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Heterozygous variants in the DYNC1H1 gene 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 with DYNC1H1, 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 different DYNC1H1 variants, and added reports for four unrelated patients identified at our center, three with novel variants. The most common features associated with DYNC1H1 were 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, DYNC1H1 is associated with variable neurodevelopmental and/or neuromuscular phenotypes that overlap. To avoid confusion DYNC1H1 disorders 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, and DYNC1H1‐related combined disorder. Our single center's experience may be evidence that disease‐causing variants in this gene are more prevalent than currently recognized. [ABSTRACT FROM AUTHOR]

ABSTRACT The heavy chain 1 of cytoplasmic dynein ( DYNC1 H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy ( SMA), hereditary motor and sensory neuropathy ( HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole-exome sequencing, we identified a novel dominant defect in the DYNC1 H1 tail domain (c.1792 C> T, p. Arg598 Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c.791 G> T, p. Arg264 Leu) in an isolated SMA patient. Her phenotype was more severe than previously described, characterized by multiple congenital contractures and delayed motor milestones, without brain malformations. The mutations in DYNC1 H1 increase the interaction with its adaptor BICD2. This relates to previous studies on BICD2 mutations causing a highly similar phenotype. Our findings broaden the genetic heterogeneity and refine the clinical spectrum of DYNC1H1, and have implications for molecular diagnostics of motor neuron diseases. [ABSTRACT FROM AUTHOR]

ABSTRACT DYNC1 H1 encodes the heavy chain of cytoplasmic dynein 1, a motor protein complex implicated in retrograde axonal transport, neuronal migration, and other intracellular motility functions. Mutations in DYNC1 H1 have been described in autosomal-dominant Charcot- Marie- Tooth type 2 and in families with distal spinal muscular atrophy ( SMA) predominantly affecting the legs ( SMA- LED). Recently, defects of cytoplasmic dynein 1 were also associated with a form of mental retardation and neuronal migration disorders. Here, we describe two unrelated patients presenting a combined phenotype of congenital motor neuron disease associated with focal areas of cortical malformation. In each patient, we identified a novel de novo mutation in DYNC1 H1: c.3581 A> G (p. Gln1194 Arg) in one case and c.9142 G> A (p. Glu3048 Lys) in the other. The mutations lie in different domains of the dynein heavy chain, and are deleterious to protein function as indicated by assays for Golgi recovery after nocodazole washout in patient fibroblasts. Our results expand the set of pathological mutations in DYNC1 H1, reinforce the role of cytoplasmic dynein in disorders of neuronal migration, and provide evidence for a syndrome including spinal nerve degeneration and brain developmental problems. [ABSTRACT FROM AUTHOR]