A Comprehensive Analysis of Allele Frequencies From 476,930 Spinal Muscular Atrophy Test Results [23M

Abstract

INTRODUCTION: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by homozygous deletion of the SMN1 gene. Disease severity is related to the copy number of the highly homologous, yet functionally insufficient, pseudogene SMN2. SMA has no cure; but prognosis improves if treatment is started early in life, with the most significant gains observed when initiated pre-symptomatically. Delay in genetic confirmation of diagnosis may be a barrier to early treatment, therefore we sought to evaluate our historical SMA testing data. METHODS: We performed a blinded review of carrier (n=460,703) and diagnostic (n=16,227) tests submitted over a 15-year period across 4 testing sites in a US population. Allele frequencies of SMN1 and SMN2 were determined for all diagnostic and carrier SMA test results in respect to available patient demographics such as sex and age at the time of testing. RESULTS: The observed SMA carrier frequency was 1:53, decreased from the commonly cited rate of 1:35-1:40, but within range of previous studies. In affected individuals, age at time of testing correlate to SMN2 copy number and aligns with a delay in disease presentation with increased SMN2 copies. CONCLUSION: Early diagnosis and treatment of SMA is critical in order to maximize the positive impact on patient quality of life and life expectancy. These data suggest a potential delay in genetic diagnosis of SMA and, therefore, would correlate to a lag in treatment course initiation. Broad implementation of newborn screening programs and timely confirmatory testing will likely improve service to the SMA community.