HPD

Inheritance Pattern: AR

Disease ID:MONDO:0010162

Submitter: Orphanet

Inheritance Pattern: Unknown

Disease ID:MONDO:0007700

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0010162

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0010162

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0010162

Submitter: ClinGen

HPD was first reported in relation to autosomal recessive Tyrosinemia Type 3 in 2000 (Rüetschi et al., 2000; PMID: 10942115). Tyrosinemia is primarily a biochemical phenotype with elevated tyrosine, 4-hydroxyphenylpyruvate, and its derivatives; it remains unclear if tyrosinemia type III is a predisposing factor that is strongly associated with cognitive delays, or if the association is purely on the basis of ascertainment bias. At least 7 unique variants (4 missense, 2 nonsense, and 1 splicing) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 7 probands in 5 publications (PMIDs: 10942115, 11073718, 28649543, 23036342, 31901053). Variants in this gene segregated with disease in 2 additional family members. Of note, this gene has been implicated in autosomal dominant Hawkinsinuria, in which the primary presentation is metabolic acidosis and a single reported pathogenic mutation has been identified. This will be assessed separately. The gene disease relationship is supported by biochemical function, animal models, and rescue experiments. The biochemical function of HPD in tyrosine metabolism accounts for the typical high plasma tyrosine and high levels of 4-hydroxyphenylpyruvate and its derivatives in urine of Tyrosinemia Type 3 patients. A homozygous loss of function mouse exhibits similar biochemical phenotypes which can be rescued by adenoviral expression of human HPD. In summary, HPD is definitively associated with autosomal recessive Tyrosinemia Type 3. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism (partial verses full loss of function), inheritance pattern (autosomal dominant verses recessive), and phenotypic variability (biochemical phenotype verses clinical manifestations). Therefore, we have split curations for the disease entities, Tyrosinemia type III and Hawkinsinuria.

Inheritance Pattern: AR

Disease ID:MONDO:0010162

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0007700

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0007700

Submitter: ClinGen

Hawkinsinuria is a rare disorder of tyrosine metabolism that can manifest with metabolic acidosis and growth arrest around the time of weaning off breast milk, typically followed by spontaneous resolution of symptoms around 1 year of age. The urinary metabolites hawkinsin, quinolacetic acid, and pyroglutamic acid can aid in identifying this condition, although their relationship to the clinical manifestations is not known (PMID: 27488560). HPD was first reported in relation to autosomal dominant Hawkinsinuria in 2000 (Tomoeda K, et al., 2000, PMID: 11073718). One variant, Asn241Ser, has been supported as causative for Hawkinsinuria and one polymorphism, Ala33Thr has been associated with the disease multiple times. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 9 probands in 6 publications (PMIDs: 11073718, 31342835, 17560158, 26226126, 30984715, 27488560). Variants in this gene segregated with disease in 1 additional family member. Of note, this gene has been implicated in autosomal recessive Tyrosinemia, type III, which is predominantly a biochemical phenotype. This has been assessed separately. The gene disease relationship is supported by its biochemical function and a mouse model which can be rescued by adenoviral expression of human HPD (PMID: 7774914, PMID: 8989996). The biochemical function of HPD in tyrosine metabolism accounts for the typical high plasma tyrosine and high levels of 4-hydroxyphenylpyruvate and its derivatives in urine of Hawkinsinuria, as well as Tyrosinemia patients. The mechanism of action of HPD involves a decarboxylation step and an oxidation step, followed by a rearrangement step to form homogentisic acid. In Hawkinsinuira a partial loss of enzyme activity, capable of decarboxylation and oxidation, but not of rearrangement, allows for dissociation of a reactive epoxide that reacts with glutathione to form the Hawkinsinuria specific metabolite hawkinsin, which can be broken down into 4-hydroxycyclohexylacetic acid. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism (partial verses full loss of function), inheritance pattern (autosomal dominant verses recessive), and phenotypic variability (biochemical phenotype verses clinical manifestations). Therefore, we have split curations for the disease entities, Tyrosinemia type III and Hawkinsinuria. This gene-disease pair was previously evaluated by the Aminoacidopathy GCEP on 06/26/2020. It was reevaluated on 10/24/2023. As a result of this reevaluation, the classification remained Limited with no new evidence identified.

Inheritance Pattern: AD

Disease ID:MONDO:0007700

Submitter: G2P