Electrophysiological and histopathological characteristics of progressive atrioventricular block accompanied by familial dilated cardiomyopathy caused by a novel mutation of lamin A/C gene

Conduction defect caused by lamin A/C gene mutation. INTRODUCTION: Mutations of lamin A/C gene (LMNA) cause dilated cardiomyopathy (DCM) with atrioventricular (AV) conduction defect, although the electrophysiological and histological profiles are not fully understood. METHODS AND RESULTS: We analyzed a large Japanese family (21 affected and 203 unaffected members) of DCM with AV block. The responsible LMNA mutation of IVS3-10A>G was novel and caused an aberrant splicing. The first clinical manifestation was low-grade AV block or atrial fibrillation (AF), which developed in affected members aged >or=30 years. We observed that the AV block progressed to third-degree within several years. The electrophysiological study of the four affected members revealed an impairment of intra-AV nodal conduction. Because of advanced AV block, pacemakers were implanted in 14 out of 21 affected members at the mean age of 44 years. Three affected members died suddenly and two affected members died of heart failure and/or ventricular tachycardia (VT) even after the pacemaker implantation. Postmortem examination showed conspicuous fibrofatty degeneration of the AV node. Endomyocardial biopsies showed remarkably deformed nuclei and substantial glycogen deposits in the subsarcolemma. CONCLUSION: The clinical phenotype in this family was characterized by (1) the first manifestation of the prolonged PQ interval or AF in adolescence, (2) progressive intra-AV nodal block to the third degree in several years, and (3) progressive heart failure after pacemaker implantation. Histological study revealed preferential degeneration at the AV node area and novel cellular damages in the working myocardium.     

Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

INTRODUCTION:

Atrioventricular (AV) block is infrequently associated with QT prolongation and torsades de pointes (TdP). It was hypothesized that patients with AV block-mediated QT-related arrhythmia may have latent congenital long QT syndrome or a vulnerable genetic polymorphism.

METHODS:

Eleven patients with complete AV block and TdP were prospectively identified. Patients underwent assessment, resting electrocardiography and telemetry at baseline, during AV block and pre-TdP. Genetic testing of KCNH2, KCNQ1, KCNE1, KCNE2 and SCN5A was performed. Thirty-three patients with AV block without TdP were included for comparison.

RESULTS:

Genetic variants were identified in 36% of patients with AV block and TdP. Patients with AV block who developed TdP had significantly longer mean (± SD) corrected QT intervals (440±93 ms versus 376±40 ms, P=0.048) and T_peak to T_end (T_p-T_e) intervals (147±25 ms versus 94±25 ms, P=0.0001) than patients with AV block alone. In patients with a genetic variant, there was a significant increase in T_p-T_e intervals at baseline, in AV block and pre-TdP compared with those who were genotype negative. A personal or family history of syncope or sudden death was more likely observed in patients with a genetic variant.

CONCLUSIONS:

TdP in the setting of AV block may be a marker of an underlying genetic predisposition to reduced repolarization reserve. The T_p-T_e interval at baseline, in AV block and pre-TdP may predict a genetic mutation or polymorphism compromising repolarization reserve. Patients with TdP in the setting of AV block represent a phenotypic manifestation of latent congenital long QT syndrome.     

Whole-exome sequencing identifies the first French MODY 6 family with a new mutation in the NEUROD1 gene

AimThe aim of the present study was to identify the affected gene in a French family with maturity-onset diabetes of the young (MODY) using whole-exome sequencing (WES).MethodsWES was performed in one patient with MODY, and candidate variants were confirmed in members of the immediate family by Sanger sequencing.ResultsIn the proband, a new heterozygous missense mutation (c.340A>C) was identified in the NEUROD1 gene by WES analysis and confirmed by Sanger sequencing. Additional Sanger sequencing of the proband's sister and mother revealed the same heterozygous mutation. The proband and his sister displayed typical clinical characteristics of MODY, while their mother had the same typical MODY features except for later onset. When clinical and biological profiles were established for all three patients, the severity of diabetes-related complications varied substantially from one family member to another.ConclusionA novel missense mutation found in NEUROD1 was associated with MODY 6 features in a single French family.     

