Whole Exome/Genome Sequencing Joint Analysis of a Family with Oligogenic Familial Hypercholesterolemia.

Autor: Ghaleb Y; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France.; Laboratory of Biochemistry and Molecular Therapeutics (LBTM), Faculty of Pharmacy, Pôle Technologie-Santé (PTS), Saint-Joseph University, Beirut 1004 2020, Lebanon., Elbitar S; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France.; Laboratory of Biochemistry and Molecular Therapeutics (LBTM), Faculty of Pharmacy, Pôle Technologie-Santé (PTS), Saint-Joseph University, Beirut 1004 2020, Lebanon., Philippi A; Institut Cochin, Bâtiment Faculté Inserm U1016, Cnrs UMR8104, Université de Paris Faculté de Médecine, F-75014 Paris, France., El Khoury P; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France.; Laboratory of Biochemistry and Molecular Therapeutics (LBTM), Faculty of Pharmacy, Pôle Technologie-Santé (PTS), Saint-Joseph University, Beirut 1004 2020, Lebanon., Azar Y; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France.; Laboratory of Biochemistry and Molecular Therapeutics (LBTM), Faculty of Pharmacy, Pôle Technologie-Santé (PTS), Saint-Joseph University, Beirut 1004 2020, Lebanon.; Laboratory for Vascular Translational Science, Paris Cité University, Sorbonne Paris Nord University, F-75013 Paris, France., Andrianirina M; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France., Loste A; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France.; Laboratory for Vascular Translational Science, Paris Cité University, Sorbonne Paris Nord University, F-75013 Paris, France., Abou-Khalil Y; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France.; Laboratory of Biochemistry and Molecular Therapeutics (LBTM), Faculty of Pharmacy, Pôle Technologie-Santé (PTS), Saint-Joseph University, Beirut 1004 2020, Lebanon.; Laboratory for Vascular Translational Science, Paris Cité University, Sorbonne Paris Nord University, F-75013 Paris, France., Nicolas G; Laboratory for Vascular Translational Science, Paris Cité University, Sorbonne Paris Nord University, F-75013 Paris, France.; INSERM U1149, CNRS ERL 8252, Centre de Recherche sur l'Inflammation, F-75018 Paris, France., Le Borgne M; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France.; Laboratory for Vascular Translational Science, Paris Cité University, Sorbonne Paris Nord University, F-75013 Paris, France., Moulin P; Department of Endocrinology, Nutrition and Metabolic Diseases, Hospices Civils de Lyon, Louis Pradel Cardiovascular Hospital, F-69500 Bron, France.; CarMen Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, F-69921 Oullins, France., Di-Filippo M; CarMen Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, F-69921 Oullins, France.; Hospices Civils de Lyon, Department of Biochemistry and Molecular Biology, F-69500 Bron, France., Charrière S; Department of Endocrinology, Nutrition and Metabolic Diseases, Hospices Civils de Lyon, Louis Pradel Cardiovascular Hospital, F-69500 Bron, France.; CarMen Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, F-69921 Oullins, France., Farnier M; EA 7460 Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne-Franche Comté, F-21078 Dijon, France., Yelnick C; Département de Médecine Interne et Immunologie Clinique Centre de Référence des Maladies Auto-Immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO) CHU de Lille, F-59037 Lille, France.; U1167 Risk Factors and Molecular Determinants of Aging-Related Diseases, Inserm CHU de Lille, Lille University, F-59000 Lille, France., Carreau V; Department of Endocrinology and Prevention of Cardiovascular Disease, Institute of Cardio Metabolism and Nutrition (ICAN), La Pitié-Salpêtrière Hospital, AP-HP, F-75005 Paris, France., Ferrières J; Department of Cardiology, Toulouse Rangueil University Hospital, UMR 1295 INSERM, F-31400 Toulouse, France., Lecerf JM; Nutrition Department, Institut Pasteur de Lille, CEDEX, F-59019 Lille, France., Derksen A; Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC H3A 