GCDH

Inheritance Pattern: AR

Disease ID:MONDO:0009281

Submitter: Myriad Women's Health

Inheritance Pattern: AR

Disease ID:MONDO:0009281

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0009281

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0009281

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009281

Submitter: ClinGen

The relationship between GCDH and glutaryl CoA dehydrogenase deficiency was evaluated using the ClinGen Clinical Validity Framework as of October 22, 2019. GCDH encodes glutaryl CoA dehydrogenase, a mitochondrial matrix enzyme composed of four identical subunits. This enzyme catalyzes the oxidative decarboxylation of glutaryl-CoA - an intermediate in the metabolism of lysine, hydroxylysine and tryptophan - to crotonyl-CoA and carbon dioxide. Deficiency of GCDH activity causes glutaric acidemia type 1 (GA-1), an autosomal recessive disorder. GA-1 is characterized by macrocephaly, acute encephalopathic crises and progressive movement disorders caused by striatal degeneration, typically with onset between the ages of 6-18 months, and often triggered by an intercurrent infection. Affected individuals present with elevated levels of glutaric acid, 3-hydroxy-glutaric acid, glutaconic acid and glutarylcarnitine and be classified as high excreters or low excreters based on the urine glutaric acid level (Larson and Goodman, 2019, PMID 31536184). Biallelic variants in GCDH were first reported in 1995 (Greenberg et al, PMID 7795610; Goodman et al, PMID 8541831). Since then, around 200 variants have been identified in GCDH. Data from 9 probands who are homozygous or compound heterozygous for GCDH variants were curated, including 9 unique variants (missense, nonsense, frameshift, splicing) (Greenberg et al, 1995, PMID 7795610; Goodman et al, 1995, PMID 8541831; Anikster et al, 1996, PMID 8900228; Moseilhy et al, 2017, PMID 27476540; Zayed et al, 2019, PMID 31062211). One of these variants, c.91+5G>T, segregates in multiple closely related kindreds of an Ojibway-speaking genetic isolate of native Americans living in the Island Lake region of northern Manitoba and nearby communities of northwestern Ontario. (Greenberg et al, 1995, PMID 7795610). An inframe deletion with a dominant-negative impact has also been reported (PMID 22231382). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of GCDH which is consistent with the biochemical abnormalities observed in individuals with GCDH deficiency (PMIDs 8287562, 8541831); functional studies (Bross et al, 2012, PMID 22231382; Ribeiro et al, 2019, PMID 31491587), the biochemical and clinical features of a Gcdh knock out mouse (Koeller et al, 2002, PMID 11854167; Zinnanti et al, 2006, PMID 16446282) and biochemical findings in the Egyptian fruit-eating bat which has GCDH deficiency in liver and kidney (McMillan et al, 1998, PMID 3182847). In summary, GCDH is definitively associated with glutaryl CoA dehydrogenase deficiency (GA-1). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.

Inheritance Pattern: AR

Disease ID:MONDO:0009281

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009281

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009281

Submitter: G2P