Family Screening Research Articles

Abstract 4128590: Identical Twins, Non-Identical Results: Genetic Testing for Cardiomyopathy

Case: A 58-year-old male (Twin A) with no medical history presented with syncope while playing paddle ball. TTE showed LVEF 15-20%. Cardiac MRI (CMR) identified transmural late gadolinium enhancement (LGE) in the inferolateral wall of the LV, but angiography showed non-obstructive CAD. Four years later, his monozygotic twin (Twin B), also with no medical history, suffered cardiac arrest while playing paddle ball. TTE showed LVEF 5-10%. CMR revealed inferolateral LGE (Figure 1) with angiography showing non-obstructive CAD. Genetic testing was performed by different companies. Twin A was found to be heterozygous for myosin light chain kinase 3 ( MYLK3 ) p.R380H (c.1139C>A), a variant of uncertain significance (VUS). While rare (gnomAD allele frequency 2.7e -4 ), MYLK3 p.R380H is not conserved across species, exchanges amino acids with similar biochemical properties, and is predicted to be benign by in silico pathogenicity tools. Notably, MYLK3 was not sequenced in Twin B, who was instead found to be heterozygous for desmoplakin ( DSP ) p.R1002W (c.3004C>T). DSP p.R1002W is highly conserved, exchanges amino acids with dissimilar properties, and is very rare (gnomAD allele frequency 2.8e -5 ). In silico testing yielded conflicting results with some tools predicting it to be damaging to protein function. Interestingly, the variant was present in both twins but was classified differently by each company: likely benign for Twin A (and therefore not reported) and VUS for Twin B. First degree relatives are advised to undergo clinical screening and cascade genetic testing for DSP p.R1002W. Discussion: The presentation described is consistent with arrhythmogenic cardiomyopathy (ACM) and the family history strongly supports a genetic etiology. DSP is a causal gene for ACM with unique clinical features that are strikingly similar to those observed herein. The differences in genes tested and variant adjudication between companies has left diagnostic uncertainty; hence, definitive pathogenicity cannot be attributed to either variant without cosegregation analysis, which is ongoing. In summary, this case illustrates the challenges of variant interpretation, and the impact that this can have on genetic counseling and family screening.

Comprehensive analysis of genotypic and phenotypic characteristics of biotinidase deficiency patients in the eastern region of Türkiye

Background. Biotin is a water-soluble vitamin that plays a key role in carboxylation. The formation of free biotin is impaired in biotinidase deficiency (BD), resulting in impaired biotin-dependent carboxylase functions. Based on the percentage of residual serum enzyme activity, BD is classified as partial and profound. Methods. Retrospective data including gender, age, parental consanguinity, family history, biotinidase activity analyses, type of deficiency (partial-profound), physical examination, treatment, and genotypes were evaluated in patients diagnosed with biotinidase deficiency in a single center in the eastern region of Türkiye. Patients whose biotinidase enzyme activity was below 30% with biallelic variants in the BTD gene were diagnosed as BD. Results. A total of 302 patients were included in the study. Parental consanguinity was present in 135 (44.7%) of them. Two hundred eighty-six (94.7%) were diagnosed by neonatal screening, 14 (4.6%) by family screening and two (0.06%) by clinical symptoms. Ninety-two (30.5%) of the patients were followed-up with profound deficiency and 210 (69.5%) with partial deficiency. A total of 306 variants were detected. Twenty different variants (3 novel - 3 rare) and 31 different genotypes were detected. The 3 most frequently detected variants were c.410G>A (p.Arg137His; 47.3%), c.1270G>C (p.Asp424His; 29.7%), and c.38_44delGCGGCTGinsTCC (p.Cys13Phefs*36; 15.3%). The 3 most frequently identified genotypes were c.410G>A (p.Arg137His) / c.1270G>C (p.Asp424His) compound heterozygous (32.4%), c.410G>A (p.Arg137His) homozygous (24.8%), and c.38_44delGCGGCTGinsTCC (p.Cys13Phefs*36) / c.1270G>C (p.Asp424His) compound heterozygous (12.2%). Patients with c.410G>A (p.Arg137His) homozygous variant, c.38_44delGCGGCTGinsTCC (p.Cys13Phefs*36) homozygous variant and c.38_44delGCGGCTGinsTCC (p.Cys13Phefs*36) / c.410G>A (p.Arg137His) compound heterozygous variant were statistically significantly associated with profound deficiency. Compound heterozygosity of c.410G>A (p.Arg137His) / c.1270G>C (p.Asp424His) variants were significantly associated with partial deficiency. Conclusions. The association between the BTD genotype and biochemical phenotype is not always consistent. Our study provides valuable data by adding variants with genotype-phenotype correlations to the literature and three novel variants, which can provide significant guidance in clinical follow-up.

Exploring interaction effects of social determinants of health with hospital admission type on academic performance: a data linkage study

ObjectiveTo investigate the moderating effects of socio-demographic social determinants of health (SDH) in the relationship between types of childhood hospitalisation (ie, none, injury, non-injury, injury+non-injury) and academic performance.Design, setting and...

