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Rare Genetic Variation in 135 Families With Family History Suggestive of X-Linked Intellectual Disability


Rare Genetic Variation in 135 Families With Family History Suggestive of X-Linked Intellectual Disability

Alba Sanchis-Juan et al. Front Genet.


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.

Keywords: Mendelian disease; X-linked; autosomal dominant; intellectual disability; mosaicism; next-generation sequencing.


Figure 1
Figure 1
(A) Relationships within the studied families. (B) Number of individuals sequenced with each NGS technology by pathogenicity of the variant. (C) Total number of variants by mode of inheritance and pathogenicity scores (including SNVs/indels and CNVs). (D) Number of unique per family reported variants by type and consequence. WES, whole-exome sequencing; TS, targeted sequencing; WGS, whole-genome sequencing; AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.
Figure 2
Figure 2
(A) Outline of the number of reported variants identified in the studied cohort. Families with reportable variants are separated in three categories: (1) number of families where affected members have the same variant (same); (2) number of families where only one family member has a variant (one); and (3) number of families where both affected individuals had different variants (different). (B) Number of families are showed by mode of inheritance of the variant/s. AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.

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