Screening for familial hypercholesterolaemia in childhood: Avon Longitudinal Study of Parents and Children (ALSPAC)

Futema, M., Cooper, J. A., Charakida, M., Boustred, C., Sattar, N. , Deanfield, J., Lawlor, D. A., Timpson, N. J., Humphries, S. E. and Hingorani, A. D. (2017) Screening for familial hypercholesterolaemia in childhood: Avon Longitudinal Study of Parents and Children (ALSPAC). Atherosclerosis, 260, pp. 47-55. (doi: 10.1016/j.atherosclerosis.2017.03.007) (PMID:28349888) (PMCID:PMC5414415)

Abstract

Background and aims: 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. Methods: 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. Results: 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. Conclusions: 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.

• Item Type: Articles
• Keywords: ALSPAC, familial hypercholesterolaemia, familial hypercholesterolaemia screening, LDL-cholesterol, next generation sequencing, total cholesterol.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sattar, Professor Naveed
• Authors: Futema, M., Cooper, J. A., Charakida, M., Boustred, C., Sattar, N., Deanfield, J., Lawlor, D. A., Timpson, N. J., Humphries, S. E., and Hingorani, A. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Atherosclerosis
• Publisher: Elsevier
• ISSN: 0021-9150
• ISSN (Online): 1879-1484
• Published Online: 08 March 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Atherosclerosis 260: 47-55
• Publisher Policy: Reproduced under a Creative Commons License