Correlating Testing for Rare Genetic Variants with a Broad Clinicopathologic Spectrum of Congenital Myopathies
Divya Jayaraman1, Casie Genetti2, Asli Aykanat3, Wathone Win2, Zaheer Valivullah4, Emily O'Heir4, Basil Darras5, Regina Laine5, Anne O'Donnell-Luria6, Alan Beggs7
1Department of Neurology, Manton Center for Orphan Disease Research, Division of Genetics and Genomics, 2Manton Center for Orphan Disease Research, Division of Genetics and Genomics, 3Department of Pediatrics, Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children’s Hospital, 4Broad Institute of MIT and Harvard, 5Department of Neurology, Boston Children's Hospital, 6Department of Pediatrics, Boston Children’s Hospital/Broad Institute of Harvard and MIT, 7Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital/Harvard Medical School
Objective:
We report genetic findings from the Beggs laboratory congenital myopathy (CM) cohort, which currently totals over 1,100 individuals and constitutes a robust dataset of existing cases.
Background:
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.
Design/Methods:
Subjects were ascertained based on clinical presentation and pathologic diagnoses suggestive of CM, and solved by a combination of single gene, panel, or genomic sequencing, and/or RNA-Seq.
Results:
Of 1,219 cases total, 739 (61%) were solved. 605 had mutations in either ACTA1, DNM2, MTM1, NEB, RYR1, SELENON, TPM2, TPM3, or TTN, which 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 134 solved cases had mutations in one of 60 different genes, including several 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 144 probands with congenital myopathy with nonspecific or no pathology, 43 (30%) had SELENON mutations; 17 (12%) had RYR1 mutations and 8 (6%) had TTN mutations.
Conclusions:
This analysis of the Beggs laboratory cohort cases, accumulated over roughly 20 years, emphasizes the crucial 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 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.