Unraveling the genetic mysteries of spinal muscular atrophy in Chinese families

Abstract

Objective: Spinal muscular atrophy (SMA) is a motor neuron disorder encompassing 5q and non-5q forms, causing muscle weakness and atrophy due to spinal cord cell degeneration. Understanding its genetic basis is crucial for genetic counseling and personalized treatment options.

Methods: This study retrospectively analyzed families of patients suspected of SMA at our institution from February 2006 to March 2024. Various molecular techniques, including multiplex ligation-dependent probe amplification analysis, long-range polymerase chain reaction (PCR) combined with nested PCR, Sanger sequencing, and whole-exome sequencing were employed to establish a thorough genetic variant profile in 680 Chinese pedigrees with clinically suspected SMA.

Results: Out of 680 families suspected of having SMA, 675 exhibited mutations in the SMN1 gene, while three families were linked to mutations in the IGHMBP2 gene. One family exhibited a genetic variation in the NEB gene, and another family exhibited a variation in the SCO2 gene. Among the families with mutations in the SMN1 gene, 645 families exhibited either E7‒E8 or E7 homozygous deletion. Some families displayed E7‒8 heterozygous deletions along with other mutations, such as E1 or E1‒6 heterozygote deletion and point mutations. Furthermore, one family demonstrated a compound-heterozygous double mutation, while another carried a type "2 + 0" mutation alongside a point mutation.

Conclusions: This study comprehensively analyzed the genetics of suspected familial SMA cases in the Chinese population, providing insights into the molecular genetic mechanisms of SMA and the utility of various detection techniques. The findings revealed important implications for genetic counseling, prenatal diagnosis, and targeted therapies in clinical practice.

Keywords: SMN1 gene; 5q SMA; Genetic diagnosis; Non-5q SMA; Prenatal diagnosis; Spinal muscular atrophy.

Fig. 1

MLPA results for 645 Chinese families with homozygous deletions in SMN1 E7‒8 or E7 regions. A Analysis of genotypes in 528 patients and affected fetuses. B Analysis of carrier genotypes in 1396 parents and sibling fetuses or children. The “0-0-3-3” genotype indicates that the copy number of exon 7 of the SMN1 gene is 0, the copy number of exon 8 of the SMN1 gene is 0, the copy number of exon 7 of the SMN2 gene is 3, and the copy number of exon 8 of the SMN2 gene is 3, respectively

Fig. 2

Point mutation data for the SMN1 gene (the blue numbers indicate the number of mutant families)

Fig. 3

Family pedigrees affected by SMA depict SMN1 E7 homozygous deletion in unaffected subjects. The MLPA results are shown in the figure

Fig. 4

MLPA analysis produced false-positive results in two families

Fig. 5

MLPA and WES analyses were performed on two SMA-afflicted children