Oligogenic basis of isolated gonadotropin-releasing hormone deficiency

Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.     

相同基因型而不同表现型的PRKAG2基因突变一家系报道

目的 位于7号染色体上的腺苷一磷酸激活的蛋白激酶γ^2调节亚单位基因（PRKAG2基因）调节代谢通路。报道一个具有PRKAG2基因突变而临床表现型不同的家系。方法 使用DNA直接测序法,对一个具有多种形式心律失常的患者家系（13例患者）进行PRKAG2外显子及外显子和内含子拼接部位序列筛查寻找基因突变。结果 心电图显示患者家系存在窦性心动过缓、短PR间期、完全性右束支传导阻滞、房室传导阻滞和房性心动过速。其中3例患者在年轻时发生猝死,没有1例有预激综合征（预激）表现,只有1例有心肌肥厚。DNA测序结果显示,该家系所有患者皆有一个PRKAG2错义突变（R302Q）。这个基因突变以前曾描述并与预激和左室肥厚有关。结论 PRKAG2基因突变不仅导致预激而且与多种临床表现型有关。完全性右束支传导阻滞、窦性心动过缓、短PR间期应该高度怀疑有PRKAG2基因突变的可能。     

Atrioventricular conduction properties in patients with prolonged pauses undergoing ablation of longstanding persistent atrial fibrillation: do pauses during atrial fibrillation matter?

Background

Atrioventricular (AV) conduction disturbances have often been considered as an etiology of prolonged pauses during atrial fibrillation (AF). We aimed to test whether there was a significant difference in the AV conduction properties between patients with and without clinically significant pauses who underwent ablation of longstanding persistent AF.

Methods

Ninety-nine patients undergoing ablation of longstanding persistent AF were divided into three groups according to the extent of pauses documented on the ambulatory electrocardiogram during AF; patients without pauses (n?=?25), with pauses of <3?s (n?=?52), and with pauses of ??3?s (n?=?22). The AV conduction properties, heart rate variability, and bradycardia-related symptoms after conversion to sinus rhythm were compared across the three groups plus a control group (n?=?35).

Results

Sinus conversion was achieved in all patients after ablation. No differences were found across the groups in the AV conduction properties including the AH and HV intervals, AV nodal effective refractory period, or Wenckebach point. A male gender (???=?0.32; p?=?0.0016), structural heart disease (???=?0.24; p?=?0.02), and the AA interval right after ablation (???=?0.35; p?=?0.0014), rather than the AV conduction properties, were independent determinants of the longest normal RR interval during AF. No patients experienced any bradycardia-related symptoms after ablation.

Conclusions

No AV conduction abnormalities were necessarily identified after the ablation even among the patients suspected of having an AV conduction disturbance during AF.     

Exome Sequencing Revealed Novel Germline Mutations in Chinese Peutz–Jeghers Syndrome Patients

Background and Aims

Peutz–Jeghers Syndrome (PJS) is an autosomal dominant disorder which predisposes to the development of various cancers. Germline mutation in the serine/threonine kinase 11 gene (STK11) is known as one of the major causes of PJS. However, a notable proportion of PJS samples do not carry any mutation in STK11, suggesting possible genetic heterogeneity in the disease and the existence of other causative variants.

Methods and Results

In order to identify other germline variants in the coding regions of the genome that are associated with PJS, we performed exome sequencing in three Chinese individuals with PJS and identified 16 common germline variants (12 protein-coding including STK11, 4 in pre-microRNAs). We further validated protein-coding variants in six PJS individuals (three with wild-type STK11) and predicted the functional impact. As result, we found that 7 coding variants are likely to have functional impacts. Especially, we identified 2 new germline variants which are represented in all six PJS samples and are independent of STK11 mutation.

Conclusions

Our study provided an exomic view of PJS. The germline variants identified in our analysis may help to resolve the complex genetic background of the disease and thus lead to the discovery of novel causative variants of PJS.     

