Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients.

PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD. METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review. RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation. CONCLUSION: We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.

Early initiation of B-vitamin supplementation may reduce symptoms and explain intrafamilial variability: Insights from two sibling pairs from the TANGO2 natural history study.

TANGO2-deficiency disorder (TDD) is an autosomal recessive condition arising from pathogenic biallelic variants in the TANGO2 gene. TDD is characterized by symptoms typically beginning in late infancy including delayed developmental milestones, cognitive impairment, dysarthria, expressive language deficits, and gait abnormalities. There is wide phenotypic variability where some are severely affected while others have mild symptoms. This variability has been documented even among sibling pairs who share the same genotype, but reasons for this variability have not been well understood. Emerging data suggest a potential link between B-complex or multivitamin supplementation and decreased metabolic crises in TDD. In this report, we describe two sibling pairs from unreladiagnosed with TDD with marked differences in symptoms. In both families, the older siblings suffered multiple metabolic crises and are clinically more affected than their younger siblings who have very mild to no symptoms; they are the least impaired among 70 other patients in our ongoing international natural history study. Unlike their older siblings, the two younger siblings started taking B-complex vitamins early between 9 and 16 months. This report delineates the mildest presentation of TDD in two families. These data may support a role for early diagnosis and initiation of vitamin supplementation to not only prevent metabolic crises but also improve neurologic outcomes in this life-threatening disorder.

Atrial tachyarrhythmias after lung transplantation in children: A common occurrence.

BACKGROUND: Atrial arrhythmia's (AA) following lung transplant in adults are a well-described clinical finding. In pediatrics, however, there are limited data with some reports suggesting that arrhythmias are rare. METHODS: We performed a single-center retrospective review of lung transplant recipients from January 2013 to June 2020. A detailed evaluation of clinical characteristics, presence of arrhythmias, and outcomes was completed. Arrhythmias were documented based on inpatient telemetry or remote Holter monitoring. Analyses assessing risk factors for arrhythmias and associations with clinical outcomes were performed. RESULTS: Ninety-one lung transplants were performed in 90 patients. Post-operative AA occurred following 19% transplants. Ectopic atrial tachycardia was seen in 14%, atrial flutter in 2%, and a combination in 2%. The majority of these arrhythmias occurred within the first 45 days post-operatively. Antiarrhythmic treatment was required in 59%, but none required ablation or electrical cardioversion. In patients followed for a year or more, 88% had resolution of their arrhythmia. Arrhythmias were not associated with mortality. In further analysis, however, the presence of arrhythmia was associated with an increased length of ICU stay (median of 12 days (IQR 6, 23) versus 5 days (IQR 4, 9); p = .019) and overall length of hospital stay (median of 26 days (IQR 19, 36) versus 17 days (IQR 19, 36); p = .043). CONCLUSIONS: Atrial tachyarrhythmias after lung transplantation are common in the pediatric population and usually occur early. Although they frequently require medical therapy and are associated with longer stays, there is no associated increased mortality. In addition, the arrhythmias typically self-resolve.

Arrhythmogenic cardiomyopathy is under-recognized in end-stage pediatric heart failure: A 36-year single-center experience.

BACKGROUND: Although ventricular failure is a late finding in adults with AC, we hypothesize that this is a presenting symptom in pediatric heart failure patients who undergo HT and that their ventricular arrhythmia burden could differentiate AC from other cardiomyopathies. METHODS: We performed a single-center retrospective cohort study reviewing 457 consecutive pediatric (≤18 years) HT recipients at our institution. Explanted hearts were examined to establish the primary diagnosis, based on pathologic findings. Demographic and clinical variables were compared between AC versus non-HCM cardiomyopathy cases. RESULTS: Forty-five percent (n = 205/457) had non-HCM cardiomyopathies as the underlying primary diagnosis. Ten cases (10/205 = 4.9%) were diagnosed with AC. All 10 had biventricular disease. In 8/10 patients (80%), AC diagnosis was unrecognized pre-HT. Compared with non-AC cardiomyopathies, the AC group was older at diagnosis (9.3 years vs. 4.3 years, p = .012) and transplant (11.1 years vs. 6.5 years, p = .010), had more ventricular arrhythmias (80.0% vs 32.8%, p = .003), and required more anti-arrhythmic use (80.0% vs 32.3%, p = .001). Genetic testing yielded causative pathogenic variants in all tested individuals (n = 5/5, 100%). CONCLUSION: AC is often an unrecognized cardiomyopathy pretransplant in children who undergo HT. Pediatric non-HCM phenotypes with heart failure who have a significant ventricular arrhythmia burden should be investigated for AC.

