Disease Penetrance Research Articles

Gender- and age-related differences in distinct phenotypes of hypertrophic cardiomyopathy-associated mutation MYBPC3–E334K

The mutation MYBPC3-E334K is a culprit mutation of hypertrophic cardiomyopathy (HCM). The pathogenicity of MYBPC3-E334K is conflicting in ClinVar because of the limited segregation data and the relatively high frequency in gnomAD (0.03% overall, with 0.3% in East Asians and 0.8% in Japanese). The main aim is to clarify the clinical importance and phenotype-genotype correlations in subjects with or without MYBPC3-E334K alone. The prevalence of MYBPC3-E334K was sequenced in 1017 HCM unrelated probands. The clinical features, morphology phenotypes, and electrical phenotypes were further analyzed according to the phenotype and genotype status in families with single-mutation MYBPC3-E334K. Nine of 1017 (0.88%) unrelated HCM probands were detected harboring MYBPC3-E334K, and three of them harbored a second variant in sarcomere protein gene. Family study and co-segregation analyses indicated that patients with single-mutation MYBPC3-E334K showed autosomal dominant mode of inheritance with incomplete penetrance. The overall disease penetrance was 52.6%, and the disease penetrance was higher in males than in females (100% in men vs 25% in women, p = 0.003). The mean age at diagnosis of males was approximately 25years younger than females (36.57 ± 18.65 vs 62.33 ± 12.10, p = 0.062). The variant MYBPC3-E334K was classified as a likely pathogenic variant, and a second sarcomere variant did not reveal obvious cumulative effects. The patients harboring single-mutation MYBPC3-E334K had incomplete penetrance, and males demonstrated higher penetrance and early onset HCM than females. A second sarcomere variant did not reveal obvious cumulative effects.

Ileal Crohn's Disease Exhibits Similar Transmural Fibrosis Irrespective of Phenotype.

INTRODUCTION:In Crohn's disease (CD), the assessment of transmural inflammation and fibrosis is of utmost importance. This study aimed to quantify these parameters in CD ileal specimens and correlate them with disease progression.METHODS:This is a retrospective unicentric study based on the analysis of archived specimens (n = 103) of primary ileal resection. Data were retrieved from a prospective national inflammatory bowel disease registry. Two pathologists, blinded for CD phenotype and clinical indications for surgery, examined 3 sections per patient and graded inflammation and fibrosis, based on a histopathological score.RESULTS:Penetrating (B3, n = 74) CD exhibited significantly higher inflammation in diseased areas, compared with stricturing (B2, n = 29) disease (score 3: 96% vs 76%, P = 0.005 in inflamed areas; 78% vs 55%, P = 0.019 in most affected areas). This was also observed for the comparison of B2 CD with B3 CD with (B3s, n = 54) and without associated stricture (B3o, n = 20): B3s vs B2: 81% vs 55%, P = 0.033 in most affected areas; B3o vs B2: 100% vs 76%, P = 0.006 in inflamed areas; 70% vs 55%, P = 0.039 in most affected areas. We could not show differences in fibrosis scores between the subphenotypes. Postoperative new penetrating events occurred only in B3s (n = 6, 11%, P = 0.043) patients. The changing of biologic therapy after surgery correlated with severe inflammation at the proximal ileal margin (55% changed vs 25% not changed, P = 0.035).DISCUSSION:In our cohort, fibrosis scores and fibromuscular changes were comparable, irrespective of CD phenotype. Inflammation severity was the major differentiator between penetrating and stricturing disease.

New advances in Amyotrophic Lateral Sclerosis genetics: Towards gene therapy opportunities for familial and young cases.