0G4, Canada.; Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada., Bernard G; Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC H3A 0G4, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada.; Department of Pediatrics, McGill University, Montréal, QC H3A 0G4, Canada.; Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada.; Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montréal, QC H4A 3J1, Canada., Gauthier MS; Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada., Coulombe B; Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada., Lütjohann D; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, F-53127 Bonn, Germany., Fin B; CEA, Centre National de Recherche en Génomique Humaine, Laboratory of Excellence GENMED (Medical Genomics), Paris-Saclay University, F-91057 Evry, France., Boland A; CEA, Centre National de Recherche en Génomique Humaine, Laboratory of Excellence GENMED (Medical Genomics), Paris-Saclay University, F-91057 Evry, France., Olaso R; CEA, Centre National de Recherche en Génomique Humaine, Laboratory of Excellence GENMED (Medical Genomics), Paris-Saclay University, F-91057 Evry, France., Deleuze JF; CEA, Centre National de Recherche en Génomique Humaine, Laboratory of Excellence GENMED (Medical Genomics), Paris-Saclay University, F-91057 Evry, France.; Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, F-75019 Paris, France., Rabès JP; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France.; Department of Biochemistry and Molecular Genetics, Ambroise Paré University Hospital (APHP), Université Paris-Saclay, F-92104 Boulogne-Billancourt, France.; UFR (Unite de Formation et de Recherche) Simone Veil-Santé, Versailles-Saint-Quentin-en-Yvelines University, F-78180 Montigny-le-Bretonneux, France., Boileau C; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France.; Laboratory for Vascular Translational Science, Paris Cité University, Sorbonne Paris Nord University, F-75013 Paris, France.; Genetic Department, AP-HP, Hôpital Bichat, F-75018 Paris, France., Abifadel M; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France.; Laboratory of Biochemistry and Molecular Therapeutics (LBTM), Faculty of Pharmacy, Pôle Technologie-Santé (PTS), Saint-Joseph University, Beirut 1004 2020, Lebanon., Varret M; INSERM, Laboratory for Vascular Translational Science (LVTS), F-75018 Paris, France.; Laboratory for Vascular Translational Science, Paris Cité University, Sorbonne Paris Nord University, F-75013 Paris, France.
Jazyk: angličtina
Zdroj: Metabolites [Metabolites] 2022 Mar 18; Vol. 12 (3). Date of Electronic Publication: 2022 Mar 18.
DOI: 10.3390/metabo12030262
Abstrakt: Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in LDLR , APOB , PCSK9 and APOE genes. We sought to identify new candidate genes responsible for the ADH phenotype in patients without pathogenic variants in the known ADH-causing genes by focusing on a French family with affected and non-affected members who presented a high ADH polygenic risk score (wPRS). Linkage analysis, whole exome and whole genome sequencing resulted in the identification of variants p.(Pro398Ala) in CYP7A1 , p.(Val1382Phe) in LRP6 and p.(Ser202His) in LDLRAP1 . A total of 6 other variants were identified in 6 of 160 unrelated ADH probands: p.(Ala13Val) and p.(Aps347Asn) in CYP7A1 ; p.(Tyr972Cys), p.(Thr1479Ile) and p.(Ser1612Phe) in LRP6 ; and p.(Ser202LeufsTer19) in LDLRAP1 . All six probands presented a moderate wPRS. Serum analyses of carriers of the p.(Pro398Ala) variant in CYP7A1 showed no differences in the synthesis of bile acids compared to the serums of non-carriers. Functional studies of the four LRP6 mutants in HEK293T cells resulted in contradictory results excluding a major effect of each variant alone. Within the family, none of the heterozygous for only the LDLRAP1 p.(Ser202His) variant presented ADH. Altogether, each variant individually does not result in elevated LDL-C; however, the oligogenic combination of two or three variants reveals the ADH phenotype.
Databáze: MEDLINE
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