Electrophysiologic Characteristics of Accessory Atrioventricular Connections in an Inherited Form of Wolff-Parkinson-White Syndrome

INTRODUCTION: A familial form of Wolff-Parkinson-White syndrome (WPW) occurs in association with hypertrophic cardiomyopathy and intraventricular conduction abnormalities. This syndrome, demonstrating autosomal dominant inheritance and segregating with a high degree of penetrance but variable expressivity, has been genetically linked to chromosome 7q3. The purpose of this study is to detail the electrophysiologic characteristics of accessory atrioventricular connections (AC) in four members of a kindred with this syndrome. METHODS AND RESULTS: We clinically evaluated 32 members of a single kindred and identified 20 individuals with ventricular preexcitation, abnormal intraventricular conduction including complete AV block and/or ventricular hypertrophy. Genetic linkage analysis mapped the disease gene in this kindred to the chromosome 7q3 locus (maximum logarithm of the odds score = 6.88, theta = 0); recombination events in affected individuals reduced the genetic interval from 7 centimorgans (cM) to 5 cM. Electrophysiologic study of four individuals with preexcitation, identified seven AC (1 right sided, 3 septal, and 3 left sided). All four individuals had inducible orthodromic tachycardia; while three had multiple AC. Bidirectional conduction was demonstrated in 6 of 7 AC. Successful ablation was accomplished in 5 of 7 AC. CONCLUSION: The electrophysiologic characteristics and location of AC in family members having this complex cardiac phenotype are similar to those seen in individuals with isolated WPW. Identification of WPW in more than one family member should prompt clinical evaluation of relatives for additional findings of ventricular hypertrophy or conduction abnormalities.     

Torsades de pointes complicating atrioventricular block: Evidence for a genetic predisposition

BACKGROUND: The prevalence of genetic risk factors has not been systematically evaluated in the setting of complete atriventricular (AV) block complicated by long QT syndrome (LQTS). OBJECTIVE: This study was performed to determine to what extent acquired LQTS in the context of AV block has a genetic substrate. METHODS: Among 420 recipients of pacemakers implanted over a 3-year period, we identified retrospectively 29 patients with complete AV block and a QT interval >600 ms in duration. A second study group included 22 randomly selected patients who had AV block and a QT interval <600 ms. Normal controls were 100 consecutive individuals without medical history. Genetic studies screening for HERG, KCNQ1 KCNE1, KCNE2, and SCN5A mutations were performed. RESULTS: We identified four mutations on genes encoding potassium channels in five patients with AV block and acquired LQTS. These mutations were not found among patients with AV block and a QT interval <600 ms in duration or in healthy volunteers. Functional expression of three HERG mutations (R328C, R696C, and R1047L) had a dominant negative effect on wild-type I(Kr). One KCNE2 mutation (R77W) identified in a patient treated with flecainide did not alter I(Kr). CONCLUSIONS: This study showed that complete AV block complicated by LQTS was associated with HERG mutations in 17% of cases. Further studies are needed to identify factors, genetic or environmental, which may be implicated in bradycardia-related abnormalities of ventricular repolarization.     

Identification of Three Novel and One Known Mutation in the WFS1 Gene in Four Unrelated Turkish Families: The Role of Homozygosity Mapping in the Early Diagnosis