Barriers to Family History Collection and Family Medical Screening Recommendation in the Sudden Death in the Young Case Registry.

Sudden death in the young (SDY) poses a public health problem affecting thousands of individuals annually in the United States. The SDY Case Registry utilizes existing infrastructure of death investigation programs, including medical examiner/coroner (ME/C) systems, to enhance understanding of SDY causes and risk factors to inform prevention strategies. This includes identifying and promoting screening recommendations for at-risk family members. To explore barriers to family history collection and familial screening recommendation procedures across Registry sites, nine individuals from seven SDY sites were interviewed. Interviews focused on logistics, methods to address barriers, and recommendations for improvements. Despite variability in practices, data analysis revealed three common themes related to barriers of these processes: (1) timing and grief, (2) lack of family history in medical records, and (3) families lost to follow-up. This study offers insights into these processes within the Registry and sheds light on broader practices within the death investigation domain. Data analysis led to recommendations for the improvement of these practices including the prioritization of three key family history questions during the initial death investigation by a designated individual in each office/system.

Quality Improvement to Identify and Address Food Insecurity During Pediatric Hospitalizations.

Hospitalized children represent a vulnerable population with high rates of unidentified food insecurity (FI). We aimed to improve FI screening for eligible families from 0% to 60%. Secondarily, we sought to provide location-based food resources to families that screened positive. In February 2021, we developed a multidisciplinary team and used the Model for Improvement to improve routine FI screening for eligible children on 1 inpatient unit at a single institution. Our primary measure was the overall percentage of eligible families screened for FI. Our secondary measure was the percentage of families with FI who received food resource information. Statistical process control charts were used to analyze the impact of our interventions. A total of 8850 families were eligible for screening during the project period. The percentage of eligible families screened for FI increased from 0 to a mean of 77%, exceeding our goal, with special cause variation noted by 5 centerline shifts. The most impactful interventions were expansion of screening to patients admitted to all services and making FI screening questions required nursing admission documentation. Eleven percent of families screened positive for FI. Provision of resources increased from 56% with manual resource insertion into the after-visit summary to 100% with special cause variation associated with automated resource provision for positive screens. Integrating FI screening into the nursing admission workflow with automated resource provision for positive screens is a feasible approach to integrating FI screening into routine clinical practice during pediatric hospitalizations.

Endocrine Perspective of Cutaneous Lichen Amyloidosis: RET-C634 Pathogenic Variant in Multiple Endocrine Neoplasia Type 2

Background: Medullary thyroid carcinoma (MTC), the third most frequent histological type of thyroid malignancy, may be found isolated or as part of multiple endocrine neoplasia type 2 (MEN2). One particular subtype of this autosomal dominant-transmitted syndrome includes an association with cutaneous lichen amyloidosis, although, generally, a tide genotype–phenotype correlation is described in patients who carry RET proto-oncogene pathogenic variants. Methods: Our objective was to provide an endocrine perspective of a case series diagnosed with RET-positive familial MTC associated with cutaneous primary lichen amyloidosis amid the confirmation of MEN2. Six members of the same family had cutaneous lesion with different features (from hyperpigmented, velvety to red/pink appearance) and four of them harbored a RET pathogenic variant at 634 codon (exon 11): c.1900T>G, p.634G (TGC634CGC). Results: All six patients were females with the lesion at the interscapular region. Except for two women, four of these subjects were investigated and had MTC (three of them with postoperatory confirmation). The youngest affected individual was 6 years old. The three adult females were confirmed with RET pathogenic variant during their 30s, while the girl underwent the familial screening as a newborn. None of them had primary hyperparathyroidism until the present time, except for one subject, and two out of the three adults also had bilateral pheochromocytoma. Notably, all patients were rather asymptomatic from the endocrine perspective at the moment when endocrine tumor/cancer was confirmed, and the skin was progressively affected a few years before the actual MEN2 confirmation. Conclusions: This case series highlights the following key message: awareness of the dermatologic findings in MTC/MEN2 patients is essential since lesions such as cutaneous lichen amyloidosis might represent the skin signature of the endocrine condition even before the actual endocrine manifestations. These data add to the limited published reports with respect to this particular presentation, noting the fact that RET-C634 is the most frequent pathogenic variant in MEN2-associated lichen amyloidosis; females are more often affected; the interscapular region is the preferred site; the age of diagnosis might be within the third decade of life, while we reported one of the youngest patients with the lesion. The same RET pathogenic variant is not associated with the same dermatologic features as shown in the vignette. The same RET mutation does not mean that all family members will present the same skin anomaly.

