title: Screening for familial hypercholesterolaemia in childhood: Avon Longitudinal Study of Parents and Children (ALSPAC).
abstract: Familial hypercholesterolaemia (FH) is an autosomal-dominant disease with frequency of 1/500 to 1/250 that leads to premature coronary heart disease. New approaches to identify FH mutation-carriers early are needed to prevent premature cardiac deaths. In a cross-sectional study of the Avon Longitudinal Study of Parents and Children (ALSPAC), we evaluated the biochemical thresholds for FH screening in childhood, and modelled a two-stage biochemical and sequencing screening strategy for FH detection.
  
  
  
  From 5083 ALSPAC children with cholesterol measurement at age nine years, FH genetic diagnosis was performed in 1512 individuals, using whole-genome or targeted sequencing of known FH-causing genes. Detection rate (DR) and false-positive rate (FPR) for proposed screening thresholds (total-cholesterol > 1.53, or LDL-C > 1.84 multiples of the median (MoM)) were assessed.
  
  
  
  Six of 1512 sequenced individuals had an FH-causing mutation of whom five had LDL-C > 1.84 MoM, giving a verification-bias corrected DR of 62.5% (95% CI: 25-92), with a FPR of 0.2% (95% CI: 0.1-0.4). The DR for the TC cut-point of 1.53 MoM was 25% (95% CI: 3.2-65.1) with a FPR of 0.4% (95% CI: 0.2-0.6). We estimated 13 of an expected 20 FH mutation carriers (and 13 of the 20 parental carriers) could be detected for every 10,000 children screened, with false-positives reliably excluded by addition of a next generation sequencing step in biochemical screen-positive samples.
  
  
  
  Proposed cholesterol thresholds for childhood FH screening were less accurate than previously estimated. A sequential strategy of biochemical screening followed by targeted sequencing of FH genes in screen-positive children may help mitigate the higher than previously estimated FPR and reduce wasted screening of unaffected parents.
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Futema
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Cooper
authors.affiliation: National Centre for Cardiovascular Prevention and Outcomes, Institute of Cardiovascular Science, University College London (UCL), London, UK.
authors.forename: Marietta
authors.initials: M
authors.lastname: Charakida
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Boustred
authors.affiliation: Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow, Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.affiliation: National Centre for Cardiovascular Prevention and Outcomes, Institute of Cardiovascular Science, University College London (UCL), London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Deanfield
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK; UCL Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: Genetic Epidemiology Group, Institute of Cardiovascular Science, Farr Institute for Health Informatics, University College London, London, UK. Electronic address: a.hingorani@ucl.ac.uk.
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000097:blood / Q000235:genetics; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics; D002648:Child; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D003430:Cross-Sectional Studies; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D005820:Genetic Testing / Q000379:methods*; D055106:Genome-Wide Association Study; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; C469745:LDLRAP1 protein, human; D004247:DNA
keywords: ALSPAC; Familial hypercholesterolaemia; Familial hypercholesterolaemia screening; LDL-cholesterol; Next generation sequencing; Total cholesterol