title: An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York, USA.
authors.forename: Minjie
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York, USA.
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Scott
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York, USA.
authors.forename: Geping
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Northwestern Reproductive Genetics, Chicago, Illinois, USA.
authors.forename: Chevonne
authors.initials: C
authors.lastname: Eversley
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Kornreich
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Edelmann
mesh_terms: D020440:Gene Duplication; D005820:Genetic Testing; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007585:Jews / Q000235:genetics*; D018895:Microsatellite Repeats; D009134:Muscular Atrophy, Spinal / Q000208:ethnology / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*
chemical_list: C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein