Monoallelic mutations in <scp> <i>SLCO2A1</i> </scp> cause autosomal dominant primary hypertrophic osteoarthropathy

Primary hypertrophic osteoarthropathy (PHO) is a rare disease inherited as recessive or irregular dominant trait and characterized by digital clubbing, pachydermia, periostosis. Biallelic mutations in HPGD SLCO2A1, disturbing prostaglandin E2 (PGE2 ) catabolism leading to increased circulating PGE2 level, cause PHO autosomal 1 (PHOAR1) 2 (PHOAR2), respectively. However, no causative genes have been reported for (PHOAD). Here, we performed Sanger sequencing whole-genome (WGS) on DNA samples from seven Chinese PHOAD families; after excluding other single-nucleotide variants (SNVs), structural variations (SVs), copy number (CNVs) the genomes, six SLCO2A1 monoallelic (c.1660G>A [p.G554R], c.664G>A [p.G222R], c.1106G>A [p.G369D], c.1065dupA [p.Q356TfsX77], c.1293delT [p.S432AfsX48], c.1807C>T [p.R603X]) probands affected family members. Then, five families with carrying biallelic mutations, verified that parents also displayed manifestations, which further confirmed pathogenicity of illustrated allelic nature PHOAR2. Subsequently, through comparison 50 PHOAR2 patients, found onset age puberty skewed penetrance rate were similar both types, but symptoms signs milder, including less severe pachydermia (p = .027) periostosis .005), frequent cutis verticis gyrata .011), acne arthralgia .037), anemia .023). The median urinary level was almost half patients (PHOAD 277.58 ng/mmoL creatinine, 473.19 creatinine; p .038). Moreover, 3-month trial oral administration etoricoxib, an effective response previously observed probands. In conclusion, our findings confirm are broaden phenotypic spectrum PHO. © 2021 American Society Bone Mineral Research (ASBMR).