<abstract xmlns="http://www.w3.org/1999/xhtml"><p>Familial hypercholesterolemia (FH) is one of the most common single gene disorders, which is mostly inherited as an autosomal dominant trait. The physical signs of FH are elevated low density lipoprotein cholesterol (LDL-C), elevated total cholesterol (TC) levels and tendon xantomas. Identification and early treatment of affected individuals is desirable and in lack of physical symptoms DNA-based diagnosis provides confirmation of diagnosis and enables early patient management. The majority of FH cases are caused by mutations in four genes (<italic>APOB, LADLR, PCSK9,</italic> and <italic>LDLRAP1</italic>). There are commercial kits available for testing of the 20 most common FH causing mutations, but the spectrum of disease-causing mutations is quite diverse in various populations and these tests cover only a minority of disease-causing genetic variants. There is therefore a need to determine the full spectrum of mutations in <italic>LDLR, APOB, PCSK9,</italic> and <italic>LDLRAP1</italic> genes in each population. Here we report mutations found in 16 patients with suspected FH in a sample from the Genome Database of the Latvian population enrolled at the Latvian Centre of Cardiology. We used the next generation sequencing approach to determine the full spectrum of mutations in coding regions of <italic>LDLR, APOB, PCSK9</italic>, and <italic>LDLRAP1.</italic> In total we found 22 missense mutations, from which only rs5742904 (Arg3527Gln) in <italic>APOB</italic> gene had been previously described as a FH-causing mutation confirming FH in one patient. Possible FH-causing mutations however, were identified in the majority of patients. The conclusion is that the most commonly employed commercial mutation panel is not sufficient for diagnosis of FH patients and NGS can help to identify FH-causing mutations in the Latvian population.</p></abstract>

Familial hypercholesterolemia (FH) is one of the most common single gene disorders, which is mostly inherited as an autosomal dominant trait. The physical signs of FH are elevated low density lipoprotein cholesterol (LDL-C), elevated total cholesterol (TC) levels and tendon xantomas. Identification and early treatment of affected individuals is desirable and in lack of physical symptoms DNA-based diagnosis provides confirmation of diagnosis and enables early patient management. The majority of FH cases are caused by mutations in four genes (APOB, LADLR, PCSK9, and LDLRAP1). There are commercial kits available for testing of the 20 most common FH causing mutations, but the spectrum of disease-causing mutations is quite diverse in various populations and these tests cover only a minority of disease-causing genetic variants. There is therefore a need to determine the full spectrum of mutations in LDLR, APOB, PCSK9, and LDLRAP1 genes in each population. Here we report mutations found in 16 patients with suspected FH in a sample from the Genome Database of the Latvian population enrolled at the Latvian Centre of Cardiology. We used the next generation sequencing approach to determine the full spectrum of mutations in coding regions of LDLR, APOB, PCSK9, and LDLRAP1. In total we found 22 missense mutations, from which only rs5742904 (Arg3527Gln) in APOB gene had been previously described as a FH-causing mutation confirming FH in one patient. Possible FH-causing mutations however, were identified in the majority of patients. The conclusion is that the most commonly employed commercial mutation panel is not sufficient for diagnosis of FH patients and NGS can help to identify FH-causing mutations in the Latvian population.

Evaluation Of Massive Parallel Sequencing As A Diagnostic Tool For Familial Hypercholesterolemia

Latvian Biomedical Research and Study Centre, Rātsupītes iela 1, Rīga, LV-1067, LATVIA

Latvian Centre of Cardiology, Pauls Stradiņš Clinical University Hospital, Rīga, Dzirciema iela 20, LV-1007, LATVIA

Faculty of Medicine, University of Latvia, Raiņa bulv. 19, Rīga, LV-1586, LATVIA

Research Institute of Cardiology, University of Latvia, Pilsoņu iela 13, Rīga, LV-1002, LATVIA

Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences.

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

LIELA APJOMA PARALĒLĀ SEKVENĒŠANA KĀ VISPILNĪGĀKAIS DIAGNOSTIKAS VEIDS IEDZIMTAI HIPERHOLESTERINĒMIJAI

Familial hypercholesterolemia (FH) is one of the most common single gene disorders, which is mostly inherited as an autosomal dominant trait. The physical...

Evaluation Of Massive Parallel Sequencing As A Diagnostic Tool For Familial Hypercholesterolemia

Published Online: Jul 14, 2015

Page range: 1 - 7

Received: Dec 01, 2013

DOI: https://doi.org/10.2478/prolas-2014-0011

Keywords
NGS, familial hypercholesterolemia, LDLR, APOB, PCSK9, LDLRAP1

© Ilze Radoviča et al.

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Evaluation Of Massive Parallel Sequencing As A Diagnostic Tool For Familial Hypercholesterolemia

Published Online: Jul 14, 2015

Page range: 1 - 7

Received: Dec 01, 2013

DOI: https://doi.org/10.2478/prolas-2014-0011

KeywordsNGS, familial hypercholesterolemia, LDLR, APOB, PCSK9, LDLRAP1

© Ilze Radoviča et al.

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Keywords
NGS, familial hypercholesterolemia, LDLR, APOB, PCSK9, LDLRAP1