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Article Dans Une Revue Metabolites Année : 2022

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

1 LVTS (UMR_S_1148 / U1148) - Laboratoire de Recherche Vasculaire Translationnelle
2 USJ - Université Saint-Joseph de Beyrouth
3 IC UM3 (UMR 8104 / U1016) - Institut Cochin
4 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
5 Hôpital Louis Pradel [CHU - HCL]
6 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
7 HCL - Hospices Civils de Lyon
8 PEC2 - Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon]
9 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
10 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
11 IHU ICAN - Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière]
12 CHU Pitié-Salpêtrière [AP-HP]
13 CERPOP - Centre d'Epidémiologie et de Recherche en santé des POPulations
14 Service Cardiologie [CHU Toulouse]
15 Institut Pasteur de Lille
16 MUHC - McGill University Health Center [Montreal]
17 IRCM - Institut de Recherches Cliniques de Montréal
18 McGill University = Université McGill [Montréal, Canada]
19 UdeM - Université de Montréal
20 University Hospital Bonn
21 CNRGH - Centre National de Recherche en Génomique Humaine
22 Medical Genomics - Laboratory of Excellence GENMED [Paris]
23 CEPH - Centre d'Etude du Polymorphisme Humain
24 Hôpital Ambroise Paré [AP-HP]
25 UVSQ Santé - Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil
Anne Philippi
  • Fonction : Auteur
Gaël Nicolas
Jean-Michel Lecerf
Dieter Lütjohann

Résumé

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.
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hal-03642664 , version 1 (01-06-2022)

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Youmna Ghaleb, Sandy Elbitar, Anne Philippi, Petra El Khoury, Yara Azar, et al.. Whole Exome/Genome Sequencing Joint Analysis of a Family with Oligogenic Familial Hypercholesterolemia. Metabolites, 2022, 12 (3), pp.262. ⟨10.3390/metabo12030262⟩. ⟨hal-03642664⟩
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