Variable Nav1.5 Protein Expression from the Wild-Type Allele Correlates with the Penetrance of Cardiac Conduction Disease in the Scn5a+/− Mouse Model

BACKGROUND: Loss-of-function mutations in SCN5A, the gene encoding Na(v)1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a(+/-) mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A. METHODOLOGY/PRINCIPAL FINDINGS: Based on ECG, 10-week-old Scn5a(+/-) mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a(+/-) mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A-mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a(+/-) mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a(+/-) mice had similar Na(v)1.5 mRNA but higher Na(v)1.5 protein expression, and moderately larger I(Na) current than severely affected Scn5a(+/-) mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a(+/-) mice than in mildly affected ones. CONCLUSIONS: Scn5a(+/-) mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a(+/-) mice, phenotype severity correlates with wild-type Na(v)1.5 protein expression

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

: Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups <0.0001); however, subjects with FH/M- and lp(a) score ≥1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level ≥190 mg/dL (or from 68% to 50%, considering a more conservative formula). Conclusions Our study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and ResultsAn lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score >= 1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups <0.0001); however, subjects with FH/M- and lp(a) score >= 1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level >= 190 mg/dL (or from 68% to 50%, considering a more conservative formula). ConclusionsOur study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH

Refinement of the diagnostic approach for the identification of children and adolescents affected by familial hypercholesterolemia: Evidence from the LIPIGEN study

Background and aims: We aimed to describe the limitations of familiar hypercholesterolemia (FH) diagnosis in childhood based on the presence of the typical features of FH, such as physical sings of cholesterol accumulation and personal or family history of premature cardiovascular disease or hypercholesterolemia, comparing their prevalence in the adult and paediatric FH population, and to illustrate how additional information can lead to a more effective diagnosis of FH at a younger age.Methods: From the Italian LIPIGEN cohort, we selected 1188 (>= 18 years) and 708 (<18 years) genetically-confirmed heterozygous FH, with no missing personal FH features. The prevalence of personal and familial FH features was compared between the two groups. For a sub-group of the paediatric cohort (N = 374), data about premature coronary heart disease (CHD) in second-degree family members were also included in the evaluation.Results: The lower prevalence of typical FH features in children/adolescents vs adults was confirmed: the prevalence of tendon xanthoma was 2.1% vs 13.1%, and arcus cornealis was present in 1.6% vs 11.2% of the cohorts, respectively. No children presented clinical history of premature CHD or cerebral/peripheral vascular disease compared to 8.8% and 5.6% of adults, respectively. The prevalence of premature CHD in first-degree relatives was significantly higher in adults compared to children/adolescents (38.9% vs 19.7%). In the sub-cohort analysis, a premature CHD event in parents was reported in 63 out of 374 subjects (16.8%), but the percentage increased to 54.0% extending the evaluation also to second-degree relatives.Conclusions: In children, the typical FH features are clearly less informative than in adults. A more thorough data collection, adding information about second-degree relatives, could improve the diagnosis of FH at younger age

Twelve Variants Polygenic Score for Low-Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

: Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P<0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (P<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, P<0.0001; 250-349 mg/dL: 1.02 versus 0.95, P=0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice

Refinement of the diagnostic approach for the identification of children and adolescents affected by familial hypercholesterolemia: Evidence from the LIPIGEN study

Background and aims: We aimed to describe the limitations of familiar hypercholesterolemia (FH) diagnosis in childhood based on the presence of the typical features of FH, such as physical sings of cholesterol accumulation and personal or family history of premature cardiovascular disease or hypercholesterolemia, comparing their prevalence in the adult and paediatric FH population, and to illustrate how additional information can lead to a more effective diagnosis of FH at a younger age. Methods: From the Italian LIPIGEN cohort, we selected 1188 (≥18 years) and 708 (&lt;18 years) genetically-confirmed heterozygous FH, with no missing personal FH features. The prevalence of personal and familial FH features was compared between the two groups. For a sub-group of the paediatric cohort (N = 374), data about premature coronary heart disease (CHD) in second-degree family members were also included in the evaluation. Results: The lower prevalence of typical FH features in children/adolescents vs adults was confirmed: the prevalence of tendon xanthoma was 2.1% vs 13.1%, and arcus cornealis was present in 1.6% vs 11.2% of the cohorts, respectively. No children presented clinical history of premature CHD or cerebral/peripheral vascular disease compared to 8.8% and 5.6% of adults, respectively. The prevalence of premature CHD in first-degree relatives was significantly higher in adults compared to children/adolescents (38.9% vs 19.7%). In the sub-cohort analysis, a premature CHD event in parents was reported in 63 out of 374 subjects (16.8%), but the percentage increased to 54.0% extending the evaluation also to second-degree relatives. Conclusions: In children, the typical FH features are clearly less informative than in adults. A more thorough data collection, adding information about second-degree relatives, could improve the diagnosis of FH at younger age

