Submission Details

NEK1 was first reported in relation to autosomal dominant amyotrophic lateral sclerosis (ALS) type 24 in 2015 (Cirulli et al., PMID: 25700176). NEK1 encodes never in mitosis gene a-related kinase 1 (Nek1) and has a role in cell cycle control and cilia regulation. NEK1 has also been associated with autosomal recessive short-rib thoracic dysplasia 6 with or without polydactyly. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism, inheritance pattern, and phenotypic variability between this disease and ALS type 24. Therefore, the following disease entities have been split into two disease entities: ALS type 24 (OMIM: 617892) and short-rib thoracic dysplasia 6 with or without polydactyly (OMIM:263520). The association between NEK1 and ALS was first established in an exome-wide gene burden analysis that identified an association between loss of function rare variants in the gene and the phenotype based on the exome sequencing of 2874 ALS cases and 6405 controls (Cirulli et al., PMID: 25700176). This curation also includes an additional 13 case-control analyses from 11 publications (PMIDs: 25700176, 26945885, 27455347, 28935222, 29149916, 30940688, 30976013, 31768050, 32920598, 34544842, 31475037). Additionally, 40 variants, including missense, nonsense, frameshift, and splicing variants, reported in 40 probands in 10 publications (PMIDs: 26945885, 28935222, 30093141, 31108397, 31475037, 32462798, 32772750, 32920598, 33445179, 34564799) are included in this curation. Based on this curation, the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function, although missense variants have also been reported in ALS probands. This gene-disease association is also supported by experimental evidence describing physical interaction with other known ALS associated genes and functional alterations in mutated patient cells (PMIDs: 30992335, 29929116, 25700176), although experimental evidence remains marginal overall. In summary, NEK1 is definitively associated with autosomal dominant ALS type 24. This has been repeatedly demonstrated in both the research and clinical diagnostic settings as shown by the genetic evidence and has been upheld over time. Although, we believe that more experimental evidence is needed to gain a greater understanding of the involvement of NEK1 in ALS pathophysiology. It is important to understand that in the clinical diagnostic setting the identification of missense variants of uncertain significance may be common and variant interpretation must be completed with caution. This classification was approved by the ClinGen ALS GCEP on 02/24/2021 (SOPv8).