Genetic risk assessment in carrier testing for spinal muscular atrophy.
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.
Molecular Pathology Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.
Shuji
S
Ogino
Debra G B
DG
Leonard
Hanna
H
Rennert
Warren J
WJ
Ewens
Robert B
RB
Wilson
D000483:Alleles; D017362:Cyclic AMP Response Element-Binding Protein; D004247:DNA / Q000235:genetics; D018628:Gene Dosage; D005787:Gene Frequency; D006580:Genetic Carrier Screening / Q000379:methods*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D016601:RNA-Binding Proteins; D018570:Risk Assessment; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein
D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein; D004247:DNA