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

Minjie Luo, Liu Liu, Inga Peter, Jun Zhu, Stuart A. Scott, Geping Zhao, Chevonne Eversley, Ruth Kornreich, Robert J. Desnick, Lisa Edelmann

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)149-156
Number of pages8
JournalGenetics in Medicine
Volume16
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

Keywords

  • Ashkenazi Jewish
  • population screening
  • spinal muscular atrophy

Fingerprint

Dive into the research topics of 'An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy'. Together they form a unique fingerprint.

Cite this