Details

Autor(en) / Beteiligte

• Ghaleb, Youmna
• Elbitar, Sandy
• Philippi, Anne
• El Khoury, Petra
• Azar, Yara
• Andrianirina, Miangaly
• Loste, Alexia
• Abou-Khalil, Yara
• Nicolas, Gaël
• Le Borgne, Marie
• Moulin, Philippe
• Di-Filippo, Mathilde
• Charrière, Sybil
• Farnier, Michel
• Yelnick, Cécile
• Carreau, Valérie
• Ferrières, Jean
• Lecerf, Jean-Michel
• Derksen, Alexa
• Bernard, Geneviève
• Gauthier, Marie-Soleil
• Coulombe, Benoit
• Lütjohann, Dieter
• Fin, Bertrand
• Boland, Anne
• Olaso, Robert
• Deleuze, Jean-François
• Rabès, Jean-Pierre
• Boileau, Catherine
• Abifadel, Marianne
• Varret, Mathilde

Titel

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

Ist Teil von

• Metabolites, 2022-03, Vol.12 (3), p.262

Ort / Verlag

Switzerland: MDPI AG

Erscheinungsjahr

2022

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in , , and 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 , p.(Val1382Phe) in and p.(Ser202His) in . A total of 6 other variants were identified in 6 of 160 unrelated ADH probands: p.(Ala13Val) and p.(Aps347Asn) in ; p.(Tyr972Cys), p.(Thr1479Ile) and p.(Ser1612Phe) in ; and p.(Ser202LeufsTer19) in . All six probands presented a moderate wPRS. Serum analyses of carriers of the p.(Pro398Ala) variant in showed no differences in the synthesis of bile acids compared to the serums of non-carriers. Functional studies of the four 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 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.