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Atherosclerosis. 2016 Jul;250:52-6. doi: 10.1016/j.atherosclerosis.2016.04.010. Epub 2016 Apr 11.

Identification of novel APOB mutations by targeted next-generation sequencing for the molecular diagnosis of familial hypobetalipoproteinemia.

Author information

1
INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France; CNRS, UMR 6291, Nantes, F-44000, France; Université de Nantes, Nantes, F-44000, France.
2
INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France; CNRS, UMR 6291, Nantes, F-44000, France; Université de Nantes, Nantes, F-44000, France; CHU Nantes, l'institut du Thorax, Nantes, F-44000, France; CIC Thorax, CHU Nantes, l'institut du Thorax, Nantes, F-44000, France.
3
INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France; CNRS, UMR 6291, Nantes, F-44000, France; Université de Nantes, Nantes, F-44000, France; CHU Nantes, l'institut du Thorax, Nantes, F-44000, France.
4
CHU Nantes, l'institut du Thorax, Nantes, F-44000, France; CIC Thorax, CHU Nantes, l'institut du Thorax, Nantes, F-44000, France.
5
Centre de Recherche en Nutrition Humaine de l'Ouest (CRNHO, INRA UMR1280), Nantes, F-44093, France.
6
Université de Nantes, Nantes, F-44000, France; CHU Nantes, l'institut du Thorax, Nantes, F-44000, France; Centre de Recherche en Nutrition Humaine de l'Ouest (CRNHO, INRA UMR1280), Nantes, F-44093, France.
7
INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France; CNRS, UMR 6291, Nantes, F-44000, France; Université de Nantes, Nantes, F-44000, France; CHU Nantes, l'institut du Thorax, Nantes, F-44000, France. Electronic address: jjschott@univ-nantes.fr.
8
INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France; CNRS, UMR 6291, Nantes, F-44000, France; Université de Nantes, Nantes, F-44000, France; CHU Nantes, l'institut du Thorax, Nantes, F-44000, France; CIC Thorax, CHU Nantes, l'institut du Thorax, Nantes, F-44000, France. Electronic address: bertrand.cariou@univ-nantes.fr.

Abstract

BACKGROUND AND AIMS:

Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by decreased plasma levels of LDL-cholesterol and apolipoprotein B (ApoB). Currently, genetic diagnosis in FHBL relies largely on Sanger sequencing to identify APOB and PCSK9 gene mutations and on western blotting to detect truncated ApoB species.

METHODS:

Here, we applied targeted enrichment and next-generation sequencing (NGS) on a panel of three FHBL genes and two abetalipoproteinemia genes (APOB, PCSK9, ANGPTL3, MTTP and SAR1B).

RESULTS:

In this study, we identified five likely pathogenic heterozygous rare variants. These include four novel nonsense mutations in APOB (p.Gln845*, p.Gln2571*, p.Cys2933* and p.Ser3718*) and a rare variant in PCSK9 (Minor Allele Frequency <0.1%). The affected family members tested were shown to be carriers, suggesting co-segregation with low LDL-C.

CONCLUSIONS:

Our study further demonstrates that NGS is a reliable and practical approach for the molecular screening of FHBL-causative genes that may provide a mean for deciphering the genetic basis in FHBL.

KEYWORDS:

APOB; Familial hypobetalipoproteinemia; Molecular diagnosis; PCSK9; Target next generation sequencing

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