Due to novel gene therapy opportunities, genetic screening is no longer restricted to familial cases of ALS (FALS) cases but also aplies to the sporadic populations (SALS). Screening of four main genes (C9orf72, SOD1, TARDBP and FUS) identified the causes in 15% of Amyotrophic Lateral Sclerosis (ALS) patients (two third of the familial cases and 8% of the sporadic ones) but their respective contribution to ALS phenotype varies according the age of disease onset. The genetic overlap between ALS and other diseases is expanding and includes frontotemporal dementia, Paget's Disease of Bone, myopathy for adult cases, HSP and CMT for young cases highlighing the importance of retrieving the exhaustive familial history for each indivdual with ALS. Incomplete disease penetrance, diversity of the possible phenotypes, as well as the lack of confidence concerning the pathogenicity of most identified variants and/or possible oligogenic inheritance are burdens of ALS genetic counseling to be delivered to patients and at risk individuals. The multitude of rare ALS genetic causes identifed seems to converge to similar cellular pathways leading to inapropriate response to stress emphacising new potential therapeutic options for the disease.

Characteristics of p.Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank

MYOC (myocilin) mutations account for 3% to 5% of primary open-angle glaucoma (POAG) cases. We aimed to understand the true population-wide penetrance and characteristics of glaucoma among individuals with the most common MYOC variant (p.Gln368Ter) and the impact of a POAG polygenic risk score (PRS) in this population. Cross-sectional population-based study. Individuals with the p.Gln368Ter variant among 77 959 UK Biobank participants with fundus photographs (FPs). A genome-wide POAG PRS was computed, and 2 masked graders reviewed FPs for disc-defined glaucoma (DDG). Penetrance of glaucoma. Two hundred individuals carried the p.Gln368Ter heterozygous genotype, and 177 had gradable FPs. One hundred thirty-two showed no evidence of glaucoma, 45 (25.4%) had probable/definite glaucoma in at least 1 eye, and 19 (10.7%) had bilateral glaucoma. No differences were found in age, race/ethnicity, or gender among groups (P > 0.05). Of those with DDG, 31% self-reported or had International Classification of Diseases codes for glaucoma, whereas 69% were undiagnosed. Those with DDG had higher medication-adjusted cornea-corrected intraocular pressure (IOPcc) (P < 0.001) vs. those without glaucoma. This difference in IOPcc was larger in those with DDG with a prior glaucoma diagnosis versus those not diagnosed (P < 0.001). Most p.Gln368Ter carriers showed IOP in the normal range (≤21 mmHg), although this proportion was lower in those with DDG (P < 0.02) and those with prior glaucoma diagnosis (P < 0.03). Prevalence of DDG increased with each decile of POAG PRS. Individuals with DDG demonstrated significantly higher PRS compared with those without glaucoma (0.37 ± 0.97 vs. 0.01 ± 0.90; P= 0.03). Of those with DDG, individuals with a prior diagnosis of glaucoma had higher PRS compared with undiagnosed individuals (1.31 ± 0.64 vs. 0.00 ± 0.81; P < 0.001) and 27.5 times (95% confidence interval, 2.5-306.6) adjusted odds of being in the top decile of PRS for POAG. One in 4 individuals with the MYOC p.Gln368Ter mutation demonstrated evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter carriers, including those with DDG, have IOP in the normal range, despite similar age. Polygenic risk score increases disease penetrance and severity, supporting the usefulness of PRS in risk stratification among MYOC p.Gln368Ter carriers.

A162 OBESITY IS A RISK FACTOR FOR THE DEVELOPMENT OF THE EXTRAINTESTINAL MANIFESTATIONS IN ULCERATIVE COLITIS, BUT NOT IN CROHN’S DISEASE