Exploring the diagnostic yield of family screening and genetic testing in adolescent individuals with pre-clinical phenotypes

Abstract Introduction Family screening and genetic testing are key components in the management strategy of individuals diagnosed with an inherited cardiac condition (ICC). Disease penetrance for most ICCs, notably cardiomyopathies is age dependent, which is why a more permissive approach towards family screening is adopted in young individuals with a pre-clinical phenotype. Study Objectives The main objective of this study was to explore the role of family screening and genetic testing in adolescent subjects with a pre-clinical phenotype has not been formally explored. Methodology Adolescent probands with a pre-clinical phenotype following a national cardiac screening program (BEAT-IT) were offered genetic testing and family screening. Probands with anterior TWI were rescreened at 16 years. Only those with persistent changes were enrolled in the study. Genetic counselling was also offered to probands and relatives. Testing was initially offered to first degree relatives. Cascade testing (clinical and genetic) was also offered to other generations if a screened relative satisfied one or more of these conditions i) phenotype positive, ii) pre-clinical phenotype, iii) clinically relevant genotype. Results 16 probands (mean age 15 years) were identified with a pre-clinical phenotype. All had an abnormal ECG (9=inferior/lateral TWI, 6=anterior TWI, 1=ST depression). A comprehensive evaluation was otherwise normal. Half were gene positive (G+), 4 had clinically relevant genotypes (n=4 inferior/lateral TWI). These were classified as likely pathogenic according to ACMG criteria (n=2 MYH7, n=1 ACTC1, n=1 MYBPC3). 71 family members were subsequently screened (59.2% female, median 43Y [IQR 27] at evaluation, 11.3% <18Y at evaluation, 67.6% first degree relatives). A substantial proportion (n=13, 18.3%) were referred for further evaluation. Two (2/8, 25.0%) were <18Y. An abnormal ECG was the commonest reason for referral (n=9, 12.7%). Three (4.2%) were given a diagnosis (n=2 HCM [both MYH7}, n=1 DCM [ACTC1]). Seven (9.9%) were referred because of an abnormal ECG (n=3 inferolateral TWI, n=2 ventricular ectopics, n=1 anterolateral TWI, n=1 ST depression). Four were G+ and were offered surveillance. Fourteen (19.7%) were offered family screening because of incorporating genetic testing into the study protocol. Genetics altered the evaluation strategy in 16.9% of screened relatives. More in-depth cascade testing identified 6 (8.5%) individuals who needed follow-up (n=1 diagnosis [DCM], n=1 abnormal ECG, n=4 G+). Gene negative individuals (6, 8.5%) were safely reassured and discharged. Conclusion Family screening in adolescent probands with pre-clinical phenotypes offers a reasonable diagnostic yield (4.2% diagnosis, 14.1% surveillance). Incorporating genetic testing into the evaluation protocol offers a more personalized strategy, altering management in a significant proportion of screened relatives (16.9%).

Health-related quality of life disparity in cardiac sarcoidosis versus other myocardial diseases

Abstract Background Sarcoidosis, a systemic inflammatory disorder, can manifest as progressive inflammatory heart disease, termed cardiac sarcoidosis (CS). Despite advances in treatment, the impact of CS on health-related quality of life (HRQoL) remains incompletely understood. This study aimed to compare HRQoL between patients with CS and those with non-inflammatory cardiomyopathies, namely dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Purpose To assess and compare HRQoL across patients with cardiac sarcoidosis and non-inflammatory cardiomyopathies. Methods A total of 240 CS patients (86% response rate), 96 DCM patients (55% response rate), and 81 HCM patients (65% response rate) completed the RAND-36 general health-related questionnaire, comprising eight dimensions. Patients listed for transplantation were excluded. Clinical data were obtained from the Finnish myocardial inflammatory diseases registry for CS patients and from medical records in hospitals for HCM and DCM patients. Results Median age ranged from 56 to 59 years across the groups. Unlike DCM, which typically presents with heart failure symptoms, a substantial proportion (82%) of CS patients presented with advanced atrioventricular block or ventricular arrhythmias, while HCM cases were often incidentally detected or identified through family screening. Most CS patients (94%) had implanted pacemakers or ICDs, compared to a lower proportion in HCM (26%) and DCM (63%). DCM patients exhibited a higher prevalence of impaired LVEF (<50%) compared to CS and HCM patients. Functional impairment, as measured by NYHA class, was most pronounced in DCM patients. CS patients experienced more adverse events between diagnosis and the study entry, particularly sustained ventricular tachycardia/ventricular fibrillation. However, heart failure hospitalizations did not significantly differ between groups. Table 1 presents a comparative analysis of patient-reported outcomes across four functional and mental dimensions to assess the relative burden of disease among patients with CS, HCM, and DCM. While the functional dimensions in CS exhibited disparities from both HCM and DCM, no significant differences were observed in the mental dimensions between CS and HCM. CS patients reported lower scores in the domains of role physical, and general health compared to either HCM or DCM counterparts. Conclusion Patients with CS demonstrated significantly poorer HRQoL compared to those with non-inflammatory cardiomyopathies. This underscores the substantial burden of disease associated with CS and highlights the importance of comprehensive management strategies to address both clinical and quality of life aspects in affected individuals.

