Submission Details

DOLK was first reported in relation to DOLK-Congenital Disorder of Glycosylation, [DOLK-CDG, (MONDO:0012556) in 2007 (Kranz C et al., 2007 PMID:17273964). DOLK-CDG is a rare autosomal recessive disorder characterized by muscular hypotonia and ichthyosis. It has been described in four children from two consanguineous families. All the affected children died during early infancy, two from dilated cardiomyopathy. The syndrome is caused by a deficiency in dolichol kinase 1 (DK1), an enzyme involved in the de novo biosynthesis of dolichol phosphate. The mutations identified in the DK1 gene led to a 96 to 98% reduction in DK activity. DOLK provides instructions for making the enzyme dolichol kinase, which facilitates the final step of the production of a compound called dolichol phosphate. This compound is critical for glycosylation, which attaches the groups of sugar molecules (oligosaccharides) to proteins.

More than 500 unique variants (e.g., synonymous, missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. 9 variants (1 nonsense, and 8 missense) that have been reported in approximately 9 probands in 5 publication (Kranz C et al., 2007 PMID:17273964; Lefeber D et al., 2011; PMID: 22242004; Helander A et al., 2013; PMID:23890587; Lieu MT et al., 2013; PMID:24144945; Rush E et al., 2017 PMID:28816422), are included in this curation. This gene-disease relationship is also supported by biochemical functions, expression, and yeast models studies (Fernandez F, Et Al., 2002; PMID: 12213788; Lefeber et al., 2011; PMID: 22242004). In summary, there is definitive evidence to support the relationship between DOLK and DOLK-CDG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date February 21, 2024 (SOP Version 10).