System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Epublish

PubMed: 40919303 DOI: 10.1016/j.gimo.2025.103445

Rare variant genetic landscape of familial chylomicronemia syndrome (FCS) in the United Kingdom.

Genet Med Open 3:103445

Authors: Bilal Bashir, Natalie Forrester, Paul Downie, Sarah Marsh, Carolyn Dent, Anthony S Wierzbicki, Charlotte Dawson, Jonathan Schofield, Fiona Jenkinson, Michael Mansfield, Dev Datta, Hannah Delaney, Yee Teoh, Paul Hamilton, Jaimini Cegla, Maryam Ferdousi, Anoushka Kamath, Pankaj Gupta, Ahai Luvai, Dawn O'Sullivan, Deanna Mamood, Jian Wang, Paul N Durrington, Robert A Hegele, Handrean Soran

Affiliations

  • Faculty of Biology Medicine and Health, University of Manchester, United Kingdom.
  • Department of Endocrinology, Diabetes and Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
  • Bristol Genetics Laboratory, North Bristol NHS Trust, Bristol, United Kingdom.
  • Department of Clinical Biochemistry, Bristol Royal Infirmary, Bristol, United Kingdom.
  • Department of Metabolic Medicine and Chemical Pathology, Guy's and St. Thomas' Hospitals, London, United Kingdom.
  • Department of Diabetes, Endocrinology and Metabolism, Queen Elizabeth Hospital NHS Foundation Trust, Birmingham, United Kingdom.
  • Department of Clinical Biochemistry and Metabolic Medicine, Royal Victoria Infirmary, Newcastle upon Tyne, New Castle, United Kingdom.
  • Leeds Centre for Diabetes and Endocrinology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
  • Lipid Unit, University Hospital Llandough, Cardiff, United Kingdom.
  • Department of Clinical Chemistry, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.
  • Department of Chemical Pathology and Metabolic Medicine, Wrexham Maelor Hospital, Wrexham, United Kingdom.
  • Centre for Medical Education, Queen's University Belfast, Belfast, United Kingdom.
  • Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
  • University Hospitals of Leicester NHS Trust, Leicester, United Kingdom.
  • North of Scotland Genetics Laboratory, Polwarth Building, Aberdeen, Scotland, United Kingdom.
  • Department of Medical Genetics, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom.
  • College of Medicine, University of Sulaimani, Sulaimani, Federal Region of Kurdistan, Iraq.
  • Robarts Research Institute, Western University, London, Ontario, Canada.

Abstract

PURPOSE

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to analyze the genotype distribution of FCS-causing genes in the United Kingdom.

METHODS

Data were anonymously collated from 2 genetic testing laboratories providing national genetic diagnosis services for severe hypertriglyceridemia in the United Kingdom.

RESULTS

As of December 2023, 880 individuals underwent genetic testing for FCS. The mean (SD) age at the time of genetic testing was 42.5 (15.3) years. After genotyping, 12.9% of the individuals (n = 114) received a genetic diagnosis of FCS. The detection rate of variant-positive multifactorial chylomicronemia syndrome, ie, heterozygous for pathogenic/likely pathogenic (P/LP) variants in 1 of the 5 canonical genes was 11.4% (n = 100).Among 114 genetically proven FCS individuals, 52.6% (n = 60) had biallelic P/LP LPL variants (ie, LPL-FCS), 45.6% (n = 52) had biallelic non-LPL P/LP variants (ie, non-LPL-FCS) and 1.7% (n = 2) individuals were digenic. Among non-LPL-FCS (n = 52), the most common gene implicated was GPIHBP1 (42.3%, n = 22), followed by APOA5 (32.7%, n = 17), LMF1 (13.5%, n = 7) and APOC2 (11.5%, n = 6). Most variant-positive multifactorial chylomicronemia syndrome harbored P/LP variants in LPL (61%) or APOA5 (37%).The geographical distribution of FCS demonstrated regional variability, where the Northwest of England had the highest number of FCS cases per million population. Individuals of European geographic ancestry predominantly had LPL-FCS (60.9%); however, genotype was more diverse in individuals of non-European origin (LPL 47.1%, GPIHBP1 30.9%, APOA5 8.8%, LMF1 7.4%, and APOC2 4.4%). Variants in specific causal genes, GPIHBP1 and LMF1, were predominantly observed in non-European FCS individuals.

CONCLUSION

The genetic architecture of FCS in the United Kingdom is complex, with a substantial proportion affected by non-LPL FCS-causing genes. It also displays a significant regional and ethnic variations.

MeSH

Research Design, Genes, Genetic Testing, Genotype, Diagnosis, Hyperlipoproteinemia Type I, Costello Syndrome