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

Authors
  • Nollet, Lukas1, 2
  • Campens, Laurence3
  • De Zaeytijd, Julie4
  • Leroy, Bart4, 5
  • Hemelsoet, Dimitri6
  • Coucke, Paul J1, 2
  • Vanakker, Olivier M7, 2
  • 1 Center for Medical Genetics, University Hospital Ghent, Ghent, Belgium. , (Belgium)
  • 2 Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. , (Belgium)
  • 3 Department of Cardiology, University Hospital Ghent, Ghent, Belgium. , (Belgium)
  • 4 Department of Ophthalmology, University Hospital Ghent, Ghent, Belgium. , (Belgium)
  • 5 Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • 6 Department of Neurology, University Hospital Ghent, Ghent, Belgium. , (Belgium)
  • 7 Center for Medical Genetics, University Hospital Ghent, Ghent, Belgium [email protected] , (Belgium)
Type
Published Article
Journal
Journal of Medical Genetics
Publisher
BMJ
Publication Date
May 01, 2022
Volume
59
Issue
5
Pages
496–504
Identifiers
DOI: 10.1136/jmedgenet-2020-107565
PMID: 33820832
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. 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. © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

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