Abstract:

Objective To report and analyze the clinical phenotypes and genotypes of two cases of spinal muscular atrophy (SMA) caused by structural variations in exon 1 of the survival motor neuron 1 (SMN1) gene. Methods A retrospective analysis was conducted on the clinical data of two children with SMA caused by structural variations in exon 1 who visited the neurology department from October 2022 to June 2024. Peripheral blood samples were collected from the patients and their parents. Diagnosis of 5q SMA was ultimately confirmed using long-range PCR (LR-PCR) combined with multiplex ligation-dependent probe amplification (MLPA) kit P021. A literature review of SMA cases associated with exon 1 variations in SMN1 gene was also conducted. Results Both of the two children with SMA caused by structural variations in exon 1 were male, type Ⅱ. Their ages of onset were 7 months and 9 months respectively, and their ages of seeking medical attention were 9 years and 1 month and 1 year and 1 month respectively. They all presented with limb muscle weakness and delayed motor development, and electromyography all indicated lesions in the anterior horn of the spinal cord. Routine MLPA testing initially identified heterozygous deletion of the SMN1 gene in both patients. Definitive diagnosis via LR-PCR combined with MLPA-P021 revealed an SMN1 exon 7 copy number of 1 on one allele, coupled with a structural deletion variant in exon 1 on the same allele. Additionally, Patient 1 harbored an SMN1/SMN2 hybrid gene on this allele. The extended diagnostic interval of 11 years for Patient 1 was attributed to both the earlier time of birth and the rarity of the combined gene conversion and structural variation. Literature review identified 7 relevant publications reporting 19 SMA cases (male-to-female ratio 12∶7) caused by exon 1 variations, including missense, nonsense, and structural deletion variants. Age of onset ranged from birth to adolescence, with primary manifestations being motor function delay or regression. Five patients were deceased; some receiving SMA-targeted therapies were reported to be stable. Conclusions Both SMA cases in this study were caused by structural variations in exon 1 of the SMN1 gene, confirming 5q SMA. When initial MLPA testing in clinically suspected SMA patients is negative (i.e., no homozygous deletion of exon 7 is detected), variations in exon 1 should be considered. The optimized LR-PCR combined with MLPA-P021 technique enables rapid and precise diagnosis. Exon 1 may represent a hotspot in the Chinese SMA variant spectrum, and gene conversion events warrant particular attention.

Key words: spinal muscular atrophy, compound heterozygous variation, exon 1, long-range PCR, child