Abstract Background Several inflammatory markers have been associated with both obesity and the risk of adverse outcomes. Studies exploring obesity as a potential risk factor in extraintestinal manifestations (EIMs) development in patients with inflammatory bowel disease (IBD) are limited. Aims To describe the relationship between obesity and EIMs development, taking into consideration various confounding risk factors. Methods We performed a retrospective cohort study using data of 5,023 IBD patients diagnosed between 1954 and 2020. We collected data on demographics, clinical features, biochemistry, medications, smoking, weight status and EIMs (hepatobiliary, musculoskeletal, dermatological, urogenital, ophthalmological, and pulmonary). Obesity was defined as measured BMI≥30.00 kg/m2, prolonged steroid use – as using any corticosteroid formulations for at least 6 months. Rates were compared using Pearson’s chi-squared test with Bonferroni’s p-value adjustment. Univariate and multivariate logistic regression models were used to determine the association between obesity, potential contributing factors and EIMs. Results Data of 2,367 ulcerative colitis (UC) patients (47.8% females) and 2,656 Crohn’s disease (CD) patients (52.2% females), aged 18–97 (median 48.0, IQR 27.0) years, were analysed. Obesity was common among IBD patients (30.1%; 95% CI 28.7–31.6%) and the rate was higher than the Alberta’s population-based one (28.2%; 95% CI 28.17–28.23%); p=0.013. Obesity was less prevalent in the UC (28.5%; 95% CI 26.3–30.6%) vs CD cohort (31.4%; 95% CI 29.4–33.4%); p=0.049. In both cohorts, the EIMs prevalence tended to be slightly higher among IBD patients living with obesity compared to those without it (UC: 19.5% vs 16.1%, p=0.106; CD: 20.2% vs. 19.6%, p=0.767); the prevalence of specific EIMs subtypes and the proportion of IBD patients with over 2 or 3 EIMs also did not differ significantly. Among UC patients, obesity was proven to be a risk factor for EIMs development (OR 1.75, 95% CI 1.15–2.67; p=0.009), along with male sex (OR 1.90, 95% CI 1.25–2.89; p=0.02), and prolonged steroid use (OR 1.88, 95% CI 1.03–3.45; p=0.04). Among CD patients, logistic regression analysis showed that stricturing and penetrating disease behaviour (OR 1.69, 95% CI 1.04–2.75; p=0.033), iron deficiency (OR 1.55, 95% CI 1.16–2.07; p=0.003) and calcium deficiency (OR 2.43, 95% CI 1.36–4.36; p=0.003) were associated with EIMs development; obesity was not an independent or adjusted risk factor (Table). Conclusions In a large IBD cohort, obesity prevalence was found to be higher than in the general population. Interestingly, obesity was established as a risk factor for the EIMs development in UC, but not in CD. Our findings highlight the need for timely assessment and management of obesity in these disorders, which may help in preventing EIMs development. Funding Agencies AbbVie

A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype

Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort. To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment. This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018. Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry. A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype. This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.

Genetic disorders of the surfactant system: focus on adult disease.

Genes involved in the production of pulmonary surfactant are crucial for the development and maintenance of healthy lungs. Germline mutations in surfactant-related genes cause a spectrum of severe monogenic pulmonary diseases in patients of all ages. The majority of affected patients present at a very young age, however, a considerable portion of patients have adult-onset disease. Mutations in surfactant-related genes are present in up to 8% of adult patients with familial interstitial lung disease (ILD) and associate with the development of pulmonary fibrosis and lung cancer.High disease penetrance and variable expressivity underscore the potential value of genetic analysis for diagnostic purposes. However, scarce genotype-phenotype correlations and insufficient knowledge of mutation-specific pathogenic processes hamper the development of mutation-specific treatment options.This article describes the genetic origin of surfactant-related lung disease and presents spectra for gene, age, sex and pulmonary phenotype of adult carriers of germline mutations in surfactant-related genes.

