This poster (#153) will be presented at the ACMG Annual Meeting by Chris Tan, our genetic counselor, Thursday March 27: 10:30am-noon. Stop by and learn more

Patient registries provide a powerful resource to identify undiagnosed patient cohorts and collect cross-sectional and longitudinal clinical information on those individuals. For rare disorders, such as the congenital myopathies, a patient registry with curated patient-reported and medical report data may serve as the ideal tool to focus molecular testing. Indeed, molecular testing, which utilizes next generation sequencing, has greatly improved the ability to simultaneously analyze multiple genetic loci. The congenital myopathies (CM) comprise a heterogeneous group of heritable muscle disorders. While muscle pathology provides a "muscle biopsy" driven classification, clinical heterogeneity within this classification and the increasing number of implicated genes underscore the need for genetic confirmation. Furthermore, preclinical research has identified gene specific targeted treatments driving a need to prepare genetically confirmed cohorts for future clinical trials.

A total of 1316 patients are registered with the Congenital Muscle Disease International Registry (CMDIR) of whom at least 160 have had a muscle biopsy with no genetic diagnosis established. Review of patient reported clinical features, clinic notes and muscle biopsy reports was performed to identify patients with centronuclear and nemaline myopathy in whom either no genetic testing had been performed or where genetic testing failed to identify a causative mutation. The scant number of muscle biopsy reports uploaded into the registry database limited reviews. Eight registrants were identified whose clinical features and muscle biopsies supported a diagnosis of centronuclear or nemaline myopathy. Next generation sequencing analysis of seventeen genes implicated in CM has been performed on four of these patients so far. Pathogenic sequence changes were identified in all four patients and included heterozygous frameshift and missense mutations in TTN (c.6555_6556ins16 and p.Arg30301Pro), a heterozygous missense mutation in ACTA1 (p.Ala172Glu), and two patients with heterozygous missense and nonsense mutations in RYRI (p.Arg109Trp and p.Arg2241*; p.Cys3402Gly and p.Arg1409*). Clinical and muscle biopsy information on all four mutation positive patients will be presented.

Our four mutation positive cases provide evidence supporting the utility of patient disease registries and multi-gene panel analysis for CM. For disorders with broad phenotypic and genotypic heterogeneity, the combined application of patient registry queries and next generation sequencing may improve the diagnostic yield of molecular testing and ensure clinical trial readiness.