OBJECTIVE:Congenital lipodystrophies (LD), including congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPLD), are rare disorders characterized by absent or abnormal adipose tissue distribution, leading to clinical, hormonal, and metabolic complications. Although these systemic features are well described, data on bone involvement is limited. This literature review summarizes current evidence on bone manifestations in genetic lipodystrophies and potential underlying mechanisms. METHODS:A systematic search was performed in PubMed, EMBASE, and the Cochrane Library using terms related to lipodystrophy and bone outcomes. No restrictions on date, language, or study design were applied. Studies reporting bone-related outcomes in genetic lipodystrophy in humans were included. Study quality was assessed using PRISMA guidelines and the JBI checklist. RESULTS:Of 2,632 studies identified, 15 met inclusion criteria. Most focused on CGL1 and CGL2; no studies were found on CGL3 or CGL4. Reported bone abnormalities in CGL1 and CGL2 included osteolytic lesions, bone cysts, osteosclerosis, and pseudo-osteopoikilosis, predominantly in long bones. Bone mineral density (BMD) was generally normal to high at trabecular sites. In contrast, FPLD2 was characterized by reduced BMD at cortical sites and lower trabecular bone score, suggesting impaired bone quality. Proposed mechanisms include reduced bone marrow adipose tissue, disrupted marrow fat conversion, and altered endocrine signaling. CONCLUSION:Bone abnormalities are characteristic yet often underrecognized features of genetic lipodystrophies, particularly CGL1 and CGL2. Current evidence underlines the broad skeletal impact of adipose dysfunction and highlights the need for standardized, genetically stratified studies to clarify bone risk and guide clinical management in congenital lipodystrophy.

Background Heterozygous variants in FBXW7 have recently been recognized as a cause of a rare neurodevelopmental disorder with variable developmental delay, neurological manifestations, and multisystem involvement. The breadth of clinical variability and penetrance remains incompletely defined.Cases presentation We report a retrospective multicenter case series of seven previously unreported individuals (five males, two females) with heterozygous FBXW7 variants identified through clinical genetic testing, aged 5-9 years at last evaluation (median 6 years). Six variants occurred de novo and one was inherited. Neurodevelopmental involvement was present in six individuals and was characterized by global developmental delay and language impairment; hypotonia was observed in all seven. Formal intellectual disability was documented in four cases, while one individual showed preserved cognitive functioning with predominant behavioral difficulties. Epileptic seizures occurred in four individuals, whereas three had no history of epilepsy. Brain MRI was available for six individuals and was normal in four, whereas two showed structural anomalies involving the corpus callosum. Extracerebral features were variably reported, most commonly constipation and recurrent respiratory/otolaryngological infections. Comparison with previously reported individuals confirmed the core neurodevelopmental phenotype and further refined the spectrum.Conclusions This case series expands the phenotypic spectrum associated with FBXW7-related neurodevelopmental disorder and highlights variable expressivity and incomplete penetrance, including clinically relevant variants presenting with mild or atypical phenotypes. These findings support considering FBXW7 across a broad range of neurodevelopmental presentations and inform genetic counseling.

In the presented case of familial mitral valve prolapse, whole exome sequencing was used to reveal a missense variant in the PDLIM7 gene. This gene is considered a possible novel candidate gene for familial MVP based on PDLIM7 knock-out mice and zebrafish showing mitral valve abnormalities.