Decreased Heart Rate Variability in Children with Acute Decompensated Heart Failure is Associated with Poor Outcomes.

Heart rate variability (HRV) is a noninvasive indicator of the health of neurocardiac interactions of the autonomic nervous system. In adults, decreased HRV correlates with increased cardiovascular mortality. However, the relationship between HRV and outcomes in children with acute decompensated heart failure (ADHF) has not been described. Patients < 21 years old hospitalized with ADHF from 2013 to 2019 were included (N = 79). Primary outcome was defined as death, heart transplant, or mechanical circulatory support (MCS). The median standard deviation of the R-to-R interval in 5-min intervals (SDNN) was calculated from telemetry data obtained across the first 24 h of admission. Patients who met the primary outcome had significantly lower median SDNN (13.8 [7.8, 29.1]) compared to those who did not (24.6 [15.3, 84.4]; p = 0.004). A median SDNN of 20 ms resulted in a sensitivity of 68% and specificity of 69%. Median SDNN < 20 ms represented decreased freedom from primary outcome (p = 0.043) and a hazard ratio of 2.2 in multivariate analysis (p = 0.016). Pediatric patients with ADHF who died, underwent heart transplant, or required MCS had significantly decreased HRV at presentation compared to those that did not. This supports HRV as a noninvasive tool to improve prognostication in children in ADHF.

Trends in hospitalization and factors associated with in-hospital death among pediatric admissions with implantable cardioverter defibrillators.

BACKGROUND: As pediatric implantable cardioverter-defibrillator (ICD) utilization increases, hospital admission rates will increase. Data regarding hospitalizations among pediatric patients with ICDs are lacking. In addition, hospital mortality rates are unknown. This study aimed to evaluate (1) trends in hospitalization rates from 2000 to 2016, (2) hospital mortality, and (3) factors associated with hospital mortality among pediatric admissions with ICDs. METHODS: The Kids' Inpatient Database (2000, 2003, 2006, 2009, 2012, 2016) was used to identify all hospitalizations with an existing ICD ≤20 years of age. ICD9/10 codes were used to stratify admissions by underlying diagnostic category as: (1) congenital heart disease (CHD), (2) primary arrhythmia, (3) primary cardiomyopathy, or (4) other. Trends were analyzed using linear regression. Hospital and patient characteristics among hospital deaths were compared to those surviving to discharge using mixed multivariable logistic regression, accounting for hospital clustering. RESULTS: Of 42 570 716 hospitalizations, 4165 were admitted ≤20 years with an ICD. ICD hospitalizations increased four-fold (p = .002) between 2000 and 2016. Hospital death occurred in 54 (1.3%). In multivariable analysis, cardiomyopathy (odds ratio [OR]: 3.5, 95% confidence interval [CI]: 1.1-11.2, p = .04) and CHD (OR: 4.8, 95% CI: 1.5-15.6, p = .01) were significantly associated with mortality. In further exploratory multivariable analysis incorporating a coexisting diagnosis of heart failure, only the presence of heart failure remained associated with mortality (OR: 8.6, 95% CI: 3.7-20.0, p < .0001). CONCLUSIONS: Pediatric ICD hospitalizations are increasing over time and hospital mortality is low (1.3%). Hospital mortality is associated with cardiomyopathy or CHD; however, the underlying driver for in-hospital death may be heart failure.

Ripple mapping: A precise tool for atrioventricular nodal reentrant tachycardia ablation.