Improving the yield of genetic testing in dilated cardiomyopathy using late gadolinium enhancement

Abstract Background Genetic testing has become an important tool in the work-up of dilated cardiomyopathy (DCM), aiding in family screening and providing information about prognosis and arrhythmic risk. Nonetheless, a significant proportion of patients with DCM present negative genetic test results. The "Madrid Score" was created to evaluate the likelihood of positive genetic tests and increase their yield in DCM patients. Purpose To determine if late gadolinium enhancement (LGE) assessment can improve the Madrid Score accuracy and increase the yield of genetic tests for DCM. Methods A single-centre retrospective study of patients diagnosed with DCM who underwent cardiac magnetic resonance (CMR) and genetic test between January 2017 and October 2023. The CMR imaging included the assessment of LGE. Multivariate logistic regression was performed and the model’s change in performance was evaluated when adding LGE. Results A total of 90 patients with the diagnosis of DCM underwent CMR and genetic test during the study period. Patient’s mean age was 51.0±14.6 years, and 57.1% were male. The genetic test was positive (G+) in 42 (46.7%), and negative (G-) in 48 (53.3%) patients. A variant of uncertain significance was present in 31 (34.4%), and these were included in the G- group. Most of the known independent predictors of a G+ given by the Madrid Score were significant in our cohort: Family history of DCM (OR: 4.82; CI: 1.73-11.60; p < 0.001), absence of hypertension (OR: 0.19; CI: 0.06-0.58; p < 0.001), absence of left bundle branch block (OR: 0.22; CI: 0.05-0.98; p = 0.047), and low electrocardiogram voltage in peripheral leads (OR: 3.13; CI: 0.87-11.26; p = 0.081). When analyzing the effect of LGE in the regression model (R2 = 0.622, p < 0.001), we found that the number of LGE segments (OR: 2.54; CI: 1.10-5.90; p = 0.031), and the presence of LGE in the anterior wall (OR: 3.01; CI: 1.42-12.04; p = 0.041), were associated with a higher rate of positive genetic tests. When comparing both regression models, the incorporation of LGE increased the prediction power of the standard Madrid Score, correctly predicting 82.0% of the tests in our sample, with a probability of a G+ result ranging from 2% when all predictors were absent to 84% when ≥6 predictors, including LGE, were present. Conclusion Our study suggests that LGE assessment may enhance the Madrid Score performance and consequently improve genetic testing decisions in DCM, potentially leading to better use of the limited resources in our health care system.

Diagnostic yield of clinical cardiac screening in first-degree relatives of SADS and unexplained cardiac arrest probands: a systematic review of the literature

Abstract Background First-degree relatives of SADS victims (defined as a sudden death of a previously healthy individual where no cause can be found despite post-mortem examination) or individuals suffering an Unexplained Cardiac Arrest (defined as a sudden cardiac arrest with successful resuscitation where no cause can be found despite thorough investigation) are recommended to undergo clinical cardiac evaluation for potential inherited cardiac conditions (ICC). However, data on the yield of family screening in these populations remains scarce. Aim This study aimed to perform the first systematic review of the diagnostic yield of clinical screening of first-degree relatives of SADS or UCA probands. A secondary aim was to compare the diagnostic yield of adult-aged and paediatric-aged relatives. Methods The systematic review was prospectively registered on PROSPERO and was undertaken utilising PRISMA guidelines. The online databases Embase, Medline and Web of Science were searched for original articles published in English from 1946 to June 2023. Included studies described the clinical cardiac screening and diagnostic yield of first-degree relatives of SADS and UCA probands. Quality of selected studies were assessed using a modified Joanna Briggs Institute (JBI) checklist. Results 14 studies met the inclusion criteria, which together included 1646 first-degree relatives of SADS probands and 656 first-degree relatives of UCA probands. 11 out of the 14 studies were retrospective cohort studies and cohort size varied from 56 – 398 (median 108, IQR 82-215). Of those studies that reported follow up length (n=8), screening ranged from one-off clinical evaluation to serial clinical screening. Overall diagnostic yield described by included studies ranged from 0 – 25%. The combined mean diagnostic yield of SADS relatives was 11.7% ± 7.5. This did not differ significantly from that of relatives of UCA probands (6.9% ± 7.4) [p=0.246]. Three studies described outcomes of clinical screening in 235 paediatric relatives, with an overall reported yield of 9.4% ± 3.4, which is not significantly different to adult populations (10.4% ± 8.4 [p=0.849]). The most common diagnosis in relatives was Long QT Syndrome followed by Brugada Syndrome. Despite probands having no heart muscle phenotype on post-mortem or clinical evaluation, 22 relatives were diagnosed with a cardiomyopathy (9.3% of all diagnoses). Conclusion Whilst there is a clear indication for clinical screening of first-degree relatives for ICCs following a SADS death or an Unexplained Cardiac Arrest, a lack of well-designed large population-based studies means that the evidence base supporting when or how relatives should be screened is not robust. The diagnostic yield in reported literature varies considerably with no difference between SADS and UCA cohorts and a similar yield in paediatric and adult relatives. This supports systematic screening for all first-degree relatives regardless of age.PRISMA Flow Diagram

Prediction of family inheritance in non-sarcomeric hypertrophic cardiomyopathy using clinical variables and 12-lead electrocardiogram artificial intelligence models

