First combined analysis of SMN1, SMN2, and NAIP copy numbers in Moroccan SMA patients and their correlation with disease severity

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused in 95% of cases by homozygous SMN1 exon 7 deletion, with severity primarily determined by the modifier genes SMN2 and NAIP copy numbers. This study, the first in the Moroccan population, simultaneously analyzed SMN1 , SMN2 , and NAIP copy numbers to investigate their relationship with SMA severity and their utility in predicting patients' phenotype. RFLP-PCR was used to screen 214 patients for SMN1 exon 7 homozygous deletion. In patients with confirmed SMA, copy number variations (CNVs) of SMN1 , SMN2 , and NAIP were analyzed by MLPA. SMN1 exon 7 was deleted in 27% (58/214) of patients. Among those analyzed by MLPA (32/58), 75% (24/32) also carried an SMN1 exon 8 deletion. SMN2 exon 7 copy number ranged from 2 to 4, with lower copies correlating with greater disease severity. NAIP exon 5 deletion was primarily seen in type I SMA. Combined SMN1 – SMN2 – NAIP genotypes showed that 80% of type I patients (8/10) had 2 SMN2 copies and 0 NAIP ; 66.7% of type II (4/6) had 3 SMN2 copies and ≥ 1 NAIP ; and 75% of type III (12/16) had either 3 SMN2 copies with 1–2 NAIP or 4 SMN2 copies with variable NAIP status. This study demonstrated an inverse correlation between SMN2 and NAIP copy numbers and SMA severity. Combined SMN1 – SMN2 – NAIP genotypes provided stronger predictive insights on disease severity than individual gene copy number. Implementing CNV analysis of these genes in Morocco could enhance SMA severity prediction and support genetic counseling.