Submission Details

PCBD1 was first reported in relation to autosomal recessive pterin-4 alpha-carbinolamine dehydratase (PCD) deficiency by Thony et al in 1998 (PMID: 9585615). PCD deficiency is a transient form of hyperphenylalaninemia caused by a deficiency in tetrahydrobiopterin (BH4) (reviewed in PMIDs: 19234759, 22729819, 16917893). BH4 is an essential cofactor for the phenylalanine, tyrosine, and tryptophan hydroxylates, thus variation in genes associated with this metabolic pathway can result in the development of hyperphenylalaninemia (reviewed in PMIDs: 19234759, 22729819, 16917893). Evidence supporting this gene-disease relationship includes case-level data, functional data, and model organisms.

Hyperphenylalaninemia disorders are heterogeneous and have been linked to neurological abnormalities, however PCBD1 appears to be linked to a more benign form of the disease (PMID: 16917893). Approximately 5% of BH4 deficiency is accounted to this variation in PCBD1 (reviewed in PMID: 19234759). BIODEF, a database of patient and variant information for some metabolic disorders, contains data for at least 30 individuals with variation in this gene (http://www.biopku.org/biodef/BIODEF_Start.asp). The majority of these individuals were noted as having transient hyperphenylalaninemia, with few noted to have a mild peripheral phenotype. The mechanism for this gene-disease relationship is perturbation of BH4 regeneration, which may lead to excessive phenylalanine and primapterin levels in blood, urine, and tissues (reviewed in PMID: 19234759).

One report has asserted a role of PCBD1 in maturity onset diabetes of the young (MODY) (Simaite et al., 2014 PMID: 24848070), based on evidence to suggest that PCBD1 binds to and acts as a cofactor for HNF1A, a gene that is implicated in MODY, and linkage data in the family at the PCBD1 locus. Review of the segregation evidence among the families reported showed non-segregation of the PCBD1 variation, meaning individuals were positive for a MODY (or an unspecified form of diabetes) and negative for the PCBD1 mutation. Furthermore, several of the implicated individuals had a diabetes phenotype and had autosomal dominant inheritance of the PCBD1, which is inconsistent with PCD deficiency’s recessive inheritance pattern. While the preliminary evidence is compelling, at this time there is insufficient evidence to link the phenotype of MODY with PCD deficiency, therefore these individuals were not included as part of the gene-disease curation at this time.

In summary, PCBD1 is definitively associated with autosomal recessive pterin-4 alpha-carbinolamine dehydratase (PCD). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy GCEP on February 22, 2019 (SOP Version 6).