Aclees taiwanensis Kono 1933

&lt;i&gt;Aclees taiwanensis&lt;/i&gt; Kȏno, 1933: 182 &lt;p&gt; Three specimens are conserved in coll. Kȏno, the two syntypes and a third non&ndash;type specimen, a female identified as &lt;i&gt;A. taiwanensis&lt;/i&gt; by Kȏno, labelled: (pr) Formosa / Shinchiku&mdash;18 / VII 1-30. / J. Sonan, / K. Miyake.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Lectotype (here designated). 1.&lt;/b&gt; Baibara. (pr) / Formosa (pr) / VII.13.1927 (hw) / K.-Kikuchi (pr); &lt;b&gt;2.&lt;/b&gt; (red label) &lt;i&gt;Aclees&lt;/i&gt; (hw) / &lt;i&gt;taiwanensis&lt;/i&gt; (hw) / &male; Kȏno (hw) / Type (pr); &lt;b&gt;3.&lt;/b&gt; (pr) (white label with red border on right) &lt;b&gt;SYNTYPE&lt;/b&gt; / The label attached by / OHARA and HIRONAGA / 2006; &lt;b&gt;4.&lt;/b&gt; (pr) 0000001066 / Sys. Ent. / Hokkaido Univ. / Japan [SEHU]; &lt;b&gt;5.&lt;/b&gt; (red label, pr) &lt;i&gt;Aclees taiwanensis&lt;/i&gt; / Kȏno, 1933 / &lt;b&gt;LECTOTYPUS&lt;/b&gt; / 2020 Meregalli &amp; Boriani des.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Paralectotype. 1.&lt;/b&gt; Formosa / Matsumura (pr) / (back of label, hw) Kanshirei (in japanese) / 14/04 07; &lt;b&gt;2.&lt;/b&gt; &lt;i&gt;Aclees&lt;/i&gt; (hw) / &lt;i&gt;taiwanensis&lt;/i&gt; (hw) / Kȏno (hw) / det. H. Kȏno (pr); &lt;b&gt;3.&lt;/b&gt; &lt;i&gt;Aclees&lt;/i&gt; (hw) / &lt;i&gt;taiwanensis&lt;/i&gt; (hw) / Kȏno (hw) / det. H. Kȏno (pr); &lt;b&gt;4.&lt;/b&gt; (pr) (white label with red border on right) &lt;b&gt;SYNTYPE&lt;/b&gt; / The label attached by / OHARA and HIRONAGA / 2006; &lt;b&gt;5.&lt;/b&gt; (pr) 0000001067 / Sys. Ent. / Hokkaido Univ. / Japan [SEHU]; &lt;b&gt;6.&lt;/b&gt; (red label, pr) &lt;i&gt;Aclees taiwanensis&lt;/i&gt; / Kȏno, 1933 / &lt;b&gt;Paralectotypus&lt;/b&gt; / 2020 Meregalli &amp; Boriani vid.&lt;/p&gt; &lt;p&gt;The paralectotype was indicated as a male by Kȏno (1933), but it is a female. It does not bear any original red type label, but the locality label confirms that this is undoubtedly the second syntype.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Distribution.&lt;/b&gt; Taiwan, type locality (Kȏno 1933). Introduced to France (Perrin 1997, as &lt;i&gt;Aclees cribratus&lt;/i&gt;) and Italy (Ciampolini &lt;i&gt;et al.&lt;/i&gt; 2005 as &lt;i&gt;A. cribratus&lt;/i&gt;; Benelli &lt;i&gt;et al.&lt;/i&gt; 2014, as &lt;i&gt;Aclees&lt;/i&gt; sp. cf. &lt;i&gt;foveatus&lt;/i&gt; Voss, 1932).&lt;/p&gt; &lt;p&gt; &lt;b&gt;Note.&lt;/b&gt; Recent research on the &lt;i&gt;Aclees&lt;/i&gt; fauna of Taiwan has led to the discovery of an additional species, morphologically sister to &lt;i&gt;A. taiwanensis&lt;/i&gt; and only differentiable with certainty based on the structure of the male genitalia and the mitochondrial cytochrome c oxidase 1 sequence (Meregalli &lt;i&gt;et al.&lt;/i&gt;, in preparation).&lt;/p&gt;Published as part of &lt;i&gt;Meregalli, Massimo, Boriani, Marco, Bollino, Maurizio &amp; Hsu, Chen-Fu, 2020, Review of the species of Aclees described by Kȏno (Coleoptera: Curculionidae: Molytinae), pp. 146-150 in Zootaxa 4768 (1)&lt;/i&gt; on pages 146-150, DOI: 10.11646/zootaxa.4768.1.10, &lt;a href="http://zenodo.org/record/3777766"&gt;http://zenodo.org/record/3777766&lt;/a&gt

