
Mendelian types of intellectual disability (ID) were first identified by documenting familial forms of the disease that had an X-linked mode of inheritance
With the availability of next-generation sequence (NGS) analysis, the systematic identification of de novo mutagenesis through trio analysis, and the increasing recognition of autosomal recessive causes of neurodevelopmental disease, the opportunity arises to re-evaluate the mechanisms of disease in families with affected individuals ascertained with the clinical assumption of X-linked disease
The Copy number variants (CNV) were at known loci, previously reported to be associated with developmental delay, ID, or schizophrenia (Figure 1D)
Summary
Mendelian types of intellectual disability (ID) were first identified by documenting familial forms of the disease that had an X-linked mode of inheritance. With the availability of next-generation sequence (NGS) analysis, the systematic identification of de novo mutagenesis through trio analysis, and the increasing recognition of autosomal recessive causes of neurodevelopmental disease, the opportunity arises to re-evaluate the mechanisms of disease in families with affected individuals ascertained with the clinical assumption of X-linked disease. To this end, we aimed to assess the contribution of genetic variation to disease in 274 individuals from 135 non-consanguineous families with suspected X-linked mode of inheritance. We studied families with multiple affected individuals with unexplained, moderate to severe non-syndromic ID using multiple NGS technologies
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