Objective:Bi-allelic mutations in the wolframin gene (WFS1) cause Wolfram syndrome 1 (WS1 or DIDMOAD) characterized by non-autoimmune diabetes mellitus, optic atrophy, diabetes insipidus, sensorineural deafness, urinary tract abnormalities, and neuropsychiatric disorders. Patients presenting with an incomplete phenotype of WS1 were evaluated using homozygosity mapping and subsequent whole-exome sequencing.Methods:Four unrelated consanguineous Turkish families, including seven affected children, and their unaffected parents and siblings were evaluated. Homozygosity mapping was performed, followed by whole-exome sequencing of WFS1. Mutations were classified according to results of “in silico” analyses, protein prediction, and functional consequences.Results:Homozygosity mapping confirmed shared homozygous regions on chromosome 4 (chr4p16.1) between the affected individuals, that was absent in their unaffected siblings. Exome sequencing identified three novel (c.1215T>A, c.554G>A, c.1525_1540dup) and one known (c.1522_1523delTA) mutations in WFS1. All mutations were predicted to cause stop codon leading to early termination of protein synthesis and complete loss-of-function. All patients were found to be homozygous for the change, with parents and other unaffected siblings being carriers.Conclusion:Our study expands the mutation spectrum of WSF1 mutations with three novel mutations. Homozygosity mapping may provide enrichment for molecular genetic analysis and early diagnosis of WS1 patients with incomplete phenotype, particularly in consanguineous pedigrees.     

Determinants of development of permanent atrial fibrillation and its treatment.

We evaluated the rate of progression of permanent atrial fibrillation (AF) and identified clinical factors that predict this event in 63 consecutive patients who had undergone AV junctional ablation and DDDR pacemaker implantation for drug-refractory paroxysmal atrial fibrillation/ flutter. Immediately after ablation, anti-arrhythmic drugs were discontinued in all cases. Permanent AF was considered to have developed if AF was present on two consecutive 6-monthly examinations with no interim documented sinus rhythm. During a mean follow-up of 23 +/- 16 months, 22 (35%) of the 63 patients developed permanent AF. The actuarial estimate of progression of permanent AF was 22%, 40% and 56%, respectively, 1, 2 and 3 years after ablation. Age and underlying heart disease were independent predictors of progression of permanent AF. Only one (6%) of 16 patients with idiopathic AF had permanent AF (low risk group). Among the 47 patients with structural heart disease, permanent AF developed in 18 (62%) of the 29 who were aged >75 years or had >12 arrhythmic episodes per year and a symptom duration >4 years (high risk group), but only in three (17%) of the remaining 18 patients who did not (intermediate risk group). In conclusion, during a 3-year follow-up period, about half of the patients with a history of drug-refractory paroxysmal AF did not develop permanent AF after AV junctional ablation and dual-chamber pacemaker implantation, even in the absence of anti-arrhythmic drug therapy. Moreover, subgroups of patients whose risk of permanent AF progression differed were identified on the basis of simple baseline clinical variables. The results of this study form the necessary background for the correct management of patients after AV junction ablation and for the planning of future trials in this field.     

The Interplay Between Titin,Polygenic Risk,and Modifiable Cardiovascular Risk Factors in Atrial Fibrillation

BackgroundCommon and rare variants, including those in the gene for the cardiac structural protein titin (TTN), have been implicated in the risk of developing atrial fibrillation (AF). However, the effect of genetic variants on risk of AF compared with established modifiable risk factors is unclear. The objective of this study was to evaluate the risk of AF and associated cardiovascular complications in TTN variant carriers and examine interactions between TTN variants or common variants and modifiable AF risk factors.MethodsWe used whole exome sequencing data of 49,881 individuals and genotyping data of 408,572 individuals from the UK Biobank to examine the associations of TTN variants, polygenic risk, and 4 risk factors (hypertension, diabetes, obesity, and smoking) with AF. Adjusted hazard ratios (aHRs) were calculated with the use of Cox proportional hazards models.ResultsTTN variant carrier status was associated with a higher risk of AF (aHR 2.10, 95% CI 1.59-2.79; P = 2.54 × 10^?7) and higher risk of dilated cardiomyopathy in AF patients (aHR 10.39, 95% CI 5.31-20.33; P = 8.37 × 10^?12). We identified additive effects between TTN variants and polygenic risk with hypertension, diabetes, obesity, and smoking on the risk of AF.ConclusionsGenetic and modifiable cardiovascular risk factors contribute to the probability of developing AF. Our findings highlight the potential utility of incorporating data from targeted sequencing or genotyping of common variants to further inform AF risk stratification and aggressive management of modifiable cardiovascular risk factors.     

