Submission Details

The relationship between TH and tyrosine hydroxylase deficiency, an autosomal recessive disorder of tyrosine metabolism, was evaluated using the ClinGen Clinical Validity Framework as of March 8th, 2019. Variants in TH were first reported in humans with this disorder in 1995 (Lüdecke et al, PMID 7814018). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Fourteen unique variants were curated (missense, nonsense, frameshift, intronic, and promoter) in 15 probands from 14 publications (Lüdecke et al, 1995, PMID 7814018; van den Heuvel et al, 1998, PMID 9703425; Janssen et al, 2000, PMID 11281275; Swaans et al, 2000, PMID 11246459; Furukawa et al, 2001, PMID 11160968; Hoffmann et al, 2003, PMID 12891655; Ribasés et al, 2007, PMID 17698383; Verbeek et al, 207, PMID 17696123; Pons et al, 2010, PMID 20198643; Ormazabal et al, 2011, PMID 21465550; Chi et al, 2012, PMID 22264700; Goswami et al, 2017, PMID 28667724; Katus et al, 2017, PMID 29225908; Feng et al, 2018, PMID 30383639). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of TH, which catalyzes the conversion of L-tyrosine to L-dopa (Nagatsu et al, 1964, PMID 5836553), functional studies (Fossbakk et al, 2014, PMID 24753243) and the biochemical features and clinical features of mouse models (Kobayashi et al, 1995, PMID 7592982; Korner et al, 2015, PMID 26276013). In summary, TH is definitively associated with TH deficiency. 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 Gene Curation Expert Panel. This curation includes data collected by Counsyl.