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During the expanded neonatal screening program conducted in 2023, we analyzed samples obtained from 1,227,130 out of 1,256,187 newborns in the Russian Federation in order to detect 5q spinal muscular atrophy (5q SMA). Within the 253-sample risk group formed based on the results of the first screening stage, 5 samples showed a discrepancy between the examination results obtained via various screening methods and quantitative MLPA (used as reference). The discrepancy between the results was caused by the presence of either a c.835-18C>T intronic variant or a c.842G>C p.(Arg281Thr) missense variant in the SMN1 gene, both of which are located in the region complementary to the sequences of annealing probes for ligation and real-time PCR. Three newborns had the c.835-18C>T variant in a compound heterozygous state with a deletion of exons 7–8 of the SMN1 gene, one newborn with two copies of the SMN1 gene had the same variant in a heterozygous state, and one newborn had both variants—c.835-18C>T and c.842G>C p.(Arg281Thr)—in a compound heterozygous state. Additional examination was carried out for these variants, involving segregation analysis in families, carriage analysis in population cohorts, and RNA analysis. Based on the obtained results, according to the ACMG criteria, the c.835-18C>T intronic variant should be classified as likely benign, and the c.842G>C p.(Arg281Thr) missense substitution as a variant of uncertain clinical significance. All five probands are under dynamic monitoring. No 5q SMA symptoms were detected in these newborns neonatally or during a 1-year follow-up period. [ABSTRACT FROM AUTHOR]

Laminopathies are a broad spectrum of hereditary diseases caused by pathogenic variants of the LMNA gene. Such phenotypic diversity is explained by the function of intermediate filaments encoded by the LMNA gene. We examined a family with an overlapping phenotype of cardiac arrhythmia, cardiomyopathy, limb–girdle muscular dystrophy, and partial lipodystrophy. The cause of the disorder was a novel LMNA(NM_170707.4):c.1488+2T>C variant. The analysis of mRNA extracted from the probands' blood showed a multitude of alternative splicing products, which was the cause of the complex phenotype in affected family members. Aside from that, we used minigene constructs to analyze the c.1488+2T>C variant, as well as other previously described variants affecting the same donor splice site in intron 8 (c.1488+1G>A, c.1488+5G>C, c.1488+5G>A). We demonstrated that these variants result in multiple splicing events, each producing splicing products with varying prevalence. Our experiments suggest that the variety of alternative transcripts contributes to complex phenotypes, while the quantitative ratio of these transcripts influences the varying severity of the disease. [ABSTRACT FROM AUTHOR]