Sex differences in disease progression and arrhythmic risk in patients with arrhythmogenic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Area Network on Cardiovascular Diseases (ERA-CVD) Background Arrhythmogenic cardiomyopathy (AC) is an inheritable heart disease characterized by high risk of life-threatening ventricular arrhythmia. Male sex has been reported as a risk factor of high disease penetrance and arrhythmia, but data on sex-specific phenotype in AC are sparse. Purpose To assess sex-specific disease progression in AC patients and structural cardiac changes at time of arrhythmic event. Methods We included consecutive AC patients in a longitudinal cohort study. We performed echocardiography at baseline according to Task Force Criteria of 2010 with additional parameters including strain. Patients were followed with repeated echocardiographic examinations. Ventricular arrhythmia was defined as aborted cardiac arrest, sustained ventricular tachycardia or appropriate therapy by an implantable cardioverter-defibrillator. In patients with documented first time ventricular arrhythmias, echocardiographic findings obtained ±30 days around the event was noted separately. Results We included 191 AC patients (46% female, 51% probands, age 41 ± 17 years) of which 88% had ≥2 echocardiographic examinations during 6.9 (IQR 4.7-9.8) years of follow up. Females and males had similar progression rate of right ventricular dimensions and left ventricular function, but right ventricular function decreased more in females (Figure). Arrhythmic events occurred in 85 (45%) patients and 39 patients had an echocardiographic examination at the time of their first event. There was no difference in right ventricular diameters or right or left ventricular function between females and males at the time of first arrhythmic event (right ventricular outflow tract diameter: 35 ± 7 mm vs. 39 ± 7 mm, p = 0.16, right ventricular fractional area change: 34 ± 9 % vs. 29 ± 11 %, p = 0.26, left ventricular global longitudinal strain: -18.8 ± 3.0 % vs. 17.2 ± 2.2 %, p = 0.12, respectively). Conclusion Disease progression was similar in male and female AC patients indicating no accelerated disease progression in males. First arrhythmic event occurred at similar cardiac dysfunction and diameters in both sexes indicating no lower risk in females. Abstract Figure.

MR Enterography of Complicated Crohn Disease: Stricturing and Penetrating Disease.

Stricturing and penetrating disease are complications of Crohn disease (CD) that significantly affect patient outcomes. Careful evaluation for such complications is critical to the interpretation of magnetic resonance enterography. This manuscript outlines the key findings related to stricturing and penetrating CD and discusses current understanding of the pathophysiology and prognosis of complicated CD based on the literature.

NOVEL GENETIC SUSCEPTIBILITY CANDIDATES IN GRANULOMATOUS AND NON-GRANULOMATOUS PEDIATRIC CROHN’S DISEASE

Non-caseating granulomas are a hallmark histopathological finding of Crohn’s disease (CD). Studies have suggested that the presence of granulomas may indicate a more aggressive CD phenotype associated with a complicated clinical course, including stricturing and/or penetrating disease, need for biologic therapy, and need for surgery. As such, identification of genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis, which in turn may optimize treatments and guide novel therapeutics to combat CD complications.

Genetic and Environmental Factors Influence the Pleomorphy of LRRK2 Parkinsonism.

Missense mutations in the LRRK2 gene were first identified as a pathogenic cause of Parkinson’s disease (PD) in 2004. Soon thereafter, a founder mutation in LRRK2, p.G2019S (rs34637584), was described, and it is now estimated that there are approximately 100,000 people worldwide carrying this risk variant. While the clinical presentation of LRRK2 parkinsonism has been largely indistinguishable from sporadic PD, disease penetrance and age at onset can be quite variable. In addition, its neuropathological features span a wide range from nigrostriatal loss with Lewy body pathology, lack thereof, or atypical neuropathology, including a large proportion of cases with concomitant Alzheimer’s pathology, hailing LRRK2 parkinsonism as the “Rosetta stone” of parkinsonian disorders, which provides clues to an understanding of the different neuropathological trajectories. These differences may result from interactions between the LRRK2 mutant protein and other proteins or environmental factors that modify LRRK2 function and, thereby, influence pathobiology. This review explores how potential genetic and biochemical modifiers of LRRK2 function may contribute to the onset and clinical presentation of LRRK2 parkinsonism. We review which genetic modifiers of LRRK2 influence clinical symptoms, age at onset, and penetrance, what LRRK2 mutations are associated with pleomorphic LRRK2 neuropathology, and which environmental modifiers can augment LRRK2 mutant pathophysiology. Understanding how LRRK2 function is influenced and modulated by other interactors and environmental factors—either increasing toxicity or providing resilience—will inform targeted therapeutic development in the years to come. This will allow the development of disease-modifying therapies for PD- and LRRK2-related neurodegeneration.