Abstract Background Hypertrophic cardiomyopathy (HCM) can be familial even in the absence of a causative sarcomeric variant, justifying periodical screening of first-degree relatives. However, indiscriminate screening may burden low-risk individuals unnecessarily. The prevalence and predictors of familial disease in non-sarcomeric HCM remain inadequately characterized. Purpose Our study aims to develop a tailored approach to family screening based on index cases’ clinical profiles. By leveraging artificial intelligence (AI) models, we aim to predict the likelihood of family disease using pertinent clinical variables and electrocardiograms (ECGs) from the proband. Methods From January 2008 to June 2022, all probands diagnosed with HCM at our Heart Institute genetics clinic were included if they had i) negative genetic testing for a (likely) pathogenic variant in a sarcomeric gene and ii) ≥1 first- or second-degree relative screened for HCM. The outcome was the presence of family disease defined as left ventricular wall thickness ≥13mm or verified autopsy report confirming HCM. Predictors of family disease were assessed at the first genetic clinic visit and considered age, sex, hypertension, and echocardiography metrics (maximal wall thickness, septal morphology, outflow tract obstruction at rest or Valsava). Using 12-lead ECGs and clinical variables, we used machine learning to train two distinct AI models. Model A utilized ECG signals only to train a ResNet model, while Model B used both ECGs and selected clinical variables (below 0.2 alpha level in logistic regressions) to train a random forest model to predict family disease. We performed evaluations at both ECG-level (one ECG used per patient) and patient-level (all available ECGs used in a patient) and we present individual and ensemble model performance. Results Among 356 families with sarcomere-negative HCM, 106 (30%) were familial. Probands were aged 53 ± 16 years, 30% female, 36% with a diagnosis of hypertension and 43% with peak outflow tract obstruction ≥30mmHg. In univariable logistic regressions, family disease was associated with age at diagnosis (OR 0.89 per 5-year, P=0.003), hypertension (OR 0.60, P=0.046) and obstruction (OR 0.52, P=0.013). The ensemble AI model, which integrated clinical and ECG data, achieved an AUC of 0.82 (95% CI: [0.795, 0.848]). It demonstrated a specificity of 0.891 (95% CI: [0.867, 0.913]) and a negative predictive value of 0.798 (95% CI: [0.772, 0.823]). When comparing ECG-level and patient-level data (1 to 10 ECGs per patient), the models consistently achieved AUC values between 0.78 and 0.81, indicating stable performance across various data subsets. Conclusion The prevalence of family inheritance in sarcomere-negative HCM can be accurately predicted using AI models that integrate clinical variables and 12-lead ECG data. This approach could enable tailored screening strategies based on the likelihood of family disease.

Prevalence and characteristics of the catecholamine induced QT prolongation syndrome

Abstract Background We have recently described large families of idiopathic ventricular fibrillation characterised by catecholamine-induced QT interval prolongation (CIQTP). The patient presented with a normal QT duration at rest but an abnormal QT prolongation during a mental stress test (MST). Objective The aim of this study was to investigate the role of this new syndrome in inherited arrhythmic diseases. Methods Consecutive patients and their relatives, identified after unexplained familial sudden cardiac death or sudden cardiac arrest, were enrolled in the study in the presence of: - no other diagnosis after cardiac ultrasound, stress test, pharmacological test with adrenaline and ajmaline. - positive MST defined by a prolongation of the QT interval (>-11ms) during MST (as previously published). Results 134 families with unexplained SCD were examined. CIQTP was diagnosed in 15 families, representing a prevalence of 11.2%. Family screening of these 15 families identified a total of 43 individuals. Seven (16%) had symptoms prior to diagnosis, including sudden cardiac arrest in one. At baseline, the QTc interval was measured at 440+/-23 ms. MST increased the QTc interval by 49+/-33 ms. The identification of QT interval prolongation was less important in the exercise test (delta QTc 17+/-52 ms at 4 minutes after exercise) and the epinephrine test (delta QTc 19+/-36 at 1 minute according to the Krahn protocol). Treatment with beta-blockers was initiated in 19 patients (44%) on the basis of symptoms and major prolongation of the QT interval during the MST. After a mean follow-up of 7+/-2 years, only one patient developed ventricular fibrillation. This episode occurred during a short period when he was no observant for the treatment. Since then, there has been no recurrence of the arrhythmia on beta-blocker therapy. All other patients, including those who were previously symptomatic remained symptom-free on treatment. Conclusion CIQTP may explain a significant part of sudden cardiac arrest or syncope in young patients. Conventional screening using ECG, exercise test and epinephrine challenge may not be able to unmask CIQTP. Then MST may be systematically proposed for the screening of patient and their family. In CIQTP patients beta blocker therapy appears to be highly efficient to prevent symptoms.