INTRODUCTION: Ablation for atrioventricular nodal reentrant tachycardia (AVNRT) classically utilizes evaluation of signal morphology within the anatomic region of the slow pathway (SP), which involves subjectivity. Ripple mapping (RM; CARTO-3© Biosense Webster Inc) displays each electrogram at its three-dimensional coordinate as a bar changing in length according to its voltage-time relationship. This allows prolonged, low-amplitude signals to be displayed in their entirety, helping identify propagation in low-voltage areas. We set out to evaluate the ability of RM to locate the anatomic site of the SP and assess its use in guiding ablation for AVNRT. METHODS: Patients ≤18 years with AVNRT in the EP laboratory between 2017 and 2021 were evaluated. RM was performed to define region of SP conduction in patients from 2019 to 2021, whereas standard electro-anatomical mapping was used from 2017 to 2019. All ablations were performed using cryotherapy. Demographics, outcomes, and analysis of variance in number of test lesions until success was compared between groups. RESULTS: A total of 115 patients underwent AVRNT ablation during the study; 46 patients were in the RM group and 69 were in the control group. There were no demographic differences between groups. All procedures, in both groups, were acutely successful. In RM group, 89% of first successful lesions were within 4 mm of the predicted site. There was significantly reduced variability in number of test lesions until success in the RM group (p = .01). CONCLUSION: RM is a novel technique that can help identify SP location, allowing for successful ablation of AVNRT with decreased variability.

Clinical exome sequencing uncovers a high frequency of Mendelian disorders in infants with stroke: A retrospective analysis.

Stroke causes significant disability and is a common cause of death worldwide. Previous studies have estimated that 1%-5% of stroke is attributable to monogenic etiologies. We set out to assess the utility of clinical exome sequencing (ES) in the evaluation of stroke. We retrospectively analyzed 124 individuals who received ES at the Baylor Genetics reference lab between 2012 and 2021 who had stroke as a major part of their reported phenotype. Ages ranged from 10 days to 69 years. 8.9% of the cohort received a diagnosis, including 25% of infants less than 1 year old; an additional 10.5% of the cohort received a probable diagnosis. We identified several syndromes that predispose to stroke such as COL4A1-related brain small vessel disease, homocystinuria caused by CBS mutation, POLG-related disorders, TTC19-linked mitochondrial disease, and RNASEH2A associated Aicardi-Goutieres syndrome. We also observed pathogenic variants in NSD1, PKHD1, HRAS, and ATP13A2, which are genes rarely associated with stroke. Although stroke is a complex phenotype with varying pathologies and risk factors, these results show that use of exome sequencing can be highly relevant in stroke, especially for those presenting <1 year of age.

Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that often leads to sudden cardiac death. The most common form of CPVT is caused by autosomal-dominant variants in the cardiac ryanodine receptor type-2 (RYR2) gene. Mutations in RYR2 promote calcium (Ca2+ ) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias. Recently, it was demonstrated that tetracaine derivative EL20 specifically inhibits mutant RyR2, normalizes Ca2+ handling and suppresses arrhythmias in a CPVT mouse model. The objective of this study was to determine whether EL20 normalizes SR Ca2+ handling and arrhythmic events in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a CPVT patient. Blood samples from a child carrying RyR2 variant RyR2 variant Arg-176-Glu (R176Q) and a mutation-negative relative were reprogrammed into iPSCs using a Sendai virus system. iPSC-CMs were derived using the StemdiffTM kit. Confocal Ca2+ imaging was used to quantify RyR2 activity in the absence and presence of EL20. iPSC-CMs harbouring the R176Q variant demonstrated spontaneous SR Ca2+ release events, whereas administration of EL20 diminished these abnormal events at low nanomolar concentrations (IC50  = 82 nM). Importantly, treatment with EL20 did not have any adverse effects on systolic Ca2+ handling in control iPSC-CMs. Our results show for the first time that tetracaine derivative EL20 normalized SR Ca2+ handling and suppresses arrhythmogenic activity in iPSC-CMs derived from a CPVT patient. Hence, this study confirms that this RyR2-inhibitor represents a promising therapeutic candidate for treatment of CPVT.

2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

Aim This executive summary of the hypertrophic cardiomyopathy clinical practice guideline provides recommendations and algorithms for clinicians to diagnose and manage hypertrophic cardiomyopathy in adult and pediatric patients as well as supporting documentation to encourage their use. Methods A comprehensive literature search was conducted from January 1, 2010, to April 30, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Structure Many recommendations from the earlier hypertrophic cardiomyopathy guidelines have been updated with new evidence or a better understanding of earlier evidence. This summary operationalizes the recommendations from the full guideline and presents a combination of diagnostic work-up, genetic and family screening, risk stratification approaches, lifestyle modifications, surgical and catheter interventions, and medications that constitute components of guideline directed medical therapy. For both guideline-directed medical therapy and other recommended drug treatment regimens, the reader is advised to follow dosing, contraindications and drug-drug interactions based on product insert materials.

