PAH

Inheritance Pattern: AR

Disease ID:MONDO:0019259

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0009861

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0017389

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0019335

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009861

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009861

Submitter: ClinGen

PAH was first reported in relation to Autosomal Recessive Phenylketonuria in 1986 (DiLella et al., PMID: 3008810). The disease entity and causal enzyme was known well before the characterization of the PAH gene, with a relatively high disease prevalence of 1/10,000 people in European populations. Norwegian physician Ivar Asbjørn Følling first characterized the disease in 1934 by linking phenylketones in the urine to the intellectual disability and other presenting phenotypes, with a later publication demonstrating the positive effect of a low phenylalanine diet on probands (Bickel, Gerrard, and Hickmans, PMID: 13138177). By the time PAH was characterized, phenylketonuria was widely examined on newborn screening panels which limits the number of probands that display symptoms aside from the biochemical abnormality. Over 500 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes a more than sufficient amount of each case-level data, segregation data, and experimental data. Since the initial characterization of PAH in 1986, there have been numerous publications detailing probands and the variants they harbor. Variants in this gene have been reported in at least 23 probands in various publications. Variants in this gene also segregated with the disease in over 10 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. The mechanism for disease is biallelic loss of function, with pathogenic mutations disrupting the ability of phenylalanine hydroxylase in combination with tetrahydrobiopterin (BH4) to catalyze the conversion of phenylalanine to tyrosine as the first step in phenylalanine metabolism (PMID: 1301187). This phenylalanine buildup causes neurological phenotypes such as intellectual disability and other serious medical problems. This gene-disease association is additionally supported by multiple mouse models, rescues, expression studies, in vitro functional assays, and its interactions with the cofactor BH4. Multiple mouse models with known pathogenic PAH mutations have been developed and well-characterized over the years, with succesful rescues being performed on these models as well. Functional assays have demonstrated decreased PAH activity and increased phenylanaine with most pathogenic PAH mutations as well as the causal factor for many missense variants being PAH protein misfolding and resulting decreased function. Finally, BH4 (via the gene QDPR) has also been definitively implicated in hyperphenylalaninemia which further supports the phenylalanine pathway deficiencies being causal for the classic phenotypes. In summary, PAH is definitively associated with Autosomal Recessive Phenylketonuria/Hyperphenylalaninemia. 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 on 04/24/2020 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0009861

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009861

Submitter: Myriad Women's Health

Inheritance Pattern: AR

Disease ID:MONDO:0016366

Submitter: Orphanet