Rare genetic variants in a cohort of patients presenting with congenital myopathy


Ultra-Rare myopathies and dystrophies (<1:100,000 worldwide)

Poster Number: 203


Asli Aykanat, MD, Casie Genetti, MS, CGC, Wathone Win, BS, Zaheer Valivullah, BS, Emily O'Heir, BS, Basil Darras MD, Regina Laine, MSN, PNP-BC, CNRN, Alan Beggs, PhD


1. Boston Children's Hospital, 2. Boston Children's Hospital, 3. Boston Children's Hospital, 4. Broad Institute of MIT and Harvard, 5. Broad Institute of MIT and Harvard, 6. Boston Children's Hospital, 7. Boston Children's Hospital, 8. Boston Children's Hospital

Congenital myopathies are a set of clinically heterogeneous disorders that can present with a range of overlapping findings making diagnosis a challenging process. Genetic testing plays a crucial role in the diagnostic process, and while a set of common causes of inherited myopathies have been established, many cases remain undiagnosed. We report 15 patients from a cohort of congenital myopathy patients whose whole exome sequencing (WES) results revealed variants in genes outside of those commonly considered to cause myopathy. All of the reported patients had a myopathic phenotype and pathology, with some showing additional symptoms. Variants in ADSSL1, CACNA1S and TRIP4 were identified as rare or newly established causes of congenital myopathy, and a case of DOK7 represents a misdiagnosis of congenital myasthenic syndrome as congenital fiber type disproportion. In contrast, patients with variants in CTBP1, EBF3, HRNPNK, GRIN1, NFIX, QRICH1 and TBCK presented initially or predominantly with myopathy, but with an additional range of symptoms. All 7 of these genes are known causes of neurodevelopmental syndromes that present prominently with global developmental delay with or without myopathy as a known feature. Finally, ACTG2, a known cause of visceral myopathies, was mutated in a patient with skeletal muscle involvement. While all reported patients shared the common symptoms of muscle weakness and hypotonia, a wide spectrum of additional symptoms were appreciated. These cases emphasize the crucial role of WES in the diagnosis of congenital myopathies as opposed to disease-based gene panels which may miss cases where the presentation does not fit the classical description of the disorder, or the causative gene has not yet been associated with the disease. Moreover, certain neurological syndromes not known to present notably with muscular symptoms may go undiagnosed if genetic screening is done based on specific clinical symptoms alone.