Spinal muscular atrophy among US Hutterites: Phenotype variability in the setting of conserved ancestral haplotype and 4 SMN2 copies

Purpose Ideal timing and treatment in asymptomatic newborns with 4 SMN2 copies remains controversial. We examined phenotypic variability among the Hutterite population with spinal muscular atrophy (SMA) and higher SMN2 dosage. Methods We enrolled individuals with SMA and children born to couples with 1 copy of SMN1 in South Dakota and Montana Hutterite communities in a natural history study that included a focused medical history and genomic screening for SMN1 deletion(s) and SMN2 copy number. Results Of the 215 Hutterite individuals enrolled, 75 carried at least 1 SMN1 deletion allele with >2 SMN2 copies. All 21 affected individuals (8 months to 41 years) had 0 SMN1 and 4 SMN2 copies but not the modifying variants SMN2 c.859G>C and SMN2 c.-44A>G . Clinical diagnoses of SMA type 3a ( N = 14), SMA type 3b ( N = 6), or SMA type 4 ( N = 1) were determined based on age of onset and maximum achieved motor function. Conclusion Although age of onset was highly variable (10 months to 25 years), most individuals presented in early childhood, indicating a need to identify biomarkers that can more accurately predict outcomes to help guide treatment intervention. This study also provides strong evidence supporting early implementation of therapies for patients with SMA with 4 copies of SMN2 .