Reclassification of theHPGDp.Ala13Glu variant causing primary hypertrophic osteoarthropathy

Abstract

Here, we highlight the case of a 31-yr-old man who had clinical features of primary hypertrophic osteoarthropathy (PHOAR) and harbored a homozygous variant (c.38C > A, p.Ala13Glu) in theHPGDgene, as indicated by whole-exome sequencing (WES). This variant has been previously classified by our laboratory as a variant of uncertain significance (VUS). However, another patient with the same phenotype and the same homozygous variant inHPGDwas subsequently reported. In reassessing the variant, the absence of this variant in the gnomAD population database, supporting computational predictions, observation in homozygosity in two probands, and specificity of the phenotype forHPGD, all provide sufficient evidence to reclassify theHPGDc.38C > A, p.Ala13Glu variant as likely pathogenic.