Evaluation of the 2021 ESC recommendations for family screening in hereditary transthyretin cardiac amyloidosis

Abstract Background The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis (ATTR) variant (ATTRv) are based on expert opinion. We aimed to (1) determine the yield of ATTR cardiomyopathy (ATTR-CM) at baseline; (2) evaluate the performance of the 2021 ESC position statement on initiating screening for ATTRv carriers; (3) establish the value of first-line tests recommended in ATTRv carriers; and (4) examine the yield of serial evaluation. Methods We included 159 relatives (median age 55.6 [interquartile range 43.2-65.9] years, 52% male) at-risk for developing ATTR-CM from 10 centres. ATTR-CM diagnosis was defined as the presence of either 1) cardiac tracer uptake in bone scintigraphy as recommended; or 2) cardiac biopsy proven positive for ATTR. Our secondary endpoint was a composite of heart failure symptoms (NYHA class³II) and conduction disorders necessitating pacemaker implantation. An individual fulfilled screening criteria as proposed by the 2021 ESC position statement if: 1) cardiac screening was performed ~10 years prior to disease onset in the proband (or in other individuals with the same variant if disease onset in the family was unknown); or 2) had extracardiac amyloidosis as diagnosed by a Neurologist or Ophthalmologist. Results At baseline, 40/159 (25%) relatives were diagnosed with ATTR-CM. Of those 40 relatives, 20 (50%) met the secondary endpoint. Relatives diagnosed with ATTR-CM were significantly older (66.5 [61.0-75.2] vs. 49.2 [40.8-58.8] years, p<0.001)(Figure 1A). Figure 1B-C visualizes the yield of screening by screening indications of the 2021 ESC position statement. Both screening for age, extra-cardiac amyloidosis or both age and extra-cardiac amyloidosis as indication to screen had a 31% (n=17/54), 18% (n=2/11) and 68% (n=19/28) yield of ATTR-CM, respectively. Diagnosis of ATTR-CM in relatives without an indication to screen was rare (3%; n=2/66). As a result, indication to screen as proposed by the 2021 ESC position statement yielded an almost excellent negative predictive value (97%). Other independent pre-screening predictors were infrequently identified variants and male sex. Of note, 13% of relatives with ATTR-CM did not show any "red flags" of cardiac amyloidosis on electrocardiogram (ECG), echocardiogram, and laboratory parameters. Excluding those who meet the secondary endpoint (i.e. those who already should have been diagnosed based on symptoms), ATTR-CM diagnosis in the absence of "red flags" increased from 13% to 26%. The yield of repeat bone scintigraphy (n=41 ATTRv carriers; follow-up 3.1 [2.2-5.2] years) at 3-years’ interval was 9.4% (Figure 2). Conclusion The recommendations made by the 2021 ESC position statement are adequate. Clinicians should adhere to the 3-year repeat bone scintigraphy as progressing to ATTR-CM in the absence of "red flags" and symptoms is not uncommon.Cardiac amyloidosis at baselineATTR-CM development during follow-up

New clinical staging proposal applied to a Fabry cardiomyopathy cohort

Abstract Background Fabry disease (FD) is a rare cause of hypertrophic cardiomyopathy (HCM), and early diagnosis is important considering the response to enzyme replacement or chaperone therapies. Recently, a practical clinical staging for Fabry cardiomyopathy was proposed by Olivotto et al 2023, considering several features, being potentially useful for standardizing the criteria for initiation and response assessment to therapy. Imaging characterization of hypertrophy and fibrosis are critical key items to determine stages. This new proposal suggested 4 main stages (0, I, II, III) according to these parameters. Stages 0 and I are further divided in 2 sub-stages according to minor findings and hypertrophy severity, respectively. Unfortunately, not all patients with Fabry cardiomyopathy are identified early in the disease, limiting the response to treatment. Aim Our study aimed to evaluate retrospectively the staging of Fabry cardiomyopathy at first imaging cardiac evaluation according to the recent proposal (1), in a cohort of 35 patients with FD at a reference centre of Fabry disease. Results At the first cardiac evaluation, the group of patients had a median age of 46 years (28-68 years), 69% were female and 5% were already under enzymatic therapy. The majority of Fabry patients (66%) were in non-hypertrophic stage 0: 4 patients in 0A with no detected cardiac involvement and 19 patients in 0B with subclinical cardiac findings (17% presenting diastolic dysfunction, 14% impaired global longitudinal strain, 6% hypertrabeculation, 6% reduced native T1, 3% short PR duration, 3% cardiac symptoms). In hypertrophic stage I, 14% of patients were classified according to the presence and severity of LVH: 3 in IA (12-15 mm) and 2 in IB (>15mm). All patients (n=3, 9%) in hypertrophic fibrotic stage II presented non-extensive late enhancement (< 3 LV segments) in the first CMR. Patients with overt dysfunction or stage III (n=4; 11%), presented diffuse myocardial fibrosis (> 3 LV segments) or impaired systolic function (LVEF < 50%). Conclusion In our cohort patients, the new staging scheme allows us to identify and classify the different stages of FD cardiomyopathy. The majority of patients were unexpectedly identified in early disease stages, but that could be related to diagnosis in the context of familial screening. This proposal seems useful for clinical staging standardization to facilitate the evaluation of responses to treatments and to predict outcomes, however, needs to be validated in larger and prospective studies.

"Hot phase" clinical presentation of biventricular arrhythmogenic cardiomyopathy: when the perfect electrical storm spontaneously stops.

