Background: CaM (calmodulin), encoded by 3 separate genes ( CALM1 , CALM2 , and CALM3 ), is a multifunctional Ca 2+ -binding protein involved in many signal transduction events including ion channel regulation. CaM variants may present with early-onset long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia, or sudden cardiac death. Most reported variants occurred de novo. We identified a novel CALM3 variant, p.Asn138Lys (N138K), in a 4-generation family segregating with LQTS. The aim of this study was to elucidate its pathogenicity and to compare it with that of p.D130G-CaM—a variant associated with a severe LQTS phenotype. Methods: We performed whole exome sequencing for a large, 4-generation family affected by LQTS. To assess the effect of the detected CALM3 variant, the intrinsic Ca 2+ -binding affinity was measured by stoichiometric Ca 2+ titrations and equilibrium titrations. L-type Ca 2+ and slow delayed rectifier potassium currents (I CaL and I Ks ) were recorded by whole-cell patch-clamp. Cav1.2 and Kv7.1 membrane expression were determined by optical fluorescence assays. Results: We identified 14 p.N138K-CaM carriers in a family where 2 sudden deaths occurred in children. Several members were only mildly affected compared with CaM-LQTS patients to date described in literature. The intrinsic Ca 2+ -binding affinity of the CaM C-terminal domain was 10-fold lower for p.N138K-CaM compared with WT-CaM. I CaL inactivation was slowed in cells expressing p.N138K-CaM but less than in p.D130G-CaM cells. Unexpectedly, a larger I Ks current density was observed in cells expressing p.N138K-CaM, but not for p.D130G-CaM, compared with WT-CaM. Conclusions: The p.N138K CALM3 variant impairs Ca 2+ -binding affinity of CaM and I CaL inactivation but potentiates I Ks . The variably expressed phenotype of this variant compared with previously published de novo LQTS-CaM variants is likely explained by a milder impairment of I CaL inactivation combined with I Ks augmentation.

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PURPOSEThe distinction between physiologic (innocent) and pathologic (organic) heart murmurs is not always easy in routine practice, leading too often to unnecessary cardiology referrals and expensive investigations. We aimed to test the hypothesis that the complete disappearance of murmur on standing can exclude cardiac disease in children.METHODS From January 2014 to January 2015, we prospectively included 194 consecutive children aged 2 to 18 years who were referred for heart murmur evaluation to pediatric cardiologists at 2 French medical centers. Heart murmur characteristics while supine and then while standing were recorded, and an echocardiogram was performed.RESULTS Overall, 30 (15%) of the 194 children had a pathologic heart murmur as determined by an abnormal echocardiogram. Among the 100 children (51%) who had a murmur that was present while they were supine but completely disappeared when they stood up, only 2 had a pathologic murmur, and just 1 of them needed further evaluation. Complete disappearance of the heart murmur on standing therefore excluded a pathologic murmur with a high positive predictive value of 98% and specificity of 93%, albeit with a lower sensitivity of 60%.CONCLUSIONS Disappearance of a heart murmur on standing is a reliable clinical tool for ruling out pathologic heart murmurs in children aged 2 years and older. This basic clinical assessment would avoid many unnecessary referrals to cardiologists. 2017;15:523-528. https://doi.org/10.1370/afm.2105. Ann Fam Med INTRODUCTIONH eart murmur is a clinical finding currently affecting about 65% to 80% of schoolchildren 1,2 and one of the most common reasons for referral to cardiologists. Most murmurs are physiologic (innocent) 3 and result from the normal pattern of blood flow through the cardiac cavities and vessels. In a few cases, however, the murmur may be the single symptom of cardiac disease, even if most congenital heart diseases are diagnosed before birth or during the first year of life. 1Differences between physiologic and pathologic murmurs are well known, 4-9 but primary care physicians in family medicine or pediatricians too frequently refer their patients to pediatric cardiologists because they fear missing a heart disease diagnosis, resulting in unneeded parental anxiety, time consumption, and expensive evaluations. 10,11 Several clinical features of the murmur such as intensity, timing, quality and pitch, and the presence of a click are subjective and require extensive training for use to distinguish between physiologic and pathologic murmur. A simple, objective, and robust clinical test to exclude cardiac disease in apparently healthy children could prevent many unnecessary referrals.McLaren et al 12 reported that the prevalence of physiologic heart murmur in schoolchildren was 65% when they were in a supine position, whereas it was only 15% when they were standing. To our knowledge, however, no study has demonstrated that the disappearance of murmur 524on standing can allow clinicians to rule out a murmur ...