BACKGROUND:Truncating titin variants (TTNtvs) are the most prevalent cause of inherited dilated cardiomyopathy. Occurrence of different ventricular arrhythmia (VA) subtypes, including premature ventricular complexes (PVCs), nonsustained ventricular tachycardia (NSVT), and sustained monomorphic VT (SMVT), has been reported. OBJECTIVES:The aim of this study was to analyze the prognostic relevance of distinct VA subtypes among TTNtv carriers and their underlying arrhythmogenic substrates. METHODS:Twenty-two TTNtv carriers referred for ablation of SMVT (n = 14) or frequent PVCs (n = 8) from 5 centers were included (mean age 56 ± 11 years; left ventricular ejection fraction 38% ± 13%; 77% male). Detailed phenotyping was performed, including Holter monitoring, cardiac imaging, and electroanatomical mapping. Patients were followed up for a median of 44 months. RESULTS:Demographic characteristics, including age, comorbidities, and left ventricular ejection fraction, were similar. NSVTs were frequent in both groups but faster in patients with SMVT (cycle length: 350 milliseconds [Q1-Q3: 315-403 milliseconds] vs 427 milliseconds [Q1-Q3: 395-469 milliseconds]). Although substrates for SMVT extended in a basal ring-like fashion with septal predominance, PVC sites of origin were limited to the basal anterior left ventricular segment. In the SMVT group, acute complete procedural success was achieved for 36%; during follow-up, 86% had recurrent VT, and 50% died of progressive heart failure. In the PVC group, complete abolition of PVCs was achieved in only 13%; at 3 months, median PVC burden was 1%, and there were no deaths or sustained VT during follow-up. VA subtype and NSVT cycle length were associated with mortality and poor VT-free survival. CONCLUSIONS:In TTNtv carriers, SMVTs but not frequent PVCs are associated with high mortality due to heart failure. Occurrence of SMVT may identify a subgroup at risk for rapid, progressive adverse remodeling. The prognostic significance of different VA subtypes needs to be confirmed in a larger cohort.

Atrial arrhythmias (AAs) in patients with left ventricular cardiomyopathy (LV-CM) are frequent and manifest at a younger age than in the general population. Different (likely) pathogenic variants (LP/PVs) in cardiomyopathy related genes are associated with variable penetrance, disease expression and progression which may be relevant for AA substrates. Data on AA ablation outcomes in patients with an LV-CM phenotype are sparse and data on genotype-specific ablation outcomes in this cohort are currently lacking. The aim of this study was to analyze outcomes of CA in LV-CM patients in relation to different genotypes. Patients who underwent CA for non-CTI dependent AAs and genetic testing for pathogenic variants in CM-associated genes (n=72, 96% with structural LV abnormalities; n=3, 4% tested during family screening) were included. Genetic testing results, ablation outcomes (one year AA-free survival) and clinical outcomes (echocardiography parameters at one year follow up) were analyzed across subgroups based on genetic findings (LP/PV-negative, TTN, LMNA, and other LP/PV). Seventy-five consecutive patients (age 58 ± 13 years, 76% male, mean LV-EF 45.8% ± 11%) who underwent CA for AAs were included (paroxysmal AF: n=24, 32%; persistent AF: n=40, 53%; AF only: n=46, 61%; AF + atypical flutter: n=8, 11%; atypical flutter only: n=11, 15%). A LP/PV was found in 28 (37%) patients (LMNA: n=13/28, 46%; TTN: n=10/28, 36%; Other LP/PV: n=5/28, 18%) (Figure 1). One-year AA-free survival did not differ between patients with and without LP/PV [LP/PV-: 65%, 95% CI (51% to 80%) vs. LP/PV+: 60%, 95% CI (41% to 78%), Log Rank=0.365] (Figure 2A). In a subgroup analysis, LMNA patients had a higher chance of 1-year AA recurrence compared to LP/PV- [HR=3.081, 95% CI (1.296-7.325)] while patients with a TTN LP/PV did not [HR=0.899, 95% CI (0.26-3.106)] (Figure 2B). In a univariable analysis, an LMNA LP/PV, AV block at baseline, LA/RA low-voltage areas were predictors of AA recurrence (p<0.1). In a multivariable analysis, an LMNA LP/PV was the only independent predictor [HR: 3.835, 95% CI (1.296-11.351), p=0.015]. At 1 year FU, left ventricular ejection fraction (LV-EF) significantly improved in TTN patients (BL 44% ± 9.2 vs. FU 48.8% ± 8.5, p=0.022), while no significant changes were observed for the other subgroups (LP/PV-: BL 45.4% ± 10.5 vs. FU 48.5% ± 8.7, p=0.063; LMNA: BL 52% ± 9.2 vs. FU 50% ± 11.8, p=0.296; Other LP/PV: BL 37.1% ± 8.4 vs. FU 39.3% ± 7.9, p=0.161). In LV-CM patients undergoing CA for AAs, LMNA LP/PVs were associated with higher recurrence rates post-ablation. In contrast, patients with TTN LP/PVs did not have a higher recurrence rate than patients without LP/PVs and, importantly, they showed improvement in LV function after ablation. These findings may inform patient selection and support the development of genotype-tailored treatment strategies.