An 18-year-old male presented with syncope during a training break. Post-syncope, he developed effort dyspnea, which he associated with the Pfizer-BioNTech COVID-19 vaccine received a week earlier. Electrocardiogram showed T inversion in V1-V3, III, and aVF, while 24-hour Holter monitoring revealed frequent ventricular premature beats. A transthoracic echocardiogram showed severe biventricular dilation and mild left ventricular (LV) dysfunction. Cardiac magnetic resonance (CMR) imaging confirmed these findings, showing moderate right ventricular (RV) systolic dysfunction with akinesia of the inferior and inferolateral walls. T2 hypersignal in the middle segment of the inferior inferior interventricular septum suggested myocardial edema. Extensive transmural late gadolinium enhancement was noted in the RV and LV walls. An implantable loop recorder was implanted. Three months later, the patient was admitted with palpitations, fever, and a positive SARS-CoV-2 test. Sustained ventricular tachycardia (VT) episodes were documented and managed with amiodarone and β-blockers. Follow-up CMR showed a slight improvement in LV ejection fraction and resolution of edema. A single-chamber implantable cardioverter-defibrillator (ICD) was implanted. Genetic testing for arrhythmogenic RV cardiomyopathy (ARVC) was negative, and family screening was normal. Two years later, pre-syncope episodes occurred, and ICD interrogation revealed nonsustained VT. The patient is awaiting VT ablation. This case highlights the diagnostic and therapeutic challenges of ARVC, particularly in differentiating it from myocarditis. The "hot-phase" presentation, vaccine association, and subsequent SARS-CoV-2 infection added complexity. CMR was crucial for diagnosis, and VT management required a combination of medical therapy and invasive procedures.

Isolated prolapse of the posterior mitral valve leaflet: phenotypic refinement, heritability and genetic etiology.

Isolated posterior leaflet mitral valve prolapse (PostMVP), a common form of MVP, often referred as fibroelastic deficiency, is considered a degenerative disease. PostMVP patients are usually asymptomatic and often undiagnosed until chordal rupture. The present study aims to characterize familial PostMVP phenotype and familial recurrence, its genetic background, and the pathophysiological processes involved. We prospectively enrolled 284 unrelated MVP probands, of whom 178 (63%) had bi-leaflet MVP and 106 had PostMVP (37%). Familial screening within PostMVP patients allowed the identification of 20 families with inherited forms of PostMVP for whom whole genome sequencing was carried out in probands. Functional in vivo and in vitro investigations were performed in zebrafishand in Hek293T cells. In the 20 families with inherited form of PostMVP, 38.8% of relatives had a MVP/prodromal form, mainly of the posterior leaflet, with transmission consistent with an autosomal dominant mode of inheritance. Compared with control relatives, PostMVP family patients have clear posterior leaflet dystrophy on echocardiography. Patients with PostMVP present a burden of rare genetic variants in ARHGAP24. ARHGAP24 encodes the filamin A binding RhoGTPase-activating protein FilGAP and its silencing in zebrafish leads to atrioventricular regurgitation. In vitro functional studies showed that variants of FilGAP, found in PostMVP families, are loss-of-function variants impairing cellular adhesion and mechano-transduction capacities. PostMVP should not only be considered an isolated degenerative pathology but as a specific heritable phenotypic trait with genetic and functional pathophysiological origins. The identification of loss-of-function variants in ARHGAP24 further reinforces the pivotal role of mechano-transduction pathways in the pathogenesis of MVP. Isolated posterior mitral valve prolapse (PostMVP), often called fibro-elastic deficiency MVP, is at least in some patients, a specific inherited phenotypic traitPostMVP has both genetic and functional pathophysiological origins Genetic variants in the ARHGAP24 gene, which encodes for the FilGAP protein, cause progressive Post MVP in familial cases, and impair cell adhesion and mechano-transduction capacities.

Treatment switch from multiple daily insulin injections to sulphonylureas in an African young adult diagnosed with HNF1A MODY: a case report

BackgroundMaturity onset diabetes of the young is one of the commonest causes of monogenic diabetes and can easily be mistaken for type 1 diabetes. A diagnosis of maturity onset diabetes of the young can have direct implications for genetic counseling, family screening, and precision diabetes treatment. However, the cost of genetic testing and identifying individuals to test are the main challenges for diagnosis and management in sub-Saharan Africa. We report the very first documented case of HNF1A maturity onset diabetes of the young in the sub-Saharan African region.Case presentationA 20-year-old female Black African young adult diagnosed with type 1 diabetes aged 14 presented for routine out-patient diabetes consultation. She was on multiple daily insulin injections; total combined dose 0.79 IU/kg/day with an HbA1c of 7.7%. The rest of her laboratory examinations were normal. On extended laboratory analysis, she had good residual insulin secretion with post-meal plasma C-peptide levels at 1150 pmol/L. She tested negative for glutamic acid decarboxylase (GAD65), islet antigen-2 (IA-2), and zinc transporter 8 (ZnT8) islet autoantibodies. Targeted next-generation sequencing (t-NGS) for monogenic diabetes was performed using DNA extracted from a buccal sample. She was diagnosed with HNF1A maturity onset diabetes of the young, with the c.607C > T; p.(Arg203Cys) pathogenic variant, which has never been reported in sub-Saharan Africa. Her clinical practitioners provided genetic and therapeutic counseling. Within 10 months following the diagnosis of maturity onset diabetes of the young, she was successfully switched from multiple daily insulin injections to oral antidiabetic tablets (sulphonylurea) while maintaining stable glycemic control (HBA1c of 7.0%) and reducing hypoglycemia. She expressed a huge relief from the daily finger pricks for blood glucose monitoring.ConclusionThis case reveals that HNF1A maturity onset diabetes of the young (and probably other causes of monogenic diabetes) can present in sub-Saharan Africa. A diagnosis of maturity onset diabetes of the young can have significant life-changing therapeutic implications.

