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Identity-by-descendancy analysis of CMTX3 links three families through a common founder

In the absence of large historical pedigrees, genetic data can be successfully used to uncover cryptic relatedness between families and confirm founder effects. Using genome-wide genotype data coupled with IBD algorithms, we determined that the 78 kb insertion 8q24.3 on chromosome Xq27.1 arose in a common ancestor of three CMTX3 families. We genetically linked the three families through 6th and 7th degree relatives (one-time distant second cousins ​​and third cousins ​​respectively) and identified an identical shared 4.42 cM region by descent on Xq27. 1 in the 16 affected individuals. Confirming a founding event in these families is not surprising, as it is unlikely that such a large DNA rearrangement would have occurred independently in three families, especially since all three families originated in the UK, from New Zealand or Australia; country with a common largely Anglo-Celtic heritage.

More than 80 genes have been implicated in CMT to date, but approximately 20% of CMT cases have no known genetic cause for the disease [1, 8]. This is in part due to the clinical and genetic heterogeneity of CMT, the rarity of the disease, and the limitations of gene discovery pipelines to uncover complex genetic variants, such as structural rearrangements, as opposed to spurious variants. -meaning more easily identified and to small insertions and deletions. [8]. These challenges are also seen in other neurological and neurodegenerative disorders, including amyotrophic lateral sclerosis, autism spectrum disorders, epileptic encephalopathy and intellectual disability, where a genetic cause of the disease remains unknown in a large proportion of cases. despite studies of heredity implying a greater genetic contribution. to illness [9,10,11,12].

Linkage analysis and genome-wide association studies combined with next-generation sequencing have successfully uncovered genetic variants implicated in these disorders. However, these methodologies have exhausted high-penetrating multigenerational families and large case-control cohorts, with alternative techniques needed to address more difficult low-penetrating families and disorders caused by rare variants. IBD mapping represents a complementary strategy that is suitable for familial and sporadic disease cohorts of all sizes, as it can uncover a cryptic relationship to create extended families, and then implicate candidate disease loci for gene discovery efforts. Here we show in CMTX3, where the causative variant was known, IBD mapping successfully confirmed a founder effect. In people with no known genetic cause of the disease, mapping of IBD may involve novel genetic loci and represents a promising technique to shed light on missing heritability in CMT and other neurological and neurodegenerative disorders.