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Case Report: Resolving a Diagnostic Odyssey in Spinal Muscular Atrophy Using HiFi Long-Read Whole Genome Sequencing

Year: 2026

Type: article

Abstract: Compound heterozygous SMN1 genotypes account for approximately 5% of spinal muscular atrophy (SMA) cases but are difficult to detect using conventional short-read sequencing due to near-identical homology between SMN1 and its paralog SMN2. We describe a patient with a decade-long diagnostic odyssey in whom whole exome and short-read whole genome sequencing failed to establish a diagnosis, despite a single SMN1 copy having been detected and dismissed as carrier status. The patient presented in childhood with progressive proximal limb weakness, tongue atrophy with fasciculations and electrophysiological evidence of chronic neurogenic disease. High-fidelity long-read whole genome sequencing resolved the SMN locus unambiguously, identifying a compound heterozygous genotype comprising an SMN1 gene deletion and a likely pathogenic missense variant (c.347 T>C; p.Ile116Thr) on the remaining allele, confirming SMA type 3. This case illustrates how long-read sequencing can resolve paralogous genomic regions intractable to short-read approaches, and highlights that a single detected SMN1 copy in a patient with a compatible phenotype warrants evaluation for a second sequence-level variant.

Source: Wellcome Open Research

DOI: 10.12688/wellcomeopenres.26627.1