Gašper Klančar1, Urh Grošelj2, Jernej Kovač3, Nevenka Bratanič2, Nataša Bratina2, Katarina Trebušak Podkrajšek4, Tadej Battelino5. 1. Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, UMC Ljubljana, Ljubljana, Slovenia; Unit of Special Laboratory Diagnostics, University Children's Hospital, UMC Ljubljana, Ljubljana, Slovenia. 2. Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, UMC Ljubljana, Ljubljana, Slovenia. 3. Unit of Special Laboratory Diagnostics, University Children's Hospital, UMC Ljubljana, Ljubljana, Slovenia. 4. Unit of Special Laboratory Diagnostics, University Children's Hospital, UMC Ljubljana, Ljubljana, Slovenia; Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. 5. Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, UMC Ljubljana, Ljubljana, Slovenia; Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. Electronic address: tadej.battelino@mf.uni-lj.si.
Abstract
BACKGROUND: Individuals with familial hypercholesterolemia (FH) who are untreated have up to 100-fold elevated risk for cardiovascular complications compared with those who are unaffected. Data for identification of FH with a universal screening for hypercholesterolemia in children are lacking. OBJECTIVES: This study sought genetic identification of FH from a cohort of children with elevated serum total cholesterol (TC) concentration, detected in a national universal screening for hypercholesterolemia. METHODS: Slovenian children born between 1989 and 2009 (n = 272) with TC >6 mmol/l (231.7 mg/dl) or >5 mmol/l (193.1 mg/dl) plus a family history positive for premature cardiovascular complications, identified in a national universal screening for hypercholesterolemia at 5 years of age were genotyped for variants in LDLR, PCSK9, APOB, and APOE. RESULTS: Of the referred children, 57.0% carried disease-causing variants for FH: 38.6% in LDLR, 18.4% in APOB, and none in PCSK9. Nine novel disease-causing variants were identified, 8 in LDLR, and 1 in APOB. Of the remaining participants, 43.6% carried the APOE E4 isoform. Estimated detection rate of FH in the universal screening program from 2009 to 2013 was 53.6% (95% confidence interval [CI]: 34.5% to 72.8%), peaking in 2013 with an upper estimated detection rate of 96.3%. Variants in LDLR, APOB, or the APOE E4 isoform occurred in 48.6%, 60.0%, and 76.5%, respectively, of patients with a family history negative for cardiovascular complications. CONCLUSIONS: Most participants who were referred from a national database of universal screening results for hypercholesterolemia had genetically confirmed FH. Data for family history may not suffice for reliable identification of patients through selective and cascade screening.
BACKGROUND: Individuals with familial hypercholesterolemia (FH) who are untreated have up to 100-fold elevated risk for cardiovascular complications compared with those who are unaffected. Data for identification of FH with a universal screening for hypercholesterolemia in children are lacking. OBJECTIVES: This study sought genetic identification of FH from a cohort of children with elevated serum total cholesterol (TC) concentration, detected in a national universal screening for hypercholesterolemia. METHODS: Slovenian children born between 1989 and 2009 (n = 272) with TC >6 mmol/l (231.7 mg/dl) or >5 mmol/l (193.1 mg/dl) plus a family history positive for premature cardiovascular complications, identified in a national universal screening for hypercholesterolemia at 5 years of age were genotyped for variants in LDLR, PCSK9, APOB, and APOE. RESULTS: Of the referred children, 57.0% carried disease-causing variants for FH: 38.6% in LDLR, 18.4% in APOB, and none in PCSK9. Nine novel disease-causing variants were identified, 8 in LDLR, and 1 in APOB. Of the remaining participants, 43.6% carried the APOE E4 isoform. Estimated detection rate of FH in the universal screening program from 2009 to 2013 was 53.6% (95% confidence interval [CI]: 34.5% to 72.8%), peaking in 2013 with an upper estimated detection rate of 96.3%. Variants in LDLR, APOB, or the APOE E4 isoform occurred in 48.6%, 60.0%, and 76.5%, respectively, of patients with a family history negative for cardiovascular complications. CONCLUSIONS: Most participants who were referred from a national database of universal screening results for hypercholesterolemia had genetically confirmed FH. Data for family history may not suffice for reliable identification of patients through selective and cascade screening.
Authors: Lee A Pyles; Christa L Lilly; Charles J Mullett; Emily S Polak; Eloise M Elliott; William A Neal Journal: J Lipid Res Date: 2017-09-04 Impact factor: 5.922
Authors: Gerald F Watts; Samuel S Gidding; Pedro Mata; Jing Pang; David R Sullivan; Shizuya Yamashita; Frederick J Raal; Raul D Santos; Kausik K Ray Journal: Nat Rev Cardiol Date: 2020-01-23 Impact factor: 32.419
Authors: Amit V Khera; Hong-Hee Won; Gina M Peloso; Kim S Lawson; Traci M Bartz; Xuan Deng; Elisabeth M van Leeuwen; Pradeep Natarajan; Connor A Emdin; Alexander G Bick; Alanna C Morrison; Jennifer A Brody; Namrata Gupta; Akihiro Nomura; Thorsten Kessler; Stefano Duga; Joshua C Bis; Cornelia M van Duijn; L Adrienne Cupples; Bruce Psaty; Daniel J Rader; John Danesh; Heribert Schunkert; Ruth McPherson; Martin Farrall; Hugh Watkins; Eric Lander; James G Wilson; Adolfo Correa; Eric Boerwinkle; Piera Angelica Merlini; Diego Ardissino; Danish Saleheen; Stacey Gabriel; Sekar Kathiresan Journal: J Am Coll Cardiol Date: 2016-04-03 Impact factor: 24.094