Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy

Bertolini, Stefano; Rabacchi, Claudio; Cefalù, Angelo Baldassare; Noto, Davide; Fasano, Tommaso; Signori, Alessio; Fresa, Raffaele; Averna, Maurizio; Calandra, Sebastiano

doi:10.1016/j.atherosclerosis.2013.01.007

Cited by 130 publications

(92 citation statements)

References 27 publications

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“…In accordance with findings from our previous study [14], more than 90% of variant-positive patients were carriers of pathogenic or likely pathogenic variants in the LDLR gene. Among these patients we discovered 4 true FH homozygotes carrying known pathogenic variants and 5 patients likely be to be compound heterozygotes (as they were carriers of two known pathogenic or likely pathogenic variants of LDLR gene).…”

Section: Discussionsupporting

confidence: 78%

“…As previously observed [14], only few patients were found to be heterozygous carriers of one of the three known APOB pathogenic variants. None of the patients was found to be homozygous/compound heterozygous for any of these variants.…”

Section: Discussionsupporting

confidence: 50%

“…Surprisingly, none of them carried one of the three GOF variants reported previously in Italian FH patients [14] or one of those reported in a recent large survey of FH patients carrying PCSK9 variants [16]. As a matter of fact, a convincing demonstration of pathogenicity of one putative GOF variant found in our FH patients [c.60_65dupGCTGCT (c.61_63triCTG), p. (Leu21tri)] is not yet available.…”

Section: Discussionmentioning

confidence: 45%

“…The most common mutations in LDLR gene were [c.1646G>A, p. (Gly549Asp) [14]. Thirty-two LDLR gene variants found in this survey had not been reported previously.…”

Section: Resultsmentioning

confidence: 73%

“…In a previous study [14] we have characterized the molecular bases of ADH in a cohort of Italian FH patients attending three Lipid Clinics in Italy and performed a systematic analysis of the clinical features of mutationpositive ADH patients. This study paved the way for the construction of the LIPIGEN network, as an integrated network aimed at the early clinical/molecular identification and treatment of patients with genetic dyslipidemias (Ref.…”

Section: Introductionmentioning

confidence: 99%

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Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

Pirillo¹,

Garlaschelli²,

Arca³

et al. 2017

Atherosclerosis Supplements

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Background: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDLcholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality.Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study). Methods: We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major candidate genes for monogenic hypercholesterolemia (LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1). Results: A total of 213 variants were detected in 1076 subjects. About 90% of them had a pathogenic or likely pathogenic variants. More than 94% of patients carried pathogenic variants in LDLR gene, 27 of which were novel. Pathogenic variants in APOB and PCSK9 were exceedingly rare. We found 4 true homozygotes and 5 putative compound heterozygotes for pathogenic variants in LDLR gene, as well as 5 double heterozygotes for LDLR/APOB pathogenic variants. Two patients were homozygous for pathogenic variants in LDLRAP1 gene resulting in autosomal recessive hypercholesterolemia. One patient was found to be heterozygous for the ApoE variant p.(Leu167del), known to confer an FH phenotype. Conclusions: This study shows the molecular characteristics of the FH patients identified in Italy over the last two years. Full phenotypic characterization of these patients and cascade screening of family members is now in progress.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 45%

“…The most common mutations in LDLR gene were [c.1646G>A, p. (Gly549Asp) [14]. Thirty-two LDLR gene variants found in this survey had not been reported previously.…”

Section: Resultsmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

Pirillo¹,

Garlaschelli²,

Arca³

et al. 2017

Atherosclerosis Supplements

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Association Between Familial Hypercholesterolemia and Prevalence of Type 2 Diabetes Mellitus

Besseling

Kastelein

Defesche

et al. 2015

JAMA

335

226

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In a cross-sectional analysis in the Netherlands, the prevalence of type 2 diabetes among patients with familial hypercholesterolemia was significantly lower than among unaffected relatives, with variability by mutation type. If this finding is confirmed in longitudinal analysis, it would raise the possibility of a causal relationship between LDL receptor-mediated transmembrane cholesterol transport and type 2 diabetes.

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Genetic diagnosis of familial hypercholesterolemia is associated with a premature and high coronary heart disease risk

Seguro¹,

Rabès

Taraszkiewicz³

et al. 2018

Clinical Cardiology

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Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy

Cited by 130 publications

References 27 publications

Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

Association Between Familial Hypercholesterolemia and Prevalence of Type 2 Diabetes Mellitus

Genetic diagnosis of familial hypercholesterolemia is associated with a premature and high coronary heart disease risk

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