An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy

Purpose: Spinal muscular atrophy is a common autosomal-recessive disorder caused by mutations of the SMN1 gene. Spinal muscular atrophy carrier screening uses dosage-sensitive methods that determine SMN1 copy number, and the frequency of carriers varies by ethnicity, with detection rates ranging from 71 to 94% due to the inability to identify silent (2 + 0) carriers with two copies of SMN1 on one chromosome 5 and deletion on the other. We hypothesized that identification of deletion and/or duplication founder alleles might provide an approach to identify silent carriers in various ethnic groups. Methods: SMN1 founder alleles were investigated in the Ashkenazi Jewish population by microsatellite analysis and next-generation sequencing. Results: An extended haplotype block, specific to Ashkenazi Jewish SMN1 duplications, was identified by microsatellite analysis, and next-generation sequencing of SMN1 further defined a more localized haplotype. Of note, six novel SMN1 sequence variants were identified that were specific to duplications and not present on single-copy alleles. The haplotype was also identified on SMN1 duplication alleles in additional ethnic groups. Conclusion: Identification of these novel variants in an individual with two copies of SMN1 significantly improves the accuracy of residual risk estimates and has important implications for spinal muscular atrophy carrier screening.