Genetic diagnosis of familial hypercholesterolaemia by targeted next‐generation sequencing. (21st May 2014)

• Record Type: Journal Article
• Authors: Maglio, C.; Mancina, R. M.; Motta, B. M.; Stef, M.; Pirazzi, C.; Palacios, L.; Askaryar, N.; Borén, J.; Wiklund, O.; Romeo, S.
• Is Part Of: Journal of internal medicine. Volume 276:Number 4(2014:Oct.)
• Page Start: 396
• Page End: 403
• Publication Date: 2014-05-21
• Subjects: Internal medicine -- Periodicals; Medicine -- Periodicals; 616
• DOI: 10.1111/joim.12263
• Languages: English
• ISSNs: 0954-6820

Abstract

<abstract abstract-type="main" id="joim12263-abs-0001"> <title>Abstract</title> <sec id="joim12263-sec-0001" sec-type="section"> <title>Objectives</title> <p>The aim of this study was to combine clinical criteria and next‐generation sequencing (pyrosequencing) to establish a diagnosis of familial hypercholesterolaemia (FH).</p> </sec> <sec id="joim12263-sec-0002" sec-type="section"> <title>Design, setting and subjects</title> <p>A total of 77 subjects with a Dutch Lipid Clinic Network score of ≥3 (possible, probable or definite FH clinical diagnosis) were recruited from the Lipid Clinic at Sahlgrenska Hospital, Gothenburg, Sweden. Next‐generation sequencing was performed in all subjects using SEQPRO LIPO RS, a kit that detects mutations in the low‐density lipoprotein receptor (<italic>LDLR)</italic>, apolipoprotein B (<italic>APOB</italic>), proprotein convertase subtilisin/kexin type 9 (<italic>PCSK9</italic>) and LDLR adapter protein 1 (<italic>LDLRAP1)</italic> genes; copy‐number variations in the <italic>LDLR</italic> gene were also examined.</p> </sec> <sec id="joim12263-sec-0003" sec-type="section"> <title>Results</title> <p>A total of 26 mutations were detected in 50 subjects (65% success rate). Amongst these, 23 mutations were in the <italic>LDLR</italic> gene, two in the <italic>APOB</italic> gene and one in the <italic>PCSK9</italic> gene. Four mutations with unknown pathogenicity were detected in <italic>LDLR</italic>. Of these, three mutations (Gly505Asp, Ile585Thr and Gln660Arg) have been previously reported in subjects with FH, but their pathogenicity has not been proved. The fourth, a mutation in <italic>LDLR</italic> affecting a splicing site (exon 6–intron 6) has not previously been reported; it was found to segregate with high cholesterol levels in the family of the proband.</p> </sec> <sec id="joim12263-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Using a combination of clinical criteria and targeted next‐generation sequencing, we have achieved FH diagnosis with a high success rate. Furthermore, we identified a new splicing‐site mutation in the <italic>LDLR</italic> gene.</p> </sec> </abstract>