HCN4 Mutations in Multiple Families With Bradycardia and Left Ventricular Noncompaction Cardiomyopathy

Background

Familial forms of primary sinus bradycardia have sometimes been attributed to mutations in HCN4, SCN5A, and ANK2. In these studies, no structural cardiac alterations were reported in mutation carriers. However, a cluster of reports in the literature describe patients presenting with sinus bradycardia in association with left ventricular noncompaction cardiomyopathy (LVNC), pointing to a shared genetic cause.

Objectives

This study sought to identify the genetic defect underlying the combined clinical presentation of bradycardia and LVNC, hypothesizing that these 2 clinical abnormalities have a common genetic cause.

Methods

Exome sequencing was carried out in 2 cousins from the index family that were affected by the combined bradycardia–LVNC phenotype; shared variants thus identified were subsequently overlaid with the chromosomal regions shared among 5 affected family members that were identified using single nucleotide polymorphism array analysis.

Results

The combined linkage analysis and exome sequencing in the index family identified 11 novel variants shared among the 2 affected cousins. One of these, p.Gly482Arg in HCN4, segregated with the combined bradycardia and LVNC phenotype in the entire family. Subsequent screening of HCN4 in 3 additional families with the same clinical combination of bradycardia and LVNC identified HCN4 mutations in each. In electrophysiological studies, all found HCN4 mutations showed a more negative voltage dependence of activation, consistent with the observed bradycardia.

Conclusions

Although mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence to our knowledge that mutations in this ion channel gene also may be associated with structural abnormalities of the myocardium.     

Guidelines for genetic testing of inherited cardiac disorders

Inherited gene variants have been implicated increasingly in cardiac disorders but the clinical impact of these discoveries has been variable. For some disorders, such as familial hypertrophic cardiomyopathy, long QT syndrome, and familial hypercholesterolaemia, genetic testing has a high yield and has become an integral part of family management. For other disorders, including dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and atrial fibrillation, relatively less is known about the genes involved and genetic testing has a lower yield. Recent advances in sequencing and array-based technologies promise to change the landscape of our understanding of the genetic basis of human disease and will dramatically increase the rate of detection of genomic variants. Since every individual is expected to harbour thousands of variants, many of which may be novel, interpretation of the functional significance of any single variant is critical, and should be undertaken by experienced personnel. Genotype results can have a wide range of medical and psychosocial implications for affected and unaffected individuals and hence, genetic testing should be performed in a specialised cardiac genetic clinic or clinical genetics service where appropriate family management and genetic counselling can be offered.     

Role of telomere shortening in anticipation of inflammatory bowel disease

BACKGROUND The existence of genetic anticipation has been long disputed in inflammatory bowel disease(IBD) in the absence of the explanatory mechanism.AIM To determine whether it was predictive of genetic anticipation, we evaluated telomere length in IBD. We hypothesized that multiplex IBD families exhibit a genetic defect impacting telomere maintenance mechanisms.METHODS We studied three IBD families with multiple affected members in three successive generations. We determined telomere length(TL) in lymphocytes and granulocytes from peripheral blood of the affected members using flow cytometry and fluorescence in-situ hybridization(flow FISH). We also performed whole exome sequencing in the blood of all available family members and used Pheno DB to identify potential candidate gene variants with recessive or dominant modes of inheritance.RESULTS Out of twenty-four patients of European descent selected to participate in the study, eleven patients, eight parent-child pairs affected by IBD, were included in the genetic anticipation analysis. Median difference in age at diagnosis between two successive generations was 16.5 years, with earlier age at onset in the younger generations. In most of the affected members, the disease harbored similar gastrointestinal and extraintestinal involvement but was more aggressive among the younger generations. TL was not associated with earlier age at onset or more severe disease in members of successive generations affected by IBD. NOD2 gene mutations were present in the Crohn's disease patients of one family. However, no gene variants were identified as potential candidates for inheritance.CONCLUSION Telomere shortening appears unlikely to be involved in mechanisms of possible genetic anticipation in IBD. Further studies using a larger sample size are required to confirm or refute our findings.     

