Rare homozygous disease-associated sequence variants in children with spinal muscular atrophy: a phenotypic description and review of the literature.

5q-associated spinal muscular atrophy (SMA) is the most common autosomal recessive neurological disease. Depletion in functional SMN protein leads to dysfunction and irreversible degeneration of the motor neurons. Over 95 % of individuals with SMA have homozygous exon 7 deletions in the SMN1 gene. Most of the remaining 4-5 % are compound heterozygous for deletion and a disease-associated sequence variant in the non-deleted allele. Individuals with SMA due to bi-allelic SMN1 sequence variants have rarely been reported. Data regarding their clinical phenotype, disease progression, outcome and treatment response are sparse. This study describes six individuals from three families, all with homozygous sequence variants in SMN1, and four of whom received treatment with disease-modifying therapies. We also describe the challenges faced during the diagnostic process and intrafamilial phenotypic variability observed between siblings.

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Copyright © 2024. Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Declaration of competing interest EMY has received advisory board honoraria from Biogen and Roche and has received research support from Biogen, Roche, Pfizer and PTC therapeutics unrelated to the content of this manuscript. MPM has received advisory board honoraria from Biogen unrelated to the content of this manuscript. IRW has received honoraria for work performed including educational activities and attendance at advisory board meetings from Biogen, Novartis, Roche and Avidity and an educational travel bursary to attend an international conference in 2016 from Biogen. IRW has received grants for research work from FSHD Global Research Foundation, FSHD Society and Fulcrum Therapeutics. None of these disclosures were related to the content of this manuscript.