Smn1 Gene Cis-Configuration Among Parents In A Cohort of Sma Patients – A Cross-Sectional Study

Objective: The majority of patients (93%).with spinal muscular atrophy (SMA) have a homozygous deletion of the SMN1 exon 7. While most carriers have one copy of exon 7, some have two SMN1 copies on one allele (cis-configuration) and none in the other allele. These carriers are missed by screening tests based on exon 7 quantification analyses, and are referred to as "silent" carriers. We investigated the prevalence of cis-configuration genotype among parents of a cohort of SMA patients. Methods: This single-site, cross-sectional study, included SMA patients from the SMA Registry and their parents who consented to perform testing of SMN1 copy number analysis by Multiplex Ligation-dependent Probe Amplification . If the test detected two SMN1 copies, the parent was considered a "silent" carrier. Demographic and clinical parameters were compared between offspring of cis-configuration parents and offspring of non-cis carrier parents (or heterozygote parents). Results: Out of 51 patients with SMA, whose both parents underwent genetic analysis, 12 patients (23%) were born to a previously undetected cis-configuration parent. No clinical differences were found between patients with cis-configuration parents and SMA offspring of non-cis carrier parents. Conclusions: The finding is limited to an affected population, yet it highlights the inability of currently used screening tests to identify silent carriers with two SMN1 copies on one chromosome 5. Until improved population screening for SMA addresses this gap, the adoption/implementation of newborn screening for SMA should be considered, in order to detect affected newborns and enable immediate initiation of disease-modifying therapy.