NOVEL GENETIC SUSCEPTIBILITY CANDIDATES IN GRANULOMATOUS AND NON-GRANULOMATOUS PEDIATRIC CROHN’S DISEASE

Abstract Background Non-caseating granulomas are a hallmark histopathological finding of Crohn’s disease (CD). Studies have suggested that the presence of granulomas may indicate a more aggressive CD phenotype associated with a complicated clinical course, including stricturing and/or penetrating disease, need for biologic therapy, and need for surgery. As such, identification of genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis, which in turn may optimize treatments and guide novel therapeutics to combat CD complications. There is relatively sparse genetic information known about CD subtypes, especially GCD. The aim of this study was to determine the extent of genetic variation between pediatric CD patients with and without a pathognomonic sub-mucosal granuloma detected at the time of diagnosis. Methods Whole-exome next-generation sequencing (WES) was performed on peripheral blood derived DNA from patients with GCD and non-GCD (NGCD). PLINK analysis was used to identify single nucleotide polymorphisms (SNPs) that were overrepresented in comparisons between groups, and subgroup allele frequencies were also compared to publically available, large population-based genomic data in gnomAD. The potential deleteriousness of single nucleotide variants was determined by the CADD scoring tool. Results WES was completed for 17 patients with GCD and 19 with NGCD. There were no significant differences in baseline clinical characteristics, treatments, nor 1-year outcomes between the groups. Overlap analyses between PLINK- and gnomAD-generated SNPs revealed significant enrichment in those associated with HLA-DQA1, LILRA1, SAA2, PCDHB, HLA-B, NOD2, and IGH shared by GCD and NGCD groups. In the meantime, GCD-specific (top candidates linked with HLA-B and MUC4) and NGCD-specific (top candidates linked with HLA-B and ACOT9) SNPs were sparse. Conclusions We are the first to examine WES-based genetic variation between treatment-naïve pediatric CD patients purely separated by the presence of a sub-mucosal epithelioid granuloma. While there were very few SNPs consistently differentiating between GCD and NGCD patients in our cohort using two distinct methodologies, we were able to identify several novel SNPs that were significantly enriched in pediatric CD patients compared to the control human genome. Our findings will require subsequent confirmation in larger but similarly scrutinized cohorts of patients.

Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance.

Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5years (range: 12 to 42years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40years), as 16 heterozygous relatives aged between 6 and 78years, including 4 older than 60years, were completely asymptomatic. Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.

Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice.

C9orf72 ALS/FTD patients show remarkable clinical heterogeneity, but the complex biology of the repeat expansion mutation has limited our understanding of the disease. BAC transgenic mice were used to better understand the molecular mechanisms and repeat length effects of C9orf72 ALS/FTD. Genetic analyses of these mice demonstrate that the BAC transgene and not integration site effects cause ALS/FTD phenotypes. Transcriptomic changes in cell proliferation, inflammation and neuronal pathways are found late in disease and alternative splicing changes provide early molecular markers that worsen with disease progression. Isogenic sublines of mice with 800, 500 or 50 G4C2 repeats generated from the single-copy C9-500 line show longer repeats result in earlier onset, increased disease penetrance and increased levels of RNA foci and dipeptide RAN protein aggregates. These data demonstrate G4C2 repeat length is an important driver of disease and identify alternative splicing changes as early biomarkers of C9orf72 ALS/FTD.

