Submission Details

The relationship between GK and glycerol kinase deficiency, an X-linked disorder of glycerol metabolism, was evaluated using the ClinGen Clinical Validity Framework as of December 8, 2020. Glycerol kinase (GK) catalyzes the phosphorylation of glycerol to glycerol-3-phosphate, which is required for the production of triglycerides. Deficiency of GK results in hyperglycerolemia and glyceroluria. Three distinct clinical phenotypes have been associated with GK deficiency. The complex infantile form results from a contiguous gene syndrome that includes GK in addition to the congenital adrenal hypoplasia gene, the Duchenne muscular dystrophy gene, or both. The juvenile and adult forms result from deleterious variants within the GK gene. The juvenile form is characterized by vomiting, metabolic acidosis, and coma in the first years of life. The adult form is usually benign and often comes to attention due hypertriglyceridemia that is refractory to treatment. Because the quantitation of glycerol is commonly used as an indirect means of determining triglyceride blood levels, GK-deficient patients appear to have elevated triglycerides. However, the finding is actually due to elevated glycerol, a finding termed pseudohypertriglyceridemia (Wu et al, 2015, PMID: 25300978 (review); Lamiquiz-Maneo et al, 2020, PMID: 33212314).

The disease mechanism is loss of function. Hemizygous variants in GK were first reported in patients with glycerol kinase deficiency in 1996 (Walker et al, PMID: 8651297). Since then, over thirty GK variants have been associated with GK deficiency (https://databases.lovd.nl/shared/variants/GK/unique ). The relationship between GK and GK deficiency is supported by case-level and experimental evidence. Seventeen unique variants from seventeen probands in nine publications were curated (Walker al, 1996, PMID: 8651297; Gaudet et al, 2000, PMID: 10736265; Dipple et al, 2001, PMID: 11479736; Sjarif et al, 1998, PMID: 9719371; Zhang et al, 2000, PMID: 10737976; Sjarif et al, 2004, PMID: 15026783; Zhang et al, 2006, PMID: 16549535; Zhang et al, 2015, PMID: 26309814; Lamiquiz-Maneo et al, 2020, PMID: 33212314). Segregation evidence from two families was also included (Gaudet et al, 2000, PMID: 10736265; Lamiquiz-Maneo et al, 2020, PMID: 33212314). Further information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. Note that only patients with isolated GK deficiency were included i.e. no patients with the contigious gene syndrome were included in this curation due to the involvement of other genes, which complicated the clinical picture and clinical validity assessment.

Experimental evidence supporting this gene-disease relationship includes the biochemical function of glycerol kinase, which is consistent with the biochemical findings of hyperglycerolemia and glyerolurina in patients (McCabe et al, 1992, PMID: 6302392; Huq et al, 1996, PMID: 8884278), the biochemical and clinical features of a Gk knock out mouse (Huq et al, 1997, PMID: 9302256), and the impact of gene therapy in the Gk knock out mouse (Kuwada et al, 2005, PMID: 16105550).

In summary, GK is definitively associated with glycerol kinase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.