Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMN(T) and SMN(C) gene copy number

Abstract

The survival motor neuron (SMN) transcript is encoded by two genes, SMN(T) and SMN(C). The autosomal recessive proximal spinal muscular atrophy that maps to 5q12 is caused by mutations in the SMN(T) gene. The SMN(T) gene can be distinguished from the SMN(C) gene by base-pair changes in exons 7 and 8. SMN(T) exon 7 is not detected in ~95% of SMA cases due to either deletion or sequence-conversion events. Small mutations in SMN(T) now have been identified in some of the remaining nondeletion patients. However, there is no reliable quantitative assay for SMN(T), to distinguish SMA compound heterozygotes from non-5q SMA-like cases (phenocopies) and to accurately determine carrier status. We have developed a quantitative PCR assay for the determination of SMN(T) and SMN(C) gene-copy number. This report demonstrates how risk estimates for the diagnosis and detection of SMA carriers can be modified by the accurate determination of SMN(T) copy number.