"Second line medications" for supraventricular arrhythmias in children: In-hospital efficacy and adverse events during treatment initiation of sotalol and flecainide.

INTRODUCTION: Sotalol and flecainide are used as second line agents in children for the treatment of supraventricular arrhythmias (SA) refractory to anti-beta adrenergic antiarrhythmics or digoxin. Efficacy and adverse events in this cohort have not been well described. Here, we report our institutional experience of second line treatment initiation for SA in children. METHODS AND RESULTS: Utilizing an institutional database, 247 patients initiated on sotalol and 81 patients initiated on flecainide were identified. Congenital heart disease (CHD) was present in 40% of patients. Arrhythmia-free discharge on single or dual agent therapy (in combination with other antiarrhythmics) was 87% for sotalol and 91% for flecainide. Neither age, sex, dosing, presence of CHD nor arrhythmia subtype were associated with alterations in in-hospital efficacy. Compared to baseline, QTc intervals in sotalol patients (436 [416-452 ms] vs. 415 [400-431 ms], p < .01) and QRS intervals in flecainide patients (75 [68-88 ms] vs. 62 [56-71 ms], p < .01) were prolonged. Dose reduction or discontinuation due to QRS prolongation occurred in 9% of patients on flecainide. QTc prolongation resulting in dose reduction/discontinuation of sotalol was encountered in 9 patients (4%) and death with documented torsade de pointes in 2 patients (1%), with 9 of 11 patients having underlying CHD. CONCLUSION: In children requiring second line agents for treatment of SA, both sotalol and flecainide appear to be highly efficacious. Although predominantly safe in otherwise healthy patients, electrocardiogram changes can occur and children with underlying cardiac disease may have an increased risk of adverse events and rhythm-related side effects during initiation.

Risk of sudden cardiac death in EXOSC5-related disease.

The RNA exosome is a multi-subunit complex involved in the processing, degradation, and regulated turnover of RNA. Several subunits are linked to Mendelian disorders, including pontocerebellar hypoplasia (EXOSC3, MIM #614678; EXOSC8, MIM #616081: and EXOSC9, MIM #618065) and short stature, hearing loss, retinitis pigmentosa, and distinctive facies (EXOSC2, MIM #617763). More recently, EXOSC5 (MIM *606492) was found to underlie an autosomal recessive neurodevelopmental disorder characterized by developmental delay, hypotonia, cerebellar abnormalities, and dysmorphic facies. An unusual feature of EXOSC5-related disease is the occurrence of complete heart block requiring a pacemaker in a subset of affected individuals. Here, we provide a detailed clinical and molecular characterization of two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination, with cardiac conduction and rhythm abnormalities including sinus node dysfunction, intraventricular conduction delay, atrioventricular block, and ventricular tachycardia (VT) due to compound heterozygous variants in EXOSC5: (1) NM_020158.4:c.341C > T (p.Thr114Ile; pathogenic, previously reported) and (2) NM_020158.4:c.302C > A (p.Thr101Lys; novel variant). A review of the literature revealed an additional family with biallelic EXOSC5 variants and cardiac conduction abnormalities. These clinical and molecular data provide compelling evidence that cardiac conduction abnormalities and arrhythmias are part of the EXOSC5-related disease spectrum and argue for proactive screening due to potential risk of sudden cardiac death.

Wolff-Parkinson-White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation.

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population. METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW. RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023). CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.

Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.

The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

Riata lead failure in pediatric and congenital heart disease patients.

