DIAGNOSIS OF SPINAL MUSCULAR-ATROPHY IN AN SMN NONDELETION PATIENT USING A QUANTITATIVE PCR SCREEN AND MUTATION ANALYSIS

We report a child with clinical findings consistent with Werdnig-Hoffm ann disease (spinal muscular atrophy type I) who was found not to have the homozygous absence of the survival motor neurone (SMNT) gene obse rved in similar to 95% of spinal muscular atrophy patients. A quantita tive PCR based dosage assay for SMNT copy number showed that this pati ent possessed a single copy of the SMNT gene. Heteroduplex and sequenc e analysis of the remaining copy of SMNT showed a 2 base pair deletion within exon 4 which produces a frameshift and premature termination o f the deduced SMNT protein. This protocol of initial SMNT gene dosage analysis followed by mutation detection allows identification of SMA c ompound heterozygotes (patients lacking one copy of SMNT and having an other mutation in their other copy), thereby increasing the sensitivit y of SMA molecular diagnosis.