Relationship functioning and impact of health coverage models for parents of childhood cancer patients: A systematic review.

The current systematic literature review aimed to summarize and evaluate existing literature regarding parental relationship functioning during and after childhood cancer, with an exploratory evaluation regarding the impact of national health coverage model (proxy for finances). This review used MEDLINE, PsychInfo, Embase, and CENTRAL search database. Articles were reviewed (N = 3060) against inclusion criteria, with 512 abstracts screened and 87 full-text retrieved and reviewed. Inclusion criteria: (1) childhood cancer, (2) measures parental relationship functioning, (3) English, and (4) new, empirical data. A modified version of the Downs and Black checklist was used to assess risk of bias. Narrative synthesis was used to present and discuss results. Final included articles (N = 36) revealed mostly positive or neutral findings across parental relationship functioning subdomains within 6months (T1) and after 6months (T2) of childhood cancer diagnosis. Sexual intimacy was negatively impacted across timepoints. Parental stress was higher than norms at T1. Marital conflict and adjustment were also worse at T1 but returned to previous levels at T2. Some variability in parental relationship functioning was observed among the different health coverage models, but these differences were not significant. Results support systematic screening and systems-based parent support programs for families of children with cancer. Mixed-methods studies examining parental relationships longitudinally and utilizing operational definitions for out-of-pocket spending are needed.

NR2E3-Associated Retinopathy Presenting with Bilateral Choroidal Neovascularization

Purpose: We describe an atypical presentation of an 11-year-old female with enhanced S-cone syndrome (ESCS). Methods: Case report. The patient underwent a thorough ophthalmic examination and investigations such as colour fundus photography, optical coherence tomography, fundus autofluorescence, fluorescein and indocyanine angiography, an electroretinogram and genetic testing. After determining the presence of secondary choroidal neovascularization, we treated her with intravitreal Ranibizumab injections. We present her progress and a brief literature review about ESCS. Results: An 11-year-old hyperopic female with no known family history of retinal disease or nyctalopia presented with bilateral reduced visual acuity (20/100 OD, 20/200 OS). Examination disclosed bilateral macular choroid neovascularization (CNV) with retinochoroidal anastomosis on the left eye, bilateral nummular deposits at the superior macular arcades. All three of her siblings, aged 7-14, were asymptomatic but were also hyperopic and had intraretinal schisis and focal loss or attenuation of the ellipsoid zone on optical coherence tomography (OCT). Electrophysiology showed a reduced scotopic response and a dramatically enhanced response to full field blue light stimuli meant to elicit a response primarily from S-cones. Genetic testing confirmed the presence of biallelic NR2E3 variants. Treatment with monthly intravitreal anti-VEGF resulted in improved visual acuity of 20/30 on the right eye, while the left eye had a persistent nodular scar and visual acuity remained at 20/200. Conclusion: We describe a case of bilateral CNV in a young patient with enhanced S-cone syndrome, discuss differentials and treatment approaches. This case highlights the risk of CNV in ESCS and the importance of family screening and follow-up in affected relatives.

Kinetics of EBV antibody-based NPC risk scores in Taiwan NPC multiplex families.

Nasopharyngeal carcinoma (NPC) risk prediction models based on Epstein-Barr virus (EBV)-antibody testing have shown potential for screening of NPC; however, the long-term stability is unclear. Here, we investigated the kinetics of two EBV-antibody NPC risk scores within the Taiwan NPC Multiplex Family Study. Among 545 participants with multiple blood samples, we evaluated the stability of a 2-marker enzyme-linked immunosorbent assay score and 13-marker multiplex serology score using the intra-class correlation coefficient (ICC) by fitting a linear mixed model that accounted for the clustering effect of multiple measurements per subject and age. We also estimated the clustering of positive tests using Fleiss's kappa statistic. Over an average 20-year follow-up, the 2-marker score showed high stability over time, whereas the 13-marker score was more variable (p < .05). Case-control status is associated with the kinetics of the antibody response, with higher ICCs among cases. Positive tests were more likely to cluster within the same individual for the 2-marker score than the 13-marker score (p < .05). The 2-marker score had an increase in specificity from ~90% for single measurement to ~96% with repeat testing. The 13-marker score had a specificity of ~73% for a single measurement that increased to ~92% with repeat testing. Among individuals who developed NPC, none experienced score reversion. Our findings suggest that repeated testing could improve the specificity of NPC screening in high-risk NPC multiplex families. Further studies are required to determine the impact on sensitivity, establish optimal screening intervals, and generalize these findings to general population settings in high-risk regions.