PURPOSE:A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants. METHODS:We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines. RESULTS:Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. The POC5 protein plays an essential role during cell cycle and cilium formation. Interestingly, POC5 localization studies in 3 proband-derived fibroblast cell lines show aberrant localization suggesting a ciliary defect. The phenotypes of the 12 families in this study fit well within the ciliopathy phenotype spectrum, except for lipodystrophy, which is not common in ciliopathies. CONCLUSION:We describe a multiorgan syndrome caused by bi-allelic LoF variants in POC5. This underscores the pleiotropic effects of POC5 variants and highlights the significance of adipose tissue and metabolic dysfunction in ciliopathies.

Genetic missense variants in TNNI3K, encoding troponin-I interacting kinase, have been associated with dilated cardiomyopathy (DCM) and observed in families with supraventricular tachycardias (SVT). Previously, a family harboring the TNNI3K -c.1615A > G (p.Thr539Ala) variant presented with congenital junctional ectopic tachycardia (CJET), an arrhythmia that arises from the atrioventricular (AV) node and His bundle. However, this was a relatively small four-generational family with limited genetic testing ( N  = 3). We here describe a multigenerational family with CJET harboring a novel ultra-rare TNNI3K variant: TNNI3K -c.1729C > T (p.Leu577Phe). Of all 18 variant carriers, 13 individuals presented with CJET, resulting in a genetic penetrance of 72%. In addition, CJET is reported in another small family harboring TNNI3K -c.2225C > T (p.Pro742Leu). Similar to the previously published CJET family, both TNNI3K variants demonstrate a substantial reduction of kinase activity. Our study contributes novel evidence supporting the involvement of TNNI3K genetic variants as significant contributors to CJET, shedding light on potential mechanisms underlying this cardiac arrhythmia.

Germline and somatic TP53 variants play a crucial role during tumorigenesis. However, genetic variations that solely affect the alternatively spliced p53 isoforms, p53 beta and p53 gamma, are not fully considered in the molecular diagnosis of Li-Fraumeni syndrome and cancer. In our search for additional cancer predisposing variants, we identify a heterozygous stop-lost variant affecting the p53 beta isoforms (p.*342Serext*17) in four families suspected of an autosomal dominant cancer syndrome with colorectal, breast and papillary thyroid cancers. The stop-lost variant leads to the 17 amino-acid extension of the p53 beta isoforms, which increases oligomerization to canonical p53 alpha and dysregulates the expression of p53's transcriptional targets. Our study reveals the capacity of p53 beta mutants to influence p53 signalling and contribute to the susceptibility of different cancer types. These findings underscore the significance of p53 isoforms and the necessity of comprehensive investigation into the entire TP53 gene in understanding cancer predisposition. Pathogenic germline variants in TP53 predispose to a variety of cancers, but variants solely affecting alternatively spliced isoforms of TP53 are understudied. Here, the authors identify a heterozygous stop-lost variant that specifically affects p53 beta isoforms and predisposes to familial cancer using germline whole-exome sequencing and functional genomics assays.

Mutations in the LMNA-gene can cause a variety of ‘laminopathies’. These laminopathies are associated with a range of phenotypes, including disorders affecting the adipose tissue, peripheral nerves, the heart, such as dilated cardiomyopathy and conduction system abnormalities, and less commonly, progeroid disorders. This case series describes two families in which two novel LMNA-gene variants were identified, and who presented with an atypical progeroid phenotype with primarily premature aortic and mitral valve stenosis. Interestingly, these families exhibited no clear evidence of multisystem involvement, illustrating the complex role of lamins A/C.

