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

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• 作者：Antoine Rimbert^a ; ^b ; ^c ; Matthieu Pichelin^a ; ^b ; ^c ; ^d ; ^e ; Simon Lecointe^a ; ^b ; ^c ; ^d ; Marie Marrec^d ; ^e ; Solena Le Scouarnec^a ; ^b ; ^c ; Elias Barrak^a ; ^b ; ^c ; ^d ; Mikael Croyal^f ; Michel Krempf^c ; ^d ; ^f ; Hervé ; Le Marec^a ; ^b ; ^c ; ^d ; Richard Redon^a ; ^b ; ^c ; ^d ; Jean-Jacques Schott^a ; ^b ; ^c ; ^d ; ^{jjschott@univ-nantes.fr" class="auth_mail" title="E-mail the corresponding author} ; Jocelyne Magré ; ^a ; ^b ; ^c ; Bertrand Cariou^a ; ^b ; ^c ; ^d ; ^e ; ^{bertrand.cariou@univ-nantes.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Familial hypobetalipoproteinemia ; Target next generation sequencing ; APOB ; PCSK9 ; Molecular diagnosis
• 刊名：Atherosclerosis
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：250
• 期：Complete
• 页码：52-56
• 全文大小：494 K

文摘

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.