HPDL

protein-coding

4-hydroxyphenylpyruvate dioxygenase like, the group of Glyoxalase domain containing family

Gene summary

The protein encoded by this intronless gene localizes to mitochondria, where it may function as 4-hydroxyphenylpyruvate dioxygenase. Clinical studies have identified several bi-allelic variants in this gene that lower the level of the encoded protein and lead to a clinically variable form of pediatric-onset spastic movement disorder. [provided by RefSeq, Aug 2020]

Previous symbols:

GLOXD1

MANE transcript

NM_032756.4

Inheritance

ClinVar variants

P:53U:62B:18

Top phenotype

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities; Spastic paraplegia 83, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr1:45,326,895-45,328,710

External References & Databases

Ensembl (ENSG00000186603)

Transcript & Mutation Effects

hg38 • Region Span ~1.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with progressive spasticity and brain white matter abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033613

Submitter: PanelApp Australia

spastic paraplegia 83, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033614

Submitter: PanelApp Australia

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

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).

neurodevelopmental disorder with progressive spasticity and brain white matter abnormalitiesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033613

Submitter: Ambry Genetics

neurodevelopmental disorder with progressive spasticity and brain white matter abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033613

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with progressive spasticity and brain white matter abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033613

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities; Spastic paraplegia 83, autosomal recessiveAR

Manifestation: Biochemical; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 32707086; 33188300; 33970200

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HPDL variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 57

not providedTotal: 34

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalitiesTotal: 34

Spastic paraplegiaTotal: 28

Spastic paraplegia 83, autosomal recessiveTotal: 11

HPDL-related disorderTotal: 4

not specifiedTotal: 3

Spastic ataxiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032756.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				8 clinvar	2 clinvar	10
missense	6 clinvar	20 clinvar	59 clinvar	8 clinvar		93
nonsense	2 clinvar	5 clinvar				7
start loss		1 clinvar	1 clinvar			2
frameshift	7 clinvar	12 clinvar	2 clinvar			21
splice donor/acceptor (+/-2bp)						0
Total	15	38	62	16	2	133

Highest pathogenic variant AF is 0.000051560994

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032756.4	RefSeq	NP_116145.1	1	MANE Select
ENST00000334815.6	Ensembl	ENSP00000335060.3	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

aromatic amino acid family metabolic process
oxidation-reduction process

Molecular Function

4-hydroxyphenylpyruvate dioxygenase activity
metal ion binding

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000334815
Coding exons: 1
Length: 1803
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.933	197	237	0.830	0.0000150	2311
Missense (PolyPhen)		63	80.043	0.78708		910
Synonymous	1.21	100	117	0.858	0.00000831	861
Loss of Function	0.592	8	10.0	0.798	6.56e-7	78

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May have dioxygenase activity. {ECO:0000305}.;

Recessive Scores

pRec: 0.157

Intolerance Scores

LoFtool: 0.623
RVIS EVS: -0.07
RVIS percentile EVS: 48.35

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.313

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium