Accelerating Novel Candidate Gene Discovery in Neurogenetic Disorders via Whole-Exome Sequencing of Prescreened Multiplex Consanguineous Families

Abstract

Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

“…7,10 This prompted us to examine the yield of this approach for dysmorphology syndromes in the same setting, i.e., multiplex consanguineous families. Another reason for limiting our study to multiplex families is that the presence of more than one affected individual with the same apparently novel phenotype facilitates the recognition of the core phenotypic features of the syndrome, notwithstanding the known phenomenon of clinical variability.…”

“…For both whole-exome and whole-genome sequencing, the candidacy of the resulting variants was based on their physical location within the autozygome of the affected individual, their population frequency, and the predicted effect on the protein as described previously. 10,14 …”

“…16 In 67% (21/31) of families, the strong candidate variant was identified in a gene that was novel at the time of analysis. These include 11 genes that we published previously 10 and 10 that we describe for the first time here ( Table 2).…”

“…[7][8][9] Recently, we published the identification of 33 novel candidate genes for various neurocognitive phenotypes, and at least 6 of these were independently found to be mutated by other investigators in the few months since the article appeared online (unpublished data). 10 However, we are not aware of any similar effort to accelerate the discovery of novel candidate genes specifically in the setting of dysmorphology syndromes. In this article, we describe our experience with members of 31 multiplex consanguineous families who appeared to have novel dysmorphology syndromes at the time of their initial evaluation; 15 of them are reported here for the first time.…”

Novel genetic causes for cerebral visual impairment

“…[14][15][16][17][18][19][20] In addition, WES has also shown to be a powerful tool for identifying autosomal-recessive and X-linked variants in persons with ID. [19][20][21][22][23][24] Here we used WES to identify underlying genetic causes for CVI.…”