Gene Validity Curation

HPD - hawkinsinuria

Gene: HPD (HGNC:5147)
Classification - 06/26/2020
Disease: hawkinsinuria (MONDO_0007700)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Aminoacidopathy EP
Evidence Summary: 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.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 4
1.7
1.7
Thodi G et al. 2016 Jan (PMID:26226126); Item CB et al. 2007 Aug (PMID:17560158); Gomez-Ospina N et al. 2016 Nov (PMID:27488560); Cruz-Camino H et al. 2019 Jul 25 (PMID:31342835);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 1.7
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
1.5
1.5
Fellman JH et al. 1972 Sep 19 (PMID:4627454);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 0.5 0.5
Endo F et al. 1995 Jan 1 (PMID:7774914);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 2

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 1.7 2 3.7 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Limited
06/26/2020
EXPERT CURATION (DATE)
Limited
06/26/2020
EVIDENCE SUMMARY
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.