Identity-by-descent 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 have determined that the 78 kb 8q24.3 insertion at chromosome Xq27.1 arose in a common ancestor of three CMTX3 families. We genetically linked the three families by 6th and 7th degree relatives (second cousins ​​once removed and third cousins ​​respectively) and identified a 4.42 cM region shared identically by descent over Xq27.1 in all 16 affected individuals. Confirming a founder event in these families is unsurprising, as such a large DNA rearrangement is unlikely to have arisen independently in three families, especially considering the three families originate from either the United Kingdom, New Zealand or Australia; countries with a common largely Anglo-Celtic heritage.

More than 80 genes have been implicated in CMT to date yet ~20% of CMT cases have no known genetic cause of disease [1, 8]. This is in part due to the clinical and genetic heterogeneity of CMT, the rarity of disease, and limitations in gene discovery pipelines to uncover complex genetic variants, such as structural rearrangements, as opposed to more readily identified missense variants and small insertions and deletions [8]. These challenges are also observed in other neurological and neurodegenerative disorders, including amyotrophic lateral sclerosis, autism spectrum disorder, epilepsy encephalopathy, and intellectual disability, where a genetic cause of disease remains unknown in a large fraction of cases despite heredity studies implicating a larger genetic contribution two diseases [9,10,11,12].

Linkage analysis and genome-wide association studies combined with next-generation sequencing have been successful in uncovering genetic variants implicated in these disorders. However, these methodologies have exhausted highly penetrant multi-generational families and large case-control cohorts, with alternative techniques required to solve more challenging low-penetrant families and disorders caused by rare variants. IBD mapping represents a complementary strategy that is appropriate for both familial and sporadic disease cohorts of all sizes as it can uncover cryptic relatedness to create extended families, and subsequently implicate candidate disease loci for gene discovery efforts. Here we show in CMTX3, where the causal variant was known, IBD mapping successfully confirmed a founder effect. In individuals with no known genetic cause of disease, IBD mapping can implicate new genetic loci and represents a promising technique to shed light on the missing heritability in CMT and other neurological and neurodegenerative disorders.

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