Jesús M Martín-Campos1, Núria Plana2, Rosaura Figueras3, Daiana Ibarretxe2, Assumpta Caixàs4, Eduardo Esteve5, Antonio Pérez6, Marta Bueno7, Marta Mauri8, Rosa Roig6, Susana Martínez6, Xavier Pintó3, Luís Masana2, Josep Julve6, Francisco Blanco-Vaca9. 1. Institut de Recerca - Hospital de la Santa Creu i Sant Pau, Serveis de Bioquímica, i d'Endocrinologia i Nutrició, IIB Sant Pau, CIBERDEM, Universitat Autònoma de Barcelona, Departaments de Bioquímica i Biologia Molecular, i Medicina, Barcelona, Spain. Electronic address: jmartinca@santpau.cat. 2. Hospital Universitari Sant Joan, Universitat Rovira i Virgili, Unitat de Medicina Vascular i Metabolisme, Unitat de Recerca en Lípids i Arteriosclerosi, IISPV, CIBERDEM, Reus, Spain. 3. Hospital Universitari de Bellvitge, Servei de Medicina Interna, Unitat de Lípids i Risc Vascular, Universitat de Barcelona, IDIBELL, CIBEROBN, FIPEC, ABS 17 de Setembre, L'Hospitalet/El Prat de Llobregat, Spain. 4. Hospital Universitari Parc Taulí, Servei d'Endocrinologia i Nutrició, Institut Investigació i Innovació Parc Taulí I3PT-Universitat Autònoma de Barcelona, Sabadell, Spain. 5. Hospital Universitari de Girona Dr Josep Trueta, Servei d'Endocrinologia i Nutrició, CIBEROBN, Girona, Spain. 6. Institut de Recerca - Hospital de la Santa Creu i Sant Pau, Serveis de Bioquímica, i d'Endocrinologia i Nutrició, IIB Sant Pau, CIBERDEM, Universitat Autònoma de Barcelona, Departaments de Bioquímica i Biologia Molecular, i Medicina, Barcelona, Spain. 7. Hospital Universitari Arnau de Vilanova, Servei d'Endocrinologia i Nutrició, Lleida, Spain. 8. Hospital de Terrassa, Servei de Medicina Interna, Terrassa, Spain. 9. Institut de Recerca - Hospital de la Santa Creu i Sant Pau, Serveis de Bioquímica, i d'Endocrinologia i Nutrició, IIB Sant Pau, CIBERDEM, Universitat Autònoma de Barcelona, Departaments de Bioquímica i Biologia Molecular, i Medicina, Barcelona, Spain. Electronic address: fblancova@santpau.cat.
Abstract
BACKGROUND: Autosomal dominant hypercholesterolemia (ADH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes, and it is estimated to be greatly underdiagnosed. The most cost-effective strategy for increasing ADH diagnosis is a cascade screening from mutation-positive probands. OBJECTIVE: The objective of this study was to evaluate the results from 2008 to 2016 of ADH genetic analysis performed in our clinical laboratory, serving most lipid units of Catalonia, a Spanish region with approximately 7.5 million inhabitants. METHODS: After the application of the Dutch Lipid Clinic Network (DLCN) clinical diagnostic score for ADH, this information and blood or saliva from 23 different lipid clinic units were investigated in our laboratory. DNA was screened for mutations in LDLR, APOB, and PCSK9, using the DNA-array LIPOchip, the next-generation sequencing SEQPRO LIPO RS platform, and multiplex ligation-dependent probe amplification (MLPA). The Simon Broome Register Group (SBRG) criteria was calculated and analyzed for comparative purposes. RESULTS: A total of 967 unrelated samples were analyzed. From this, 158 pathogenic variants were detected in 356 patients. The main components of the DLCN criteria associated with the presence of mutation were plasma LDL cholesterol (LDLc), age, and the presence of tendinous xanthomata. The contribution of family history to the diagnosis was lower than in other studies. DLCN and SBRG were similarly useful for predicting the presence of mutation. CONCLUSION: In a real clinical practice, multicenter setting in Catalonia, the percentage of positive genetic diagnosis in patients potentially affected by ADH was 38.6%. The DLCN showed a relatively low capacity to predict mutation detection but a higher one for ruling out mutation.
BACKGROUND:Autosomal dominant hypercholesterolemia (ADH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes, and it is estimated to be greatly underdiagnosed. The most cost-effective strategy for increasing ADH diagnosis is a cascade screening from mutation-positive probands. OBJECTIVE: The objective of this study was to evaluate the results from 2008 to 2016 of ADH genetic analysis performed in our clinical laboratory, serving most lipid units of Catalonia, a Spanish region with approximately 7.5 million inhabitants. METHODS: After the application of the Dutch Lipid Clinic Network (DLCN) clinical diagnostic score for ADH, this information and blood or saliva from 23 different lipid clinic units were investigated in our laboratory. DNA was screened for mutations in LDLR, APOB, and PCSK9, using the DNA-array LIPOchip, the next-generation sequencing SEQPRO LIPO RS platform, and multiplex ligation-dependent probe amplification (MLPA). The Simon Broome Register Group (SBRG) criteria was calculated and analyzed for comparative purposes. RESULTS: A total of 967 unrelated samples were analyzed. From this, 158 pathogenic variants were detected in 356 patients. The main components of the DLCN criteria associated with the presence of mutation were plasma LDL cholesterol (LDLc), age, and the presence of tendinous xanthomata. The contribution of family history to the diagnosis was lower than in other studies. DLCN and SBRG were similarly useful for predicting the presence of mutation. CONCLUSION: In a real clinical practice, multicenter setting in Catalonia, the percentage of positive genetic diagnosis in patients potentially affected by ADH was 38.6%. The DLCN showed a relatively low capacity to predict mutation detection but a higher one for ruling out mutation.