Clinical and subclinical findings in heterozygous <i>ABCC6</i> carriers: results from a Belgian cohort and clinical practice guidelines.

Abstract

Biallelic pathogenic variants in the <i>ATP-binding cassette subfamily C member 6</i> (<i>ABCC6</i>) gene cause pseudoxanthoma elasticum, a multisystemic ectopic calcification disorder, while heterozygous <i>ABCC6</i> variants are associated with an increased risk of cardiovascular and cerebrovascular disease. As the prevalence of pathogenic <i>ABCC6</i> variants in the general population is estimated at ~1%, identifying additional <i>ABCC6</i>-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 <i>ABCC6</i> 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 <i>ABCC6</i> carriers. The phenotype of 56 individuals carrying heterozygous pathogenic <i>ABCC6</i> 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. We found that <i>ABCC6</i> 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. In this study, we delineated the multisystemic <i>ABCC6</i> 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 <i>ABCC6</i>-related health problems.