RT Journal Article SR Electronic T1 Clinical and subclinical findings in heterozygous ABCC6 carriers: results from a Belgian cohort and clinical practice guidelines JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2020-107565 DO 10.1136/jmedgenet-2020-107565 A1 Lukas Nollet A1 Laurence Campens A1 Julie De Zaeytijd A1 Bart Leroy A1 Dimitri Hemelsoet A1 Paul J Coucke A1 Olivier M Vanakker YR 2021 UL http://jmg.bmj.com/content/early/2021/04/04/jmedgenet-2020-107565.abstract AB Background Biallelic pathogenic variants in the ATP-binding cassette subfamily C member 6 (ABCC6) gene cause pseudoxanthoma elasticum, a multisystemic ectopic calcification disorder, while heterozygous ABCC6 variants are associated with an increased risk of cardiovascular and cerebrovascular disease. As the prevalence of pathogenic ABCC6 variants in the general population is estimated at ~1%, identifying additional ABCC6-related (sub)clinical manifestations in heterozygous carriers is of the utmost importance to reduce this burden of disease. Here, we present a large Belgian cohort of heterozygous ABCC6 carriers with comprehensive clinical, biochemical and imaging data. Based on these results, we formulate clinical practice guidelines regarding screening, preventive measures and follow-up of ABCC6 carriers.Methods The phenotype of 56 individuals carrying heterozygous pathogenic ABCC6 variants was assessed using clinical (eg, detailed ophthalmological examinations), biochemical, imaging (eg, cardiovascular and abdominal ultrasound) and genetic data. Clinical practice guidelines were then drawn up.Results We found that ABCC6 heterozygosity is associated with distinct retinal alterations (‘comet-like’) (24%), high prevalence of hypercholesterolaemia (>75%) and diastolic dysfunction (33%), accelerated lower limb atherosclerosis and medial vascular disease, abdominal organ calcification (26%) and testicular microlithiasis (28%), though with highly variable expression.Conclusion In this study, we delineated the multisystemic ABCC6 heterozygosity phenotype characterised by retinal alterations, aberrant lipid metabolism, diastolic dysfunction and increased vascular, abdominal and testicular calcifications. Our clinical practice guidelines aimed to improve early diagnosis, treatment and follow-up of ABCC6-related health problems.Data are available upon reasonable request.