Genetic risk assessment in carrier testing for spinal muscular atrophy

Authors

  • Shuji Ogino,

    1. Molecular Pathology Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
    Current affiliation:
    1. Department of Pathology, Brigham and Woman's Hospital, Harvard Medical School, Boston, Massachussetts.
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  • Debra G.B. Leonard,

    1. Molecular Pathology Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
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  • Hanna Rennert,

    1. Molecular Pathology Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
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  • Warren J. Ewens,

    1. Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Robert B. Wilson

    Corresponding author
    1. Molecular Pathology Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
    • University of Pennsylvania, Department of Pathology and Laboratory Medicine, Room 509A Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104.
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Abstract

As evidenced by the complete absence of a functionally critical sequence in exon 7, approximately 94% of individuals with clinically typical spinal muscular atrophy (SMA) lack both copies of the SMN1 gene at 5q13. Hence most carriers have only one copy of SMN1. Combining linkage and dosage analyses for SMN1, we observed unaffected individuals who have two copies of SMN1 on one chromosome 5 and zero copies of SMN1 on the other chromosome 5. By dosage analysis alone, such individuals, as well as carriers of non-deletion disease alleles, are indistinguishable from non-carrier individuals. We report that approximately 7% of unaffected individuals without a family history of SMA have three or four copies of SMN1, implying a higher frequency of chromosomes with two copies of SMN1 than previously reported. We present updated calculations for disease and non-disease allele frequencies and we describe how these frequencies can be used for genetic risk assessment in carrier testing for SMA. © 2002 Wiley-Liss, Inc.

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