Aclees hirayamai Kono 1933

&lt;i&gt;Aclees hirayamai&lt;/i&gt; Kȏno, 1933: 183. &lt;p&gt;Only the two syntypes are conserved in coll. Kȏno (Fig. 2).&lt;/p&gt; &lt;p&gt; &lt;b&gt;Lectotype (here designated). 1.&lt;/b&gt; (pr) URAI / Formosa / (VI-8&mdash;10. -26) / &lt;i&gt;Col.&lt;/i&gt; M. Kato; &lt;b&gt;2.&lt;/b&gt; &lt;i&gt;Aclees&lt;/i&gt; / &lt;i&gt;hirayamai&lt;/i&gt; / &male; Kȏno (hw) / Type (pr); &lt;b&gt;3.&lt;/b&gt; (pr) (white label with red border on right) &lt;b&gt;SYNTYPE&lt;/b&gt; / The label attached by / OHARA and HIRONAGA / 2006; &lt;b&gt;4.&lt;/b&gt; (pr) 0000000999 / Sys. Ent. / Hokkaido Univ. / Japan [SEHU]; &lt;b&gt;5.&lt;/b&gt; (red label, pr) &lt;i&gt;Aclees hirayamai&lt;/i&gt; / Kȏno, 1933 / &lt;b&gt;LECTOTYPUS&lt;/b&gt; / 2020 Meregalli &amp; Boriani des.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Paralectotype. 1.&lt;/b&gt; LOO-CHOO (pr) / IRIOMOTE (pr) / VI-1932 (hw) / S. HIRAYAMA (pr); &lt;b&gt;3.&lt;/b&gt; (pr) (white label with red border on right) &lt;b&gt;SYNTYPE&lt;/b&gt; / The label attached by / OHARA and HIRONAGA / 2006; &lt;b&gt;4.&lt;/b&gt; (pr) 0000001000 / Sys. Ent. / Hokkaido Univ. / Japan [SEHU]; &lt;b&gt;X.&lt;/b&gt; (red label, pr) &lt;i&gt;Aclees hirayamai&lt;/i&gt; / Kȏno, 1933 / &lt;b&gt;PARALECTOTYPUS&lt;/b&gt; / 2020 Meregalli &amp; Boriani vid.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Distribution.&lt;/b&gt; Taiwan, type locality (Kȏno 1933); China, Japan (Morimoto 1982).&lt;/p&gt; &lt;p&gt; Kȏno (1942) described a further species of &lt;i&gt;Aclees&lt;/i&gt;, &lt;i&gt;A. saipanensis&lt;/i&gt; Kȏno, 1942, from the Island of Saipan. This was based on a single female holotype. We illustrate it here (Fig. 3).&lt;/p&gt;Published as part of &lt;i&gt;Meregalli, Massimo, Boriani, Marco, Bollino, Maurizio &amp; Hsu, Chen-Fu, 2020, Review of the species of Aclees described by Kȏno (Coleoptera: Curculionidae: Molytinae), pp. 146-150 in Zootaxa 4768 (1)&lt;/i&gt; on page 150, DOI: 10.11646/zootaxa.4768.1.10, &lt;a href="http://zenodo.org/record/3777766"&gt;http://zenodo.org/record/3777766&lt;/a&gt

Aclees saipanensis Kono 1942

&lt;i&gt;Aclees saipanensis&lt;/i&gt; Kȏno, 1942: 19 &lt;p&gt; &lt;b&gt;Holotype&lt;/b&gt;. &lt;b&gt;1.&lt;/b&gt; VII-25, 1939 / Nanyou [=South Sea Islands] Saipan (in Japanese) / S. Kawata (hw); &lt;b&gt;2.&lt;/b&gt; &lt;i&gt;Aclees&lt;/i&gt; / &lt;i&gt;saipanensis&lt;/i&gt; / Kȏno (hw) / Type (pr); &lt;b&gt;3.&lt;/b&gt; (pr) (white label with red border on right) &lt;b&gt;HOLOTYPE&lt;/b&gt; / Appended label by / OHARA, HI- NARI, KANBE / SUZUKI and HIRONAGA / 2007; &lt;b&gt;4.&lt;/b&gt; (red label, pr) &lt;i&gt;Aclees saipanensis&lt;/i&gt; / Kȏno, 1942 / &lt;b&gt;HOLOTYPUS&lt;/b&gt; / 2020 Meregalli vidit.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Distribution.&lt;/b&gt; Northern Mariana Islands, Saipan, type locality (Kȏno 1942).&lt;/p&gt;Published as part of &lt;i&gt;Meregalli, Massimo, Boriani, Marco, Bollino, Maurizio &amp; Hsu, Chen-Fu, 2020, Review of the species of Aclees described by Kȏno (Coleoptera: Curculionidae: Molytinae), pp. 146-150 in Zootaxa 4768 (1)&lt;/i&gt; on page 150, DOI: 10.11646/zootaxa.4768.1.10, &lt;a href="http://zenodo.org/record/3777766"&gt;http://zenodo.org/record/3777766&lt;/a&gt