DYNC1H1 was first reported in relation to Charcot-Marie-Tooth in 2011 (PMID: 21820100). Over time the phenotypic spectrum of DYNC1H1 has expanded to include not only Charcot-Marie Tooth (CMT), but also Spinal Muscular Atrophy, lower extremity-predominant (SMALED), and Complex Cortical Dysplasia with brain malformations. Due to the distinct differences in phenotype, we decided to split the Complex Cortical Dysplasia assertion. The CMT and SMALED phenotypes however can be viewed clinically quite similarly, based on disease presentation and electrophysiological analysis. Therefore, the latter two disease entities were lumped into one, Distal Hereditary Motor Neuronopathy.
DYNC1H1 encodes Cytoplasmic dynein 1 heavy chain 1, a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
In this curation, we scored genetic evidence for 16 different missense variants, which were reported to be de novo in 12 probands. Additional linkage analysis increased the genetic evidence score to 10.6. Experimental evidence further supports the gene-disease relationship. Patient cells have been shown to have a delay in Golgi reassembly after nocodazole drug treatment (PMID: 24307404). Other mutations have shown increased affinity for a DYNC1H1 binding partner, BICD2 (PMID: 25512093). A mouse model with a conditional null allele of Dync1h1 showed a motor phenotype, further supporting the role of the gene in disease, although a gain-of-function mechanism is more likely in patients (PMID:36218033).
In summary, DYNC1H1 is definitively associated with autosomal dominant distal hereditary neuronopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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