Reentrant and nonreentrant forms of atrio-ventricular nodal tachycardia mimicking atrial fibrillation

BACKGROUND: Atrial fibrillation (AF) manifests disorganized atrial activity and irregular R-R intervals on electrocardiogram (ECG). Variation in R-R intervals can also be seen with other supraventricular tachycardias that may mimic AF. OBJECTIVE: We report our observations on three patients who were referred to our center to undergo pulmonary vein (PV) isolation for erroneously diagnosed AF in the setting of dual atrio-ventricular (AV) nodal pathways manifesting as AV nodal reentrant tachycardia (AVNRT) and/or double response during sinus rhythm. METHODS AND RESULTS: These three subjects (two females) were derived from a group of 456 consecutive patients undergoing AF ablation at our center over a 3-year period. All three patients had been symptomatic for over 2 years, having failed two or more antiarrhythmic medications. In each case AF was initially diagnosed on ECG and/or recordings from ambulatory monitoring. However, in all three cases the correct diagnosis was established during the invasive electrophysiologic study. In one patient during the stimulation protocol, two narrow complex tachycardias were serially induced (cycle lengths: 305 and 360 msecs; VA time: 60 and 240 msecs). The latter was confirmed to be atypical AVNRT and during this tachycardia, block in upper pathway was observed. In the other two patients, sinus rhythm with repetitive runs of double response and isolated junctional beats were observed in the absence of retrograde conduction. Successful slow pathway modification was performed in each subject and all three patients have remained arrhythmia free over a mean follow-up of 31 +/- 16 months off antiarrhythmic medications. CONCLUSIONS: AF can be erroneously diagnosed in patients with dual AV nodal pathways manifesting double response and/or AVNRT. Incorporating a stimulation protocol as a part of the AF ablation procedure may help in diagnosing these rare clinical presentations that can be cured by slow pathway modification alone.     

Admixed phenotype of NEDD4L associated periventricular nodular heterotopia: A case report

Rationale:Periventricular nodular heterotopia-7 (PVNH7) is a neurodevelopmental disorder associated with improper neuronal migration during neurogenesis in cortex development caused by pathogenic variants in the NEDD4L gene.Patient concerns:We report the case of a polystigmatized 2-year-old boy having significant symptomatologic overlap with PVNH7, such as delayed psychomotor and mental development, seizures and infantile spasms, periventricular nodular heterotopia, polymicrogyria, cleft palate, 2 to 3 toe syndactyly, hypotonia, microretrognathia, strabismus, and absent speech and walking. The patient showed also distinct symptoms falling outside PVNH7 symptomatology, also present in the proband''s older brother, such as blue sclerae, hydronephrosis, transversal palmar crease (found also in their father), and bilateral talipes equinovarus. In addition, the patient suffered from many other symptoms.Diagnoses:The boy, his brother and their parents were subjected to whole-exome sequencing. Because of uncertainties in symptomatology and inheritance pattern, the top-down approach was hard to apply. Using the bottom-up approach, we identified a known pathogenic variant, NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys, in the proband''s genome that absented in any other analyzed family member, suggesting its de novo origin.Interventions and outcomes:The patient was treated with Convulex 300 mg/mL for the successful seizure control and Euthyrox 25mg for the treatment of thyroid malfunction. He also took various supplements for the metabolism support and digestion regulation. Moreover, the patient underwent the corrective surgeries of cleft palate and talipes equinovarus.Lessons:We successfully identified the causative mutation NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys explaining symptoms overlapping those reported for PVNH7. Symptoms shared with the brother were not explained by this variant, since he was not a carrier of the pathogenic NEDD4L variant. These are most likely not extended phenotypes of PVNH7, rather an independent clinical entity caused by a yet unidentified genetic factor in the family, highlighting thus the importance of thorough evaluation of symptomatology and genomic findings in affected and unaffected family members, when such data are available.