HomeCirculation: Genomic and Precision MedicineVol. 16, No. 6New Genetic Variant in the MYH7 Gene Associated With Hypoplastic Right Heart Syndrome and Hypertrophic Cardiomyopathy in the Same Family No AccessResearch ArticleRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessResearch ArticleRequest AccessFull TextNew Genetic Variant in the MYH7 Gene Associated With Hypoplastic Right Heart Syndrome and Hypertrophic Cardiomyopathy in the Same Family Elizaveta Polyakova, Janine M. van Gils, J. Lauran Stöger, Philippine Kiès, Anastasia D. Egorova, Tamara T. Koopmann, Tessa van Dijk, Marco C. DeRuiter, Daniela Q.C.M. Barge-Schaapveld and Monique R.M. Jongbloed Elizaveta PolyakovaElizaveta Polyakova Center for Congenital Heart Disease Amsterdam-Leiden (E.P., P.K., A.D.E., M.C.D., M.R.M.J.), Leiden University Medical Center, the Netherlands. Department of Anatomy and Embryology (E.P., J.M.v.G., M.C.D., M.R.M.J.), Leiden University Medical Center, the Netherlands. , Janine M. van GilsJanine M. van Gils https://orcid.org/0000-0003-2429-7462 Department of Anatomy and Embryology (E.P., J.M.v.G., M.C.D., M.R.M.J.), Leiden University Medical Center, the Netherlands. , J. Lauran StögerJ. Lauran Stöger Department of Radiology (J.L.S.), Leiden University Medical Center, the Netherlands. , Philippine KièsPhilippine Kiès Center for Congenital Heart Disease Amsterdam-Leiden (E.P., P.K., A.D.E., M.C.D., M.R.M.J.), Leiden University Medical Center, the Netherlands. Department of Cardiology (P.K., A.D.E., M.R.M.J.), Leiden University Medical Center, the Netherlands. , Anastasia D. EgorovaAnastasia D. Egorova https://orcid.org/0000-0001-9312-2338 Center for Congenital Heart Disease Amsterdam-Leiden (E.P., P.K., A.D.E., M.C.D., M.R.M.J.), Leiden University Medical Center, the Netherlands. Department of Cardiology (P.K., A.D.E., M.R.M.J.), Leiden University Medical Center, the Netherlands. , Tamara T. KoopmannTamara T. Koopmann Department of clinical Genetics (T.T.K., T.v.D., D.Q.C.M.B.-S.), Leiden University Medical Center, the Netherlands. , Tessa van DijkTessa van Dijk https://orcid.org/0000-0002-2334-9278 Department of clinical Genetics (T.T.K., T.v.D., D.Q.C.M.B.-S.), Leiden University Medical Center, the Netherlands. , Marco C. DeRuiterMarco C. DeRuiter https://orcid.org/0000-0002-0528-7464 Center for Congenital Heart Disease Amsterdam-Leiden (E.P., P.K., A.D.E., M.C.D., M.R.M.J.), Leiden University Medical Center, the Netherlands. Department of Anatomy and Embryology (E.P., J.M.v.G., M.C.D., M.R.M.J.), Leiden University Medical Center, the Netherlands. , Daniela Q.C.M. Barge-SchaapveldDaniela Q.C.M. Barge-Schaapveld Department of clinical Genetics (T.T.K., T.v.D., D.Q.C.M.B.-S.), Leiden University Medical Center, the Netherlands. and Monique R.M. JongbloedMonique R.M. Jongbloed Correspondence to: Monique R.M. Jongbloed, MD, PhD, Center for Congenital Heart Disease Amsterdam-Leiden, Leiden University Medical Center, Postal Zone S-1-P, PO Box 9600, 2300 RC Leiden, the Netherlands. Email E-mail Address: [email protected] Center for Congenital Heart Disease Amsterdam-Leiden (E.P., P.K., A.D.E., M.C.D., M.R.M.J.), Leiden University Medical Center, the Netherlands. Department of Anatomy and Embryology (E.P., J.M.v.G., M.C.D., M.R.M.J.), Leiden University Medical Center, the Netherlands. Department of Cardiology (P.K., A.D.E., M.R.M.J.), Leiden University Medical Center, the Netherlands. Originally published11 Oct 2023https://doi.org/10.1161/CIRCGEN.123.004184Circulation: Genomic and Precision Medicine. 2023;16FootnotesFor Sources of Funding and Disclosures, see page 579.Correspondence to: Monique R.M. Jongbloed, MD, PhD, Center for Congenital Heart Disease Amsterdam-Leiden, Leiden University Medical Center, Postal Zone S-1-P, PO Box 9600, 2300 RC Leiden, the Netherlands. Email m.r.m.jongbloed@lumc.nlReferences1. Hinton RB, Michelfelder EC, Marino BS, Bove KE, Ware SM. A fetus with hypertrophic cardiomyopathy, restrictive, and single-ventricle physiology, and a beta-myosin heavy chain mutation.J Pediatr. 2010; 157:164–166. doi: 10.1016/j.jpeds.2010.02.044CrossrefMedlineGoogle Scholar2. Theis JL, Hu JJ, Sundsbak RS, Evans JM, Bamlet WR, Qureshi MY, O'Leary PW, Olson TM. Genetic association between hypoplastic left heart syndrome and cardiomyopathies.Circ Genom Precis Med. 2021; 14:e003126. doi: 10.1161/CIRCGEN.120.003126LinkGoogle Scholar3. van der Woude SFS, Rijnberg FM, Hazekamp MG, Jongbloed MRM, Kenjeres S, Lamb HJ, Westenberg JJM, Roest AAW, Wentzel JJ. The influence of respiration on blood flow in the Fontan circulation: insights for imaging-based clinical evaluation of the total cavopulmonary connection.Front Cardiovasc Med. 2021; 8:683849. doi: 10.3389/fcvm.2021.683849CrossrefMedlineGoogle Scholar4. Kelly MA, Caleshu C, Morales A, Buchan J, Wolf Z, Harrison SM, Cook S, Dillon MW, Garcia J, Haverfield E, et al. Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.Genet Med. 2018; 20:351–359. doi: 10.1038/gim.2017.218CrossrefMedlineGoogle Scholar5. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17:405–424. doi: 10.1038/gim.2015.30CrossrefMedlineGoogle Scholar6. van Rijsingen IA, Hermans-van Ast JF, Arens YH, Schalla SM, de Die-Smulders CE, van den Wijngaard A, Pinto YM. Hypertrophic cardiomyopathy family with double-heterozygous mutations; does disease severity suggest doubleheterozygosity?Neth Heart J. 2009; 17:458–463. doi: 10.1007/BF03086304CrossrefMedlineGoogle Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails December 2023Vol 16, Issue 6 Advertisement Article Information Metrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.123.004184PMID: 37818629 Originally publishedOctober 11, 2023 Keywordscardiomyopathiesheart ventricleshumanshypoplastic left heart syndromeuniventricular heartPDF download Advertisement Subjects Cardiomyopathy Congenital Heart Disease Genetics

