Introduction and objectivesUp to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. Mutations in CSRP3 have been associated with HCM, but evidence supporting pathogenicity is inconclusive. In this study, we describe an HCM cohort with a missense variant in CSRP3 (p.Cys150Tyr) with supporting evidence for pathogenicity and a description of the associated phenotype. MethodsCSRP3 was sequenced in 6,456 index cases with a diagnosis of HCM and in 5,012 probands with other cardiomyopathies. In addition, 3,372 index cases with hereditary cardiovascular disorders other than cardiomyopathies (mainly channelopathies and aortopathies) were used as controls. ResultsThe p.(Cys150Tyr) variant was identified in 11 unrelated individuals of the 6,456 HCM probands, and it was not identified in patients with other cardiomyopathies (p<0.0001) or in our control population (p<0.0001). Ten of the index cases were heterozygous and one was homozygous. Homozygous had a more severe phenotype. Family screening identified 17 other carriers. Wild-type individuals showed no signs of disease. The mean age at diagnosis of affected individuals was 55 ± 13 years, and the mean left ventricular wall thickness was 18 ± 3 mm. The variant showed highly age-dependent penetrance. After a mean follow-up of 11 (±8) years, no adverse events were reported in any of the HCM patients. ConclusionsThe p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hypertrophic cardiomyopathy in heterozygous carriers.
Here we report an infant with clinical findings suggestive of Jervell and Lange-Nielsen syndrome (JLNS), including a prolonged QT interval (LQTS) and chronic bilateral sensorineural deafness. NGS analysis revealed one known heterozygous pathogenic missense variant, KCNQ1 p.R259L, previously associated with LQTS but insufficient to explain the cardioauditory disorder. In a screening of proximal intronic regions, we found a heterozygous variant, KCNQ1 c.1686−9 T > C, absent from controls and previously undescribed. Several splicing prediction tools returned low scores for this intronic variant. Driven by the proband’s phenotype rather than the neutral predictions, we have characterized this rare intronic variant. Family analysis has shown that the proband inherited the missense and the intronic variants from his mother and father, respectively. A minigene splicing assay revealed that the intronic variant induced an additional transcript, arising from skipping of exon 14, which was translated into a truncated protein in transfected cells. The splice-out of exon 14 creates a frameshift in exon 15 and a stop codon in exon 16, which is the last exon of KCNQ1. This mis-spliced transcript is expected to escape nonsense-mediated decay and predicted to encode a truncated loss-of-function protein, KCNQ1 p.L563Kfs*73. The analysis of endogenous KCNQ1 expression in the blood of the proband’s parents detected the aberrant transcript only in the patient’s father. Taken together, these analyses confirmed the proband’s diagnosis of JLNS1 and indicated that c.1686−9 T > C is a cryptic splice-altering variant, expanding the known genetic spectrum of biallelic KCNQ1 variant combinations leading to JLNS1.
We have detected a high prevalence of AF in patients with DP. The diagnose of AF led to change in treatment. Four clinical variables increase the likelihood of developing this arrhythmia.
Introduction Filamin C gene (FLNC) missense mutations have been previously reported in association with restrictive cardiomyopathy (RCM). The association of FLNC missense variants with non-compaction cardiomyopathy has been reported only in a single proband, but familiar or functional evidence on its causative effect is limited. Overlapping traits among cardiomyopathies related to the same genetic substrate is an emerging and a challenging scenario nowadays. Purpose To report a new pathogenic FLNC missense variant in association with a particular form of restrictive/non-compaction overlapping cardiomyopathy. Methods The probands fulfill the diagnostic criteria for RCM based on current guidelines. Genetic testing in the probands was performed by NGS, using a broad gene panel (containing over 240 genes). Clinical and genetic cascade screening were expanded to first-degree relatives when it was possible. All mutation carriers underwent clinical assessment including physical examination, 12-lead ECG, echocardiography, cardiac magnetic resonance (MRI), 24h Holter monitoring, and ergometry. None of them had major systemic illnesses nor clinical symptoms of muscular involvement. Results The p.Gly2011Arg variant in the FLNC gene was the only relevant variant in the three probands. This variant is virtually absent in the general population (gnomAD). The variant showed a de novo presentation in the first family and segregated with the phenotype in the four studied relatives from the second family (three affected carriers and one unaffected non-carrier). In the third case no familial information was available. This variant affects an ultraconserved residue and is located in a relevant sub-region of Filamin-C, which is necessary for its interaction with other Z-disc proteins. Detailed clinical information is available on all carriers (n=5, 1 male). The average age at diagnosis is 17 years [1–36]. An abnormal ECG was the earliest clinical manifestation (left ventricular hypertrophy by voltage criteria and extensive repolarization abnormalities). Significant hypertrabeculations, mainly at the anterolateral wall and basal anteroseptal segments, was present in all affected carriers. Interestingly, none of them showed an abnormal late-gadolinium enhancement pattern on MRI. The four carriers who were older than 35 years were found to have severe restrictive pattern on echocardiography (functional parameters and secondary features such as bi-atrial dilation), all four suffered from limiting dyspnea, and two are under pre-transplant workup (A-II-1 and B-III-1). One of them had a cardioembolic event (femoral acute ischemia, A-II-1). One relative has recently died from advanced heart failure (B-II-2). Conclusion This is the first description on this overlapping (restrictive/non-compaction cardiomyopathy) and aggressive phenotype associated with a missense FLNC variant. This description widens the clinical spectrum related to FLNC missense mutations. Pedigrees and clinical characterization Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Health in Code
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