The relationship between HPDL and Leigh syndrome spectrum (LSS) was evaluated using the ClinGen Clinical Validity Framework as of June 30, 2021. The HPDL gene encodes 4-hydroxyphenylpyruvate dioxygenase-like protein, a putative iron-containing oxygenase. The mechanism underlying how pathogenic variants in this gene affect mitochondria and cause disease is unclear.
The HPDL gene was first reported in relation to autosomal recessive LSS in 2020 (PMID: 32707086). Evidence supporting the relationship between HPDL and LSS includes case-level data and experimental data. This curation included nine unique variants identified in five cases from two publications (PMID: 32707086, 33970200). Of note, variants in HPDL have also been associated with infantile-onset encephalopathy and spastic paraplegia. No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by expression and animal models (PMIDs: 18853439, 33188300).
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 30, 2021 (SOP Version 7).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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