DYNC1H1-related disorders: A description of four new unrelated patients and a comprehensive review of previously reported variants

摘要

Heterozygous variants in theDYNC1H1gene have been associated chiefly with intellectual disability (ID), malformations in cortical development (MCD), spinal muscular atrophy (SMA), and Charcot-Marie-Tooth axonal type 20 (CMT), with fewer reports describing other intersecting phenotypes. To better characterize the variable syndromes associated withDYNC1H1, we undertook a detailed analysis of reported patients in the medical literature through June 30, 2019. In sum we identified 200 patients from 143 families harboring 103 differentDYNC1H1variants, and added reports for four unrelated patients identified at our center, three with novel variants. The most common features associated withDYNC1H1were neuromuscular (NM) disease (largely associated with variants in the stem domain), ID with MCD (largely associated with variants in the motor domain), or a combination of these phenotypes. Despite these trends, exceptions are noted throughout. Overall,DYNC1H1is associated with variable neurodevelopmental and/or neuromuscular phenotypes that overlap. To avoid confusionDYNC1H1disorders may be best categorized at this time by more general descriptions rather than phenotype-specific nomenclature such as SMA or CMT. We therefore propose the terms:DYNC1H1-related NM disorder,DYNC1H1-related CNS disorder, andDYNC1H1-related combined disorder. Our single center's experience may be evidence that disease-causing variants in this gene are more prevalent than currently recognized.