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. 2025 Feb 25;26(5):1984.
doi: 10.3390/ijms26051984.

Exploring the Prevalence of SMN1 Duplication and Deletion in Russia and Its Impact on Carrier Screening

Kristina Mikhalchuk  1 , Aleksander Polyakov  1 , Viktoria V Zabnenkova  1 , Olga Ismagilova  1 , Olga Shchagina  1
Affiliations

Exploring the Prevalence of SMN1 Duplication and Deletion in Russia and Its Impact on Carrier Screening

Kristina Mikhalchuk et al. Int J Mol Sci. .

Abstract

5q spinal muscular atrophy (5q SMA) is one of the most prevalent autosomal recessive disorders worldwide. In 5q SMA, cases of silent carriers have been reported, including SMN1 duplications, intragenic subtle variants, de novo variants, and mosaicism. This study included DNA samples from 3412 unexamined unrelated individuals with no known family history of 5q SMA. In addition, we studied 15 families in which the children had a confirmed diagnosis of 5q SMA caused by a homozygous deletion of exon 7 of SMN1. Each family included one parent who was a carrier of a heterozygous deletion of SMN1, while the other parent had two copies of SMN1. The copy number of SMN1 and SMN2 was detected by MLPA. Two previously reported genetic markers of SMN1 duplication, c.*3+80T>G and c.*211_*212del, were tested in 143 Russian residents with three copies of SMN1 and 15 parents with two copies of SMN1. The frequency of a heterozygous carrier of exon 7 deletion of SMN1 is 1 in 36 individuals (95% CI 33 to 39). The frequency of exon 7 duplication of SMN1 is 1 in 25 individuals (95% CI 20 to 30). Only three individuals of the studied SMN1 duplication carriers were detected to have genetic markers of SMN1 duplication. The study of SMN1 duplication genetic markers (c.*3+80T>G and c.*211_*212del) in Russian residents reveals only 1.9% of SMN1 duplication carriers.

Keywords: 5q SMA; SMN1; c.*211_*212del; c.*3+80T>G; carrier screening; deletion; duplication; genotype (2 + 0); markers; silent carrier; spinal muscular atrophy.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure A1
Figure A1
A comprehensive experimental workflow diagram.
Figure 1
Figure 1
Genotype variants in individuals without 5q SMA. Non-carriers carry at least one copy of SMN1 on each chromosome (genotypes 1 + 1, 2 + 1, 2 + 2). The majority of carriers have only one copy of SMN1, with no SMN1 on the other chromosome (genotype 1 + 0). Silent carriers have two copies of SMN1 on one chromosome, while SMN1 is absent on the other chromosome (genotype 2 + 0), which is not identified by routine quantitative methods. Silent carriers may also have two copies of SMN1 on each of the chromosomes, but one of the copies may carry an intragenic subtle variant (genotypes 1 + 1V, 2 + 1V). In addition, quantitative carrier screening is unable to detect germline mosaicism by variants in SMN1.
Figure 2
Figure 2
Example of allele distribution with SMN1 in two families (a,b). In the first pedigree example (a), individuals requested carrier screening for a deletion in exon 7 of SMN1, individuals with two copies of SMN1 by MLPA (I.1, I.3, I.4, II.2) carry two copies of SMN1 on two alleles. In the second pedigree example (b), some individuals with two copies of SMN1 by MLPA (I.5, II.4) can carry two copies of SMN1 on the one allele (silent carriers of SMN1 deletion). Thus, when one partner is identified as a carrier of SMN1 deletion (II.3) and the other partner has two copies of SMN1 (II.4), it is recommended to determine the copy number of SMN1 in the parents of the partner with two copies of the SMN1. Individuals (I.2, I.6, I.7, I.8, II.1) carry one copy of SMN1 by MLPA. Chromosome 5 is schematically represented in blue, while the number of SMN1 copies, detected by MPLA, is schematically represented in orange. In this representation, one orange hexagon schematically represents one copy of SMN1, and two hexagons represent two copies of SMN1.
Figure 3
Figure 3
Molecular screening design of a cohort of 3412 unrelated Russian individuals and 15 families and 100 unrelated carriers of exon 7 deletion of SMN1.
Figure 4
Figure 4
Analysis of genetic markers of SMN1 duplication (c.*3+80T>G and c.*211_*212del). The figure shows fragments of electropherograms analyzing DNA samples (#DNA 1669, 1502, 206, 605, 1303, 1754) of Russian residents with three copies of SMN1. The presence of two genetic markers of SMN1 duplication was detected in two Russian residents (track 2 and track 4), in other samples these markers were not detected. In the last track (8), there was a negative control for the reaction. The lengths of the amplified fragments range from 104 to 114 base pairs (b.p.) (Table 4).
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