2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-<em>SMN1</em> </and <em>SMN2 </em>Gene-Specific Sequencing Enhances the Clinical Sensitivity of Spinal Muscular Atrophy Diagnostic Testing

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A study conducted by The James Molecular Laboratory at Polaris, The Ohio State University James Cancer Center, aimed to enhance the clinical sensitivity of spinal muscular atrophy (SMA) diagnostic testing. SMA is a motor neuron disease that affects 1 in 10,000 live births. The majority of SMA patients have gene conversion/deletion alleles involving the SMN1 gene. The remaining cases have intragenic SMN1 variants in -trans with a deletion/conversion allele. Determining whether a disease-associated variant is localized to SMN1 is complicated by the presence of the paralogous gene SMN2. To address this issue, the laboratory developed a gene-specific sequencing assay for SMN1 and SMN2. The assay, combined with copy number assessment of SMN1 and SMN2, provides a more comprehensive diagnostic testing strategy and increases the likelihood of identifying eligible therapy patients. <br /><br />In the study cohort, gene-specific sequencing was performed on 83 patients. The majority of patients had compound heterozygous variants, with a median age at referral of 5.52 years. The most common variants identified were putative loss-of-function variants, including nonsense, frameshift, and splice site variants. Missense variants were also identified, primarily clustering within the tudor domain (exon 3) and the YG box (exon 6). Notably, two frequently reported SMN1 variants were absent in this cohort. <br /><br />In one interesting case, an asymptomatic newborn with a single copy of SMN1 was found to have a variant localized to SMN2, ruling out a diagnosis of SMA. <br /><br />The study concluded that the gene-specific sequencing assay allows for the definitive assignment of disease-associated variants to either SMN1 or SMN2. It can also be used to reduce the possibility of an SMA diagnosis in asymptomatic or non-typical cases. The functional impact and frequencies of missense variants in these genes require further research for better classification guidelines.

Asset Subtitle

Presenting Author - Matthew Avenarius, PhD, FACMG; Co-Author - Jin Fang, BS; Co-Author - Pamela Snyder, BS; Co-Author - Thomas W. Prior, PhD, FACMG; Co-Author - Dan Jones, MD, PhD; Co-Author - Cecelia Miller, PhD;

Meta Tag

Genetic Testing

Methodology

Sequencing

Co-Author Jin Fang, BS

Co-Author Pamela Snyder, BS

Co-Author Thomas W. Prior, PhD, FACMG

Co-Author Dan Jones, MD, PhD

Co-Author Cecelia Miller, PhD

Presenting Author Matthew Avenarius, PhD, FACMG

Keywords

spinal muscular atrophy

diagnostic testing

motor neuron disease

gene conversion

SMN1 gene

intragenic SMN1 variants

paralogous gene SMN2

gene-specific sequencing assay

copy number assessment

therapy patients