A de novo deletion underlying spinal muscular atrophy: implications for carrier testing and genetic counseling.

Spinal muscular atrophy (SMA) is an autosomal recessive disease most commonly caused by homozygous deletion of the SMN1 gene. Parents of affected children are typically carriers, with a recurrence risk of 25% for future pregnancies. Their close relatives have up to 50% chance of being carriers. Carriers typically possess a single copy of the SMN1 gene; however, some parents carry two copies of SMN1. Current standard diagnostic carrier tests are unable to distinguish between silent carriers with two copies on one chromosome (2 + 0 genotype) and non-carriers (1 + 1 genotype), where a de novo deletion occurred. This distinction is crucial for recurrence risk assessment, which highlights the unsolved challenge to carrier testing and genetic counseling. We combined microsatellite marker analysis, SMN copy number analysis, Sanger sequencing, long-read sequencing and de novo assembly to investigate the cause of the absence of SMN1 in a pedigree with an SMA patient identified through newborn screening, whose parents each carried two SMN1 copies. Our analysis revealed that the father is a silent carrier, while de novo assembly of the SMN locus showed a 1.4 megabase (Mb) de novo deletion between mother and child. This deletion encompasses SMN1 and SMN2 and represents the first reported nucleotide-level resolved SMA-causing deletion to date. Our findings allowed informed counseling of at-risk relatives and illustrate the complexity of SMA carrier testing and counseling. This case underscores the feasibility of and need for advanced genetic testing for SMA carriership in select cases, to improve genetic counseling practices, risk assessment, and family planning.