TY - JOUR
T1 - Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features
AU - Cefalu', Angelo Baldassare
AU - Averna, Maurizio
AU - Suppressa, Patrizia
AU - Trenti, Chiara
AU - Calabrò, Paolo
AU - Rabacchi, Claudio
AU - Sbrana, Francesco
AU - Casula, Manuela
AU - D'Erasmo, Laura
AU - D'Addato, Sergio
AU - Calandra, Sebastiano
AU - Pavanello, Chiara
AU - Ripoli, Carlo
AU - Ibba, Anastasia
AU - Pasta, Andrea
AU - Negri, Emanuele A.
AU - D'Addato, Sergio
AU - Buonuomo, Paola Sabrina
AU - Pisciotta, Livia
AU - Zenti, Maria Grazia
AU - Sampietro, Tiziana
AU - Sileo, Fulvio
AU - Bartuli, Andrea
AU - Iannuzzo, Gabriella
AU - Cicero, Arrigo
AU - Tarugi, Patrizia
AU - Bertolini, Stefano
AU - Catapano, Alberico L.
AU - Arca, Marcello
AU - Bucci, Marco
AU - Fasano, Tommaso
PY - 2020
Y1 - 2020
N2 - Background and aims: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma levels of low density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease (ASCVD). HoFH is caused by pathogenic variants in several genes, such as LDLR, APOB and PCSK9, responsible for autosomal dominant hypercholesterolemia (ADH), and LDLRAP1 responsible for autosomal recessive hypercholesterolemia (ARH). Aim of this study was the review of the clinical and molecular features of patients with HoFH identified in Italy from 1989 to 2019. Methods: Data were collected from lipid clinics and laboratories, which had performed molecular diagnosis in suspected HoFH. Clinical data included baseline lipid levels and ASCVD events. Results: A total of 125 subjects with ADH were identified, of whom 60 were true homozygotes, 58 compound heterozygotes and 7 double heterozygotes for LDLR (likely) pathogenic variants. Compared with compound heterozygotes, true homozygotes showed a more severe lipid phenotype and more ASCVD events. ADH carriers of LDLR negative variants (R-NEG) presented with a more aggressive phenotype, as compared to carriers of LDLR defective variants (R-DEF). Kaplan-Meier analysis showed that the median age of ASCVD event-free survival was 25 years of age in R-NEG as opposed to 50 years of age in R-DEF patients. A total of 66 patients with ARH were also identified, of whom 46 were homozygotes and 20 compound heterozygotes. The phenotypic features of ARH patients were similar to those of R-DEF/ADH patients. Overall, 45% ADH patients and 33% ARH patients did not meet the classic diagnostic criteria for HoFH. Conclusions: In our cohort, the phenotypic variability of HoFH was dependent on the candidate gene involved and the functional impact of its variants on the LDL receptor pathway.
AB - Background and aims: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma levels of low density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease (ASCVD). HoFH is caused by pathogenic variants in several genes, such as LDLR, APOB and PCSK9, responsible for autosomal dominant hypercholesterolemia (ADH), and LDLRAP1 responsible for autosomal recessive hypercholesterolemia (ARH). Aim of this study was the review of the clinical and molecular features of patients with HoFH identified in Italy from 1989 to 2019. Methods: Data were collected from lipid clinics and laboratories, which had performed molecular diagnosis in suspected HoFH. Clinical data included baseline lipid levels and ASCVD events. Results: A total of 125 subjects with ADH were identified, of whom 60 were true homozygotes, 58 compound heterozygotes and 7 double heterozygotes for LDLR (likely) pathogenic variants. Compared with compound heterozygotes, true homozygotes showed a more severe lipid phenotype and more ASCVD events. ADH carriers of LDLR negative variants (R-NEG) presented with a more aggressive phenotype, as compared to carriers of LDLR defective variants (R-DEF). Kaplan-Meier analysis showed that the median age of ASCVD event-free survival was 25 years of age in R-NEG as opposed to 50 years of age in R-DEF patients. A total of 66 patients with ARH were also identified, of whom 46 were homozygotes and 20 compound heterozygotes. The phenotypic features of ARH patients were similar to those of R-DEF/ADH patients. Overall, 45% ADH patients and 33% ARH patients did not meet the classic diagnostic criteria for HoFH. Conclusions: In our cohort, the phenotypic variability of HoFH was dependent on the candidate gene involved and the functional impact of its variants on the LDL receptor pathway.
UR - http://hdl.handle.net/10447/458062
M3 - Article
VL - 312
SP - 72
EP - 78
JO - ATHEROSCLEROSIS
JF - ATHEROSCLEROSIS
SN - 0021-9150
ER -