BACKGROUND: Implantable cardioverter defibrillator (ICD) lead failures occur at higher rates in pediatric and congenital heart disease (CHD) patients. OBJECTIVE: To determine the rate and timing of Riata lead failure in pediatric and CHD patients. METHODS: This was a retrospective, multicenter cohort study of pediatric patients and adults with CHD with implantation of a Riata or Riata ST lead between 2002 and 2009. The prevalence and timing of electrical failure and conductor coil externalization (CCE) were determined. RESULTS: Fifty-eight patients and 63 leads from seven centers were included. Median (interquartile range [IQR]) age at implant was 14.4 (11.5-18.7) years and median follow-up was 8.7 (7.3-11.1) years. The underlying diagnosis was a primary arrhythmia disorder in 45%, cardiomyopathy in 31%, and CHD in 28% of patients. Electrical failure occurred in 43% and CCE in 16% of leads at median lead ages of 4.7 (3.4-7.5) and 4.3 (3.9-7.0) years, respectively. Median lead survival free from electrical failure or CCE was 7.9 (95% confidence interval, 5.8-10.0) years. Forty-one percent of leads were functional at the end of the follow-up period, and 33% were extracted with a complication rate of 5%. CONCLUSIONS: The rate of Riata lead electrical failure was high in children and patients with CHD, while the rate of CCE was comparable with published data. Counseling on lead management should factor in the high rate of electrical failure with considerations for elective replacement.

Association of Wolff-Parkinson-White With Left Ventricular Noncompaction Cardiomyopathy in Children.

BACKGROUND: Wolff-Parkinson-White (WPW) has been associated with left ventricular noncompaction (LVNC) in children. Little is known about the prevalence of this association, clinical outcomes, and treatment options. METHODS: Retrospective review of subjects with LVNC. LVNC was defined by established criteria; those with congenital heart disease were excluded. Electrocardiograms (ECGs) were reviewed for presence of pre-excitation. Outcomes were compared between those with isolated LVNC and those with WPW and LVNC. RESULTS: A total of 348 patients with LVNC were identified. Thirty-eight (11%) were found to have WPW pattern on ECG, and 84% of those with WPW and LVNC had cardiac dysfunction. In Kaplan-Meier analysis, there was significantly lower freedom from significant dysfunction (ejection fraction ≤ 40%) among those with WPW and LVNC (P < .001). Further analysis showed a higher risk of developing significant dysfunction in patients with WPW and LVNC versus LVNC alone (hazard ratio 4.64 [2.79, 9.90]). Twelve patients underwent an ablation procedure with an acute success rate of 83%. Four patients with cardiac dysfunction were successfully ablated, 3 having improvement in function. CONCLUSION: WPW is common among children with LVNC and is associated with cardiac dysfunction. Ablation therapy can be safely and effectively performed and may result in improvement in function.

Distinct Cellular Basis for Early Cardiac Arrhythmias, the Cardinal Manifestation of Arrhythmogenic Cardiomyopathy, and the Skin Phenotype of Cardiocutaneous Syndromes.

RATIONALE: Arrhythmogenic cardiomyopathy is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. Homozygous DSP (desmoplakin) and JUP (junction protein plakoglobin) mutations are responsible for a subset of patients with arrhythmogenic cardiomyopathy who exhibit cardiac arrhythmias and dysfunction, palmoplanter keratosis, and hair abnormalities (cardiocutaneous syndromes). OBJECTIVE: To determine phenotypic consequences of deletion of Dsp in a subset of cells common to the heart and skin. METHODS AND RESULTS: Expression of CSPG4 (chondroitin sulfate proteoglycan 4) was detected in epidermal keratinocytes and the cardiac conduction system. CSPG4pos cells constituted ≈5.6±3.3% of the nonmyocyte cells in the mouse heart. Inducible postnatal deletion of Dsp under the transcriptional control of the Cspg4 locus led to ventricular arrhythmias, atrial fibrillation, atrioventricular conduction defects, and death by 4 months of age. Cardiac arrhythmias occurred early and in the absence of cardiac dysfunction and excess cardiac fibroadipocytes, as in human arrhythmogenic cardiomyopathy. The mice exhibited palmoplantar keratosis and progressive alopecia, leading to alopecia totalis, associated with accelerated proliferation and impaired terminal differentiation of keratinocytes. The phenotype is similar to human cardiocutaneous syndromes caused by homozygous mutations in DSP. CONCLUSIONS: Deletion of Dsp under the transcriptional regulation of the CSPG4 locus led to lethal cardiac arrhythmias in the absence of cardiac dysfunction or fibroadiposis, palmoplantar keratosis, and alopecia, resembling the human cardiocutaneous syndromes. The findings offer a cellular basis for early cardiac arrhythmias in patients with arrhythmogenic cardiomyopathy and cardiocutaneous syndromes.

Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data.

High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.