Familial erythrocytosis associated with an EGLN1 (PHD2) variant of uncertain significance with emerging evidence of pathogenicity

Familial erythrocytosis is a rare disorder most often linked to germline alterations affecting erythropoiesis and oxygen-sensing pathways. The EGLN1 gene encodes prolyl hydroxylase domain-containing protein 2 (PHD2), a central regulator of the hypoxia-inducible factor (HIF) pathway that modulates erythropoietin (EPO) production. This report describes a mother and son with longstanding erythrocytosis, both harbouring a heterozygous EGLN1 variant of uncertain significance (c.806T>C, p.Ile269Thr), in whom secondary causes and JAK2 -mutated myeloproliferative neoplasms were excluded. Both individuals required serial phlebotomy for haematocrit control and biochemical as well as molecular testing supported congenital erythrocytosis. The EGLN1 variant has been reported rarely and is supported by in-silico and functional data suggesting deleterious effects on PHD2 protein stability and function. Based on the aggregate evidence derived from a European cohort, this variant has previously been proposed to meet the criteria for pathogenic classification under the ACMG guidelines. This case adds clinical and functional evidence supporting ACMG/AMP-based classification of EGLN1 c.806T>C (p.Ile269Thr) as likely pathogenic in familial erythrocytosis.