A next-gen sequencing method for tricky spinal muscular atrophy carrier screen

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Despite rapid advances, not all genetic diseases can be detected using next-generation sequencing (NGS). Alterations in genes with highly repetitive sequences or in two nearly identical genes can make getting an accurate result challenging in a clinical setting. Such is the case with spinal muscular atrophy (SMA), a relatively common disorder with an incidence of about 1 in 10,000 and a carrier frequency varying from 1/40 to 1/100 in different ethnic groups. Two nearly identical genes, SMN1 and SMN2, can contribute to disease incidence and severity. Current diagnostic methods include polymerase chain reaction (PCR) coupled with restriction fragment-length polymorphism analysis. Due to difficulty using NGS sequencing, SMA carrier detection has not been included in NGS panels to date. Here, Feng et al. report the development of an NGS-based carrier screen with nearly 100% sensitivity and specificity. The approach, they note, is amenable to being integrated into existing NGS-based carrier screening panels. The researchers validated the new method, called paralogous gene copy-number analysis by ratio and sum, in a clinical setting using 6,738 samples that included a cross-section of ethnic groups. Among these samples, African Americans and Hispanics had the lowest frequencies of SMN deletion, at 1.0 and 0.9%, respectively, whereas Asians had the highest, at 2.4%. The findings represent the first report of an NGS-based clinical method for copy-number analysis of genes with a high degree of sequence identity. —Karyn Hede, News Editor