title: Identification of novel APOB mutations by targeted next-generation sequencing for the molecular diagnosis of familial hypobetalipoproteinemia.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France; CNRS, UMR 6291, Nantes, F-44000, France; Université de Nantes, Nantes, F-44000, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Rimbert
authors.affiliation: 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.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Pichelin
authors.affiliation: 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.
authors.forename: Simon
authors.initials: S
authors.lastname: Lecointe
authors.affiliation: CHU Nantes, l'institut du Thorax, Nantes, F-44000, France; CIC Thorax, CHU Nantes, l'institut du Thorax, Nantes, F-44000, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Marrec
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France; CNRS, UMR 6291, Nantes, F-44000, France; Université de Nantes, Nantes, F-44000, France.
authors.forename: Solena
authors.initials: S
authors.lastname: Le Scouarnec
authors.affiliation: 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.
authors.forename: Elias
authors.initials: E
authors.lastname: Barrak
authors.affiliation: Centre de Recherche en Nutrition Humaine de l'Ouest (CRNHO, INRA UMR1280), Nantes, F-44093, France.
authors.forename: Mikael
authors.initials: M
authors.lastname: Croyal
authors.affiliation: 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.
authors.forename: Michel
authors.initials: M
authors.lastname: Krempf
authors.affiliation: 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.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Marec
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Redon
authors.affiliation: 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.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France; CNRS, UMR 6291, Nantes, F-44000, France; Université de Nantes, Nantes, F-44000, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Magré
authors.affiliation: 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.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
mesh_terms: D000012:Abetalipoproteinemia / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053299:Apolipoprotein B-100 / Q000235:genetics*; D008078:Cholesterol, LDL / Q000235:genetics; D018389:Codon, Nonsense; D015723:Gene Library; D014644:Genetic Variation; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D000071449:Proprotein Convertase 9 / Q000235:genetics; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C569471:APOB protein, human; D053299:Apolipoprotein B-100; D008078:Cholesterol, LDL; D018389:Codon, Nonsense; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: APOB; Familial hypobetalipoproteinemia; Molecular diagnosis; PCSK9; Target next generation sequencing