Clinical characteristics of family members according to <i>LMNA</i> mutation carrier status.

<p>Mean values ± standard deviation or absolute frequencies and percentage of patients.</p><p>AF = atrial fibrillation; AVB = atrioventricular block; BMI = body mass index; CMRI = cardiac magnetic resonance imaging; DBP = diastolic blood pressure; Echo = echocardiography; LGE = late gadolinium enhancement; LVEDD = left ventricular end-diastolic diameter; LVEF = left ventricular ejection fraction; NSVT = non-sustained ventricular tachycardia; PVCs = premature ventricular complexes; RVEF = right ventricular ejection fraction; RVOT = right ventricular outflow tract; SBP = systolic blood pressure; SVT = sustained ventricular tachycardia.</p><p>*RVOT value by echocardiography was available in 19 of 20 patients, 9 of whom were <i>LMNA</i> mutation-positive subjects.</p><p>†CMRI was performed in 15 subjects, 7 of whom were <i>LMNA</i> mutation carriers.</p><p>Clinical characteristics of family members according to <i>LMNA</i> mutation carrier status.</p

Family pedigree and mutation identification.

<p>(A) Electropherogram of the <i>LMNA</i> gene variant. (B) The 7 duplicated amino acids (LLNSKEA) are highly conserved among <i>LMNA</i> gene homologs in vertebrates. (C) Family pedigree of the index patient with the novel <i>LMNA</i> gene mutation.</p

Clinical characteristics of <i>LMNA</i> mutation-positive family members.

<p>AF = atrial fibrillation; ARVC = arrhythmogenic right ventricular cardiomyopathy; AVB = atrioventricular block; CMR = cardiac magnetic resonance imaging; Com = comments; Echo = echocardiography; EF = ejection fraction; F = female; FU = Follow-up; Gen = Gender; HT = heart transplantation; ICD = implantable cardioverter-defibrillator; ILR = implantable loop recorder; LBBB = left bundle-branch block; LGE = late gadolinium enhancement; LV = left ventricle; LVEDD = left ventricular end-diastolic diameter; M = male; m = minor; Mj = major; np = not performed; NSVT = non-sustained ventricular tachycardia; PM = pacemaker; PVCs = premature ventricular complexes; RBBB = right bundle-branch block; RV = right ventricle; RVOT = right ventricular outflow tract; SB = sinus bradycardia; Sub = Subject; SVT = sustained ventricular tachycardia; TFC = Task Force criteria.</p><p>*at diagnosis/clinical presentation (years);</p><p>**Morphology of NSVT was determinable in 4 of 6 <i>LMNA</i> mutation-positive family members having NSVT;</p><p>***for ARVC diagnosis Mj/m.</p><p>Clinical characteristics of <i>LMNA</i> mutation-positive family members.</p

Clinical characteristics of index patient and <i>LMNA</i> mutation-positive family members.

<p>Index patient’s electrocardiogram (ECG) showing, at clinical presentation, (A) sinus rhythm, first-degree AV block, and PVC of LBBB morphology and, 13 years later, (B) complete AV block. (C) Asystole documented on implantable loop recorder memory (subject III-8). (D) Sustained VT detected on telemetry monitoring, effectively terminated by internal ICD shock (subject III-1). (E) Episodes of non-sustained VT with LBBB morphology and inferior axis (subject III-5) on 12-lead Holter monitoring. (E) Episodes of non-sustained VT with RBBB morphology and superior axis (subject IV-2) on 12-lead Holter monitoring.</p

CMR imaging of <i>LMNA</i> mutation-positive family members.

<p>(A) Short-axis cine (a) and LGE sequences in the Short-axis (b) and 2-chambers long-axis views (c). Bulging (arrow in a) and LGE of the RV free wall (arrowheads in b). Linear midwall LGE is localized at the interventricular septum and LV inferior wall (arrowheads in c) (subject III-5). (B) and (C) LGE sequences in the short axis (a) and 4-chambers long axis views (b). LGE with linear midwall pattern is shown on the LV inferior wall and basal interventricular septum (arrowheads) (subjects III-8, and IV-2).</p

Analysis of nuclear envelope integrity under stressing condition in LMNA transfected HL-1 cells.

<p>Nuclear WT LMNA (A) and DUP LMNA (B) signals in control (CTR) and stressing conditions (Hyperosmolarity, Hypoxia, Oxidative stress). The merged signals of LMNA proteins and the RFP nuclear marker are shown in the insets. Confocal XY planar projections are depicted in each experimental condition.</p

Apoptosis assay in LMNA transfected HL-1 cells.

<p>(A) Representative XY confocal planar projections of LMNA transfected cells (green) labelled with EthD-1 (red) in control conditions are depicted. (B) Quantitative analysis of apoptotic cells in control and under hyperosmotic (Hyper), hypoxic (Hypoxia), and oxidative (H₂O₂) conditions. Data are reported as % of apoptotic cells (double-labelled cells) in overall LMNA-expressing cells (green labelled cells). Statistical analysis was performed on 3 independent experiments and significance calculated by Student’s T-test for unpaired samples. *<i>P</i>< 0.0002 is relative to CTR vs. stressing conditions in WT LMNA expressing cells and **<i>P</i> < 0.0001 is relative to CTR vs. stressing conditions in DUP LMNA expressing cells.</p

Immunofluorescence confocal analysis of LMNA transfected HL-1 cells.

<p>Cells transfected with both LMNA WT and DUP are depicted. LMNA is visualized in green, Nuclear Pores in red, and colocalization in yellow in the merge panels. In the insets, a merged image of LMNA and Phalloidin-TRITC is shown. Planar XY projections were depicted in each experimental condition.</p

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies