Rare Cause 5q SMA: Molecular Genetic and Clinical Analyses of Intragenic Subtle Variants in the SMN Locus

Spinal muscular atrophy 5q (5q SMA) is one of the most prevalent autosomal recessive disorders globally. The underlying cause of 5q SMA is attributed to variants in SMN1. Exon 7 of SMN1 is not detectable in major of probands with 5q SMA, and minor of probands have a combination of the deletion and an intragenic subtle variant in the second allele. From 1991 to 2023, DNA samples from 2796 probands representing unrelated families were analyzed at the Research Centre for Medical Genetics for the diagnosis of 5q SMA. The copy number of Exon 7 of SMN1 and SMN2 was determined for all probands by MLPA. Subsequently, direct automated Sanger sequencing was employed to perform intragenic subtle variant screenings in all 116 probands with one copy of Exon 7 of SMN1. The diagnosis of 5q SMA was confirmed in 1495 probands. Among the 41 probands with one copy of Exon 7 of SMN1 from the initial 116 tested, 24 intragenic subtle variants in SMN1/SMN2 were documented. The aim of this study was to identify and characterize intragenic subtle variants in SMN1 and analyze their relationship with clinical manifestations in probands with 5q SMA in the Russian cohort.