A homozygous double mutation in SMN1: a complicated genetic diagnosis of SMA

Abstract Spinal muscular atrophy ( SMA ), the most common autosomal recessive cause of infant death, is typically diagnosed by determination of SMN 1 copy number. Approximately 3–5% of patients with SMA retain at least one copy of the SMN 1 gene carrying pathogenic insertions, deletions, or point mutations. We report a patient with SMA who is homozygous for two mutations carried in cis : an 8 bp duplication (c.48_55dup GGATTCCG ; p.Val19fs*24) and a point mutation (c.662C>T; p.Pro221Leu). The consanguineous parents carry the same two mutations within one SMN 1 gene copy. We demonstrate that a more accurate diagnosis of the disease is obtained through a novel diagnostic assay and development of a capillary electrophoresis method to determine the copy number of their mutant alleles. This illustrates the complexity of SMN mutations and suggests additional testing (gene sequencing) may be appropriate when based on family lines.