Background: Truncating variants in desmoplakin ( DSP tv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSP tv cardiomyopathy. Methods: Individuals with DSP tv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSP tv performed. Results: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSP tv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSP tv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P <0.0001). Conclusions: In the largest series of individuals with DSP tv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

HomeCirculationVol. 147, No. 2Highlights From the Circulation Family of Journals No AccessNewsRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessNewsRequest AccessFull TextHighlights From the Circulation Family of Journals Originally published9 Jan 2023https://doi.org/10.1161/CIRCULATIONAHA.122.063478Circulation. 2023;147:178–182FootnotesCirculation is available at www.ahajournals.org/journal/circ eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails January 10, 2023Vol 147, Issue 2 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.063478 Originally publishedJanuary 9, 2023 PDF download Advertisement

ABSTRACT Background Variants in KCNH2 , encoding the hERG channel which is responsible for the rapid component of the cardiac delayed rectifier K + current (I Kr ), are causal to Long QT Syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2 :c.2717C>T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making. Methods A genotype-phenotype overview of the patients and relatives was created. The biophysiological effects were assessed by manual whole-cell patch-clamp using HEK293a cells expressing: (I) wild type (WT) KCNH2 , (II) KCNH2 -p.S906L alone (homozygous, Hm) or (III) KCNH2 -p.S906L in combination with WT (1:1) (heterozygous, Hz). A calibrated automated patch-clamp assay using Flp-In HEK293 was used to follow up on the functional data. Results Incomplete penetrance of LQTS2 in KCNH2 :p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2 , or AKAP9 . The phenotype of carriers of KCNH2 :p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch-clamp showed a reduced current density by 69.8%, and 60.4% in KCNH2-p.S906L-Hm and KCNH2 -p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2 -p.S906L-Hm compared to KCNH2 -WT. Assessment of KCNH2-p.S906L-Hz, by calibrated automatic patch-clamp showed a reduction in current density by 35.6%. Conclusion The reduced current density in the KCNH2 -p.S906L-Hz indicates a moderate loss of function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2 :p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.