Neural endophenotypes and predictors of laryngeal dystonia penetrance and manifestation

Focal dystonias are the most common forms of isolated dystonia; however, the etiopathophysiological signatures of disorder penetrance and clinical manifestation remain unclear. Using an imaging genetics approach, we investigated functional and structural representations of neural endophenotypes underlying the penetrance and manifestation of laryngeal dystonia in families, including 21 probands and 21 unaffected relatives, compared to 32 unrelated healthy controls. We further used a supervised machine-learning algorithm to predict the risk for dystonia development in susceptible individuals based on neural features of identified endophenotypes. We found that abnormalities in prefrontal-parietal cortex, thalamus, and caudate nucleus were commonly shared between patients and their unaffected relatives, representing an intermediate endophenotype of laryngeal dystonia. Machine learning classified 95.2% of unaffected relatives as patients rather than healthy controls, substantiating that these neural alterations represent the endophenotypic marker of dystonia penetrance, independent of its symptomatology. Additional abnormalities in premotor-parietal-temporal cortical regions, caudate nucleus, and cerebellum were present only in patients but not their unaffected relatives, likely representing a secondary endophenotype of dystonia manifestation. Based on alterations in the parietal cortex and caudate nucleus, the machine learning categorized 28.6% of unaffected relative as patients, indicating their increased lifetime risk for developing clinical manifestation of dystonia. The identified endophenotypic neural markers may be implemented for screening of at-risk individuals for dystonia development, selection of families for genetic studies of novel variants based on their risk for disease penetrance, or stratification of patients who would respond differently to a particular treatment in clinical trials.

Psychosocial Stress Hastens Disease Progression and Sudden Death in Mice with Arrhythmogenic Cardiomyopathy.

Physiological stressors, such as exercise, can precipitate sudden cardiac death or heart failure progression in patients with arrhythmogenic cardiomyopathy (ACM). Yet, whether and to what extent a highly prevalent and more elusive environmental factor, such as psychosocial stress (PSS), can also increase ACM disease progression is unexplored. Here, we first quantified perceived stress levels in patients with ACM and found these levels correlated with the extent of arrhythmias and cardiac dysfunction. To determine whether the observed correlation is due to causation, we inflicted PSS-via the resident-intruder (RI) paradigm—upon Desmoglein-2 mutant mice, a vigorously used mammalian model of ACM. We found that ACM mice succumbed to abnormally high in-trial, PSS mortality. Conversely, no sudden deaths occurred in wildtype (WT) counterparts. Desmoglein-2 mice that survived RI challenge manifested markedly worse cardiac dysfunction and remodeling, namely apoptosis and fibrosis. Furthermore, WT and ACM mice displayed similar behavior at baseline, but Desmoglein-2 mice exhibited heightened anxiety following RI-induced PSS. This outcome correlated with the worsening of cardiac phenotypes. Our mouse model demonstrates that in ACM-like subjects, PSS is incisive enough to deteriorate cardiac structure and function per se, i.e., in the absence of any pre-existing anxious behavior. Hence, PSS may represent a previously underappreciated risk factor in ACM disease penetrance.

P.arg102ser is a common Pde6a mutation causing autosomal recessive retinitis pigmentosa in Pakistani families.

To explore the genetic cause of autosomal recessive retinitis pigmentosa in consanguineous families. The multi-centre study was conducted from July 2015 to June 2018 at Liaquat University of Medical and Health Sciences, Jamshoro, the University of Sindh, Jamshoro, and Islamia University, Bahawalpur, Pakistan, and comprised families affected with non-syndromic autosomal recessive retinitis pigmentosa. Ophthalmological investigations were done to assess the fundus of the patients and the status of the disease. Pedigrees were drawn and family histories were recorded to find out the mode of inheritance. A 10cc sample of whole blood was obtained from each participant and deoxyribonucleic acid was extracted. Homozygosity mapping was performed using three short tandem repeat polymorphisms closely linked to phosphodiesterase 6A gene, and the linked families were Sanger-sequenced for identification of the mutation. Bioinformatic tools were used to design amplification refractory mutation system assay and to assess the protein structure and pathogenic effects of the mutation. In the 80 consanguineous families, there were 464 individuals, and, of them, 236(51%) were affected with their age ranging between 4 and 80 years. Family history and pedigree drawings revealed autosomal recessive retinitis pigmentosa with early childhood onset. Linkage analysis indicated the homozygosity in 6(7.5%) families. Sanger-sequencing revealed a common mutation c.304C>A (p.Arg102Ser); segregating with the disease in the linked families. The findings may offer effective genetic counselling and minimise disease penetration in consanguineous families.

