Submission Details

DCTN1 encodes dynactin 1 (dctn1/P150-Glued) and is the largest polypeptide of the dynactin complex, which binds microtubules and cytoplasmic dynein. It has a role in axon maintenance, regulating vesicle and organelle transport via direct binding to microtubules, the molecular motor dynein, and various cargoes. DCTN1 was first reported in relation to distal hereditary motor neuronopathy type 7B (dHMN7B; OMIM: 607641) in 2003 (Puls et al., PMID: 12627231). This association led to interest in screening a cohort of individuals with ALS (OMIM: 105400) for variants in DCTN1, and heterozygous missense variants of interest were found in four cases (Munch et al. 2004, PMID: 15326253). The gene was finally associated with Perry Syndrome (OMIM: 168605) through genome-wide linkage analyis (Farrer et al. 2009, PMID: 19136952). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we did not find a distinct difference between the molecular mechanism, phenotypic variability, or inheritance pattern of dHMN7B and ALS; therefore, these diseases were lumped for the purposes of gene curation. However, we found a difference in phenotypic variability between Perry Syndrome and ALS, and these disease entities were split. The gene was curated for the lumped ALS and dHMN7B, but the curation for Perry Syndrome was not completed as it is considered outside the phenotypic scope of the GCEP.

The association between DCTN1 and ALS was first established in a candidate gene analysis that used Sanger sequencing to assess all exons of the gene in 108 familial and 142 sporadic ALS cases, finding variants in 4 individuals (Munch et al, 2004, PMID: 15326253). No case-control analyses were scorable for the curation of DCTN1. The dHMN7B family in which the first variant in DCTN1 was identified was the only family segregation included in the scoring (Puls et al., PMID: 12627231). Additionally, 11 variants - including 10 missense variants and 1 insertion variant - reported in 11 probands from 10 publications were scored in this curation. Based on the curation, a genetic evidence score of 4.7 was reached. The majority of variants identified in DCTN1 appear to be missense variants.

The gene-disease association is also supported by experimental evidence describing a physical interaction with another known ALS associated protein, TDP-43 (PMIDs: 33924373); aberrant expression in patient cells (PMID: 17620987); functional alterations in non-patient cells (PMIDs: 33924373); and establishment of model organisms and rescues (PMIDs: 18094236, 29490687, 31291987, 23408943, and 18305234). An experimental evidence score of 5.25 was reached.

In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, particularly regarding the molecular mechanism of pathogenic variants, no convincing contradictory evidence has emerged.This classification was approved by the ClinGen ALS GCEP on the meeting date July 27, 2023 (SOP Version 9).