Skeletal dysplasia

Gene: HPGD

Green List (high evidence)

Comment on mode of inheritance: Out of more than 70 Primary hypertrophic osteoarthropathy (PHO) patients reported in literature, only 3 of them habroured monoallelic HPGD variants and only direct HPGD/SLCO2A1 Sanger sequencing was used in these studies. Some het carrier family members in recessive pedigrees presented with mild digital clubbing - not in scope of this panel. Based on available literature, the evidence for a dominant association is limited and the mode of inheritance should be changed to BIALLELIC only. An expert_review tag was added to ensure GMS agreement regarding this change.

Created: 10 Sep 2026, 3:56 p.m. | Last Modified: 10 Sep 2026, 4:07 p.m.

Panel Version: 10.8

PMID: 35813463 Lu et al., 2022
Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. Direct HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. All patients were negative for SLCO2A1 mutations.
The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia).
Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants.

PMID: 26135126 Yuan et al., 2015
Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Seq method: Sanger seq of HPGD only.
Heterozygous individuals (P8 and P9) were het for the c.310_311del variant. Both individuals had digital clubbing. P8 also showed pachydermia, while P9 presented with periostosis, joint swelling, and hyperhidrosis. The authors acknowledge the possiblity that a second undetectable null mutation may have been missed in the het patients, due to limitations of Sanger sequencing. They were negative for SLCO2A1 mutations.
Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4.

PMID: 18500342 Uppal et al., 2008
Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. Only HPGD was sequenced, using PCR amplification.

HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.

Created: 10 Sep 2026, 3:33 p.m. | Last Modified: 10 Sep 2026, 4:04 p.m.

Panel Version: 10.8

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Digital clubbing, isolated congenital , OMIM:119900; Cranioosteoarthropathy, OMIM:259100; Hypertrophic osteoarthropathy, primary, autosomal recessive 1, OMIM:259100

Publications

• 18500342
• 26135126
• 35813463

Green List (high evidence)

Other sclerosing bone disorders gp of SD. Het carriers can have mild skeletal features. Several cases; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Cranioosteoarthropathy 259100; Digital clubbing, isolated congenital 119900; Hypertrophic osteoarthropathy, primary, autosomal recessive 1 259100

I don't know

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: HPGD; Initial rating suggestion: green

Created: 6 Mar 2019, 11:36 a.m.

Comment on list classification: Used diagnostically by Ana Beleza (Guy's and St Thomas' NHS Foundation Trust)

Created: 21 Jun 2016, 12:55 p.m.

Green List (high evidence)

Tier 1

Created: 17 Jun 2016, 8:04 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Cranioosteoarthropathy 259100; Digital clubbing, isolated congenital 119900; Hypertrophic osteoarthropathy, primary, autosomal recessive 1 259100

Variants in this GENE are reported as part of current diagnostic practice