Delayed Diagnosis of Spinal Muscular Atrophy in Two Chinese Families due to Novel SMN1 Deletions

ABSTRACT Autosomal recessive spinal muscular atrophy (SMA) is a leading cause of infant and child mortality, with homozygous deletion in exon 7 of the SMN1 gene being a major genetic cause. However, routine genetic testing methods may overlook structural variants outside of exon 7, potentially leading to misdiagnosis of SMA patients. Here, we reported two Chinese SMA patients who primarily exhibited developmental delays. Physical examinations revealed markedly reduced muscle strength and tone in their extremities, and electromyography suggested extensive neurogenic damage in the anterior horn of the spinal cord. The MLPA results indicated a single copy number of SMN1 in both patients, which is inconsistent with the typical genetic pattern of SMA. Through RNA sequencing and ultra‐long read sequencing, we ultimately identified a rare structural variant involving the deletion of exons 2a–5 in both unrelated patients. This confirmed the presence of compound heterozygous variants in the SMN1 gene as the actual genetic cause. To our knowledge, this is the first case where a combination of RNA sequencing and ultra‐long read sequencing has been used to diagnose SMA. We demonstrated the significant value of RNA sequencing in cases where children are highly suspected of having SMA but present negative results in routine genetic testing. This underscores the crucial role of accurate genetic testing methods in achieving early diagnosis of SMA.