BACKGROUND: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function. METHODS: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K . We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays. RESULTS: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation. CONCLUSIONS: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.

The arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the phenotype associated with the variant c.1211dup (p.Val406Serfs*4) in the plakophilin‑2 gene (PKP2) and compare it with previously reported Dutch PKP2 founder variants. Clinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers. Using data from the Netherlands ACM Registry, c.1211dup was compared with 3 other truncating PKP2 variants (c.235C > T (p.Arg79*), c.397C > T (p.Gln133*) and c.2489+1G > A (p.?)). Of the 106 carriers, 47 (44

AIMS:During the diagnostic work-up of patients with idiopathic ventricular fibrillation (VF), next-generation sequencing panels can be considered to identify genotypes associated with arrhythmias. However, consensus for gene panel testing is still lacking, and variants of uncertain significance (VUS) are often identified. The aim of this study was to evaluate genetic testing and its results in idiopathic VF patients. METHODS AND RESULTS:We investigated 419 patients with available medical records from the Dutch Idiopathic VF Registry. Genetic testing was performed in 379 (91%) patients [median age at event 39 years (27-51), 60% male]. Single-gene testing was performed in 87 patients (23%) and was initiated more often in patients with idiopathic VF before 2010. Panel testing was performed in 292 patients (77%). The majority of causal (likely) pathogenic variants (LP/P, n = 56, 15%) entailed the DPP6 risk haplotype (n = 39, 70%). Moreover, 10 LP/P variants were found in cardiomyopathy genes (FLNC, MYL2, MYH7, PLN (two), TTN (four), RBM20), and 7 LP/P variants were identified in genes associated with cardiac arrhythmias (KCNQ1, SCN5A (2), RYR2 (four)). For eight patients (2%), identification of an LP/P variant resulted in a change of diagnosis. In 113 patients (30%), a VUS was identified. Broad panel testing resulted in a higher incidence of VUS in comparison to single-gene testing (38% vs. 3%, P < 0.001). CONCLUSION:Almost all patients from the registry underwent, albeit not broad, genetic testing. The genetic yield of causal LP/P variants in idiopathic VF patients is 5%, increasing to 15% when including DPP6. In specific cases, the LP/P variant is the underlying diagnosis. A gene panel specifically for idiopathic VF patients is proposed.

Abstract Background Patients with a univentricular heart form a morphological heterogenous group of patients at the most severe end of the congenital heart disease (CHD) spectrum. Over the past decades, more awareness and knowledge has been raised on the genetic contributions to CHD. To date, only a limited number of genes have been identified in the hypoplastic heart, mainly in left-sided hypoplasia. There is still much more to be elucidated in this field. Case summary Here, we present a follow-up report of a case of an adult patient after Fontan palliation, born with a.o. tricuspid atresia with hypoplastic right ventricle and pulmonary stenosis. This patient encountered a myriad of late sequalae involving multiple organ systems during the course of his young adult life, including refractory protein losing enteropathy (PLE). Concomitant extracardiac anomalies, in addition to the complex CHD and its complications, prompted for genetic evaluation. Whole exome sequencing showed a variant of uncertain significance in the BRAF gene [NM_004333.4:c.1897T > C p.(Tyr633His)], associated with Noonan spectrum disorders, that is also infamous for lymphoedema and PLE. The variant regards an evolutionarily highly conserved amino acid and is assumed pathogenic according to all prediction programmes. The mutation was most likely de novo. Discussion Genetic screening can provide new insights in the complex and varied phenotype of the (adult) Fontan patient and in the myriad of complications encountered. Adult CHD cardiologists should be aware of genetic syndromes underlying a CHD, concomitant extracardiac anomalies, and a complex clinical course with a broad spectrum of late sequelae.

PurposeHeterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies.MethodsIndex patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire.ResultsA total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25% and 16.7% of the cases and in-hospital mortality rates were 9.5% and 0%, respectively.ConclusionP/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range.