Submission Details

The relationship between GCH1 and GTP cyclohydrolase I deficiency, a disorder of tetrahydrobiopterin (BH4) synthesis, was evaluated using the ClinGen Clinical Validity Framework as of November 25, 2020. GCH1 encodes GTP cyclohydrolase I (GTPCH) which catalyzes the first step in the synthesis of BH4, a cofactor for tyrosine hydroxylase, trypthophan hydroxylase, and phenylalanine hydroxylase.

Lumping and splitting: Monoallelic variants in GCH1 have been associated with dopa-responsive dystonia (DRD, also known as hereditary progressive dystonia with marked diurnal fluctuation, Segawa syndrome, dystonia 5). DRD is characterized by childhood-onset dystonia with marked diurnal fluctuation, and a dramatic and sustained response to relatively low doses of levodopa (Furukawa, 2019, PMID: 20301681). Individuals with monoallelic variants in GCH1 typically have less than 50% GTPCH activity, leading to the suggestion that there may be a dominant negative effect from the altered protein and/or mRNA (Hirano et al, 1988, PMID 9749603; Suzuki et al, 1999, PMID 10582612; Hwu et al, 2000, PMID 11026444; Garavaglia et al, 2004, PMID 15303002). Biallelic variants in GCH1 typically result in severe deficiency of GTPCH activity, and result in hyperphenylalaninemia due to secondary PAH deficiency. This can be identified by newborn screening. However, patients with phenotypes that are intermediate between the classic DRD and severe GTPCH deficiency symptoms have been described, such those with severe DRD and additional neurological features but without hyperphenylalaninemia (for review, see Table in Brüggemann et al 2012, PMID 22473768). Because the mechanism of disease in both the monoallelic and biallelic cases is loss of function of GTPCH, and there is a range of GTPCH activity that can cause disease, the decision was made to curate GCH1 for GTPCH deficiency with semi-dominant inheritance. Note that heterozygous parents of biallelic individuals are usually reported as unaffected, although there are some exceptions (Furukawa et al, 1998, PMID 9667588; Bodzioch et al, 2010, PMID 20842687). Reduced penetrance has been reported for individuals with monoallelic GCH1 variants, with penetrance varying according to age and diagnostic criteria. In addition, some variants (e.g. p.Arg184His and p.Lys224Arg) have been reported in monallelic and biallelic individuals. This data was presented to the ClinGen Lumping and Splitting Working Group on November 3, 2020 and there was agreement that GTPCH deficiency should be curated as a semi-dominant trait, including individuals with monoallelic and biallelic GCH1 variants.

Clinical Validity Summary: The relationship between GCH1 and GTPCH deficiency is supported by case-level and experimental evidence. Monoallelic variants in GCH1 were first reported in individuals with DRD in 1994 (Ichinose et al, PMID 7874165) and biallelic variants in 1995 (Blau et al, PMID 7869202). More than 100 variants have been reported to be associated with GTPCH deficiency. In this curation, twenty four unique variants (missense, frameshift, nonsense, splice site) in 22 probands (14 monoallelic, 8 biallelic) from 11 publications were included (Ichinose et al, 1994, PMID 7874165; Blau et al, 1995, PMID 7869202; Ichinose et al, 1005, PMID 7730309; Bandmann et al, 1998, PMID 9778264; Furukawa et al, 1998, PMID 9667588; Hwu et al, 1999, PMID 10987649; Hahn et al, 2001, PMID 11346370; Nardocci et al, 2003, PMID 12552057; Trender-Gerhard et al, 2009, PMID 19332422; Sato et al, 2014, PMID 23660475; Dobričić et al, 2017, PMID 28958832). The data includes a large family demonstrating segregation of a variant with monoallelic DRD (Hahn et al, 2001, PMID 11346370). Further information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. Experimental evidence supporting this gene-disease relationship includes the biochemical function of GTPCH, which is consistent with the biochemical and clinical abnormalities observed in these patients (Burg and Brown, 1968, PMID 4296838; Wijemanne and Jankovic, 2015, PMID 26100751), and various mouse models including a GTPCH null mouse (Douglas et al, 2015, PMID 25557619), ethyl nitroso urea-generated hph-1 mouse (Hyland et al, 2003, PMID 12891653), and a mouse with a knock in missense variant analogous to a variant identified in a human patient (Jiang et al, 2019, PMID 30742839). In summary, GCH1 is definitively associated with GTPCH deficiency. 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.