O.01 Correlating molecular genetic testing for rare genetic variants with a broad clinicopathologic spectrum of congenital myopathies

Congenital myopathies (CMs) are a group of clinically heterogeneous disorders presenting with a range of overlapping findings, making diagnosis challenging. Despite advances in genetic testing, many cases remain undiagnosed. The Beggs' laboratory CM cohort, which currently totals over 1,100 individuals, constitutes a robust dataset of existing cases. Subjects were ascertained based on clinical presentation and pathologic diagnoses suggestive of CM. We report that over 65% have been solved by a combination of single gene, panel, or genomic sequencing, and/or RNA-Seq. Of 727 solved cases, 610 had mutations in either ACTA1, DNM2, MTM1, NEB, RYR1, SELENON, TPM2, TPM3, or TTN. All these genes are well-known causes of congenital myopathy. While all patients shared a myopathic pattern of weakness and hypotonia, a wide spectrum of clinicopathologic features were appreciated among the cases. The remaining 117 cases had mutations in one of 52 different genes, including a number of rare or novel genes, as well as some more commonly mutated non-CM disease genes in patients who presented atypically for those associated conditions. Among a heterogeneous group of 96 probands with congenital myopathy with nonspecific or no pathology, 31 (32%) had SELENON mutations; 9 (9.4%) had RYR1 mutations and 6 (6.25%) had TTN mutations. This survey of the Beggs' laboratory cohort cases, accumulated over roughly 20 years, emphasizes the crucial and growing role of WES/WGS in establishing a molecular genetic diagnosis of CM, as opposed to disease-based gene panels or single-gene testing, which may miss cases where the presentation does not fit the classical description of the disorder, or where multiple genes may present with overlapping clinicopathologic diagnoses. Moreover, certain syndromes not known to present predominantly with myopathic symptoms may go undiagnosed if genetic testing is done in a more targeted fashion based on specific clinical symptoms or pathologic diagnosis alone.