Mechanotransduction and Adrenergic Stimulation in Arrhythmogenic Cardiomyopathy: An Overview of in vitro and in vivo Models.

Arrhythmogenic Cardiomyopathy (AC) is a rare inherited heart disease, manifesting with progressive myocardium degeneration and dysfunction, and life-threatening arrhythmic events that lead to sudden cardiac death. Despite genetic determinants, most of AC patients admitted to hospital are athletes or very physically active people, implying the existence of other disease-causing factors. It is recognized that AC phenotypes are enhanced and triggered by strenuous physical activity, while excessive mechanical stretch and load, and repetitive adrenergic stimulation are mechanisms influencing disease penetrance. Different approaches have been undertaken to recapitulate and study both mechanotransduction and adrenergic signaling in AC, including the use of in vitro cellular and tissue models, and the development of in vivo models (particularly rodents but more recently also zebrafish). However, it remains challenging to reproduce mechanical load stimuli and physical activity in laboratory experimental settings. Thus, more work to drive the innovation of advanced AC models is needed to recapitulate these subtle physiological influences. Here, we review the state-of-the-art in this field both in clinical and laboratory-based modeling scenarios. Specific attention will be focused on highlighting gaps in the knowledge and how they may be resolved by utilizing novel research methodology.

Unraveling the Genotype‐Phenotype Relationship in Hypertrophic Cardiomyopathy: Obesity‐Related Cardiac Defects as a Major Disease Modifier

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric septal thickening and diastolic dysfunction. More than 1500 mutations in genes encoding sarcomere proteins are associated with HCM. However, the genotype‐phenotype relationship in HCM is incompletely understood and involves modification by additional disease hits. Recent cohort studies identify obesity as a major adverse modifier of disease penetrance, severity, and clinical course. In this review, we provide an overview of these clinical findings. Moreover, we explore putative mechanisms underlying obesity‐induced sensitization and aggravation of the HCM phenotype. We hypothesize obesity‐related stressors to impact on cardiomyocyte structure, metabolism, and homeostasis. These may impair cardiac function by directly acting on the primary mutation‐induced myofilament defects and by independently adding to the total cardiac disease burden. Last, we address important clinical and pharmacological implications of the involvement of obesity in HCM disease modification.

Penetrance of hypertrophic cardiomyopathy and outcome in sarcomeric mutation carriers

Abstract Background Predictive genetic screening of the first degree relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM. Purpose To establish the role of sex and genotype in HCM penetrance as well as the rate of major adverse clinical events in SP mutation carriers and following the diagnosis of HCM. Methods Retrospective analysis of consecutive adult and paediatric SP mutation carriers identified during family screening and who did not fulfill diagnostic criteria for HCM at first evaluation. Results 321 individuals from 170 families [median age first evaluation 15.2 years (IQR 7.3–32.6); 153 (47.7%) males] were evaluated. Causal SP genes were: MYBPC3 (n=133 (41.4%)), MYH7 (n=77 (24.0%)), TNNI3 (n=51 (15.9%)), TNNT2 (n=40 (12.5%)), TPM1 (n=9 (2.8%)), MYL2 (n=6 (1.9%)), and ACTC1 (n=1 (0.3%)); 4 (1.3%) carried multiple mutations. After a median follow up of 7.4 years (IQR 2.5–12.7), 89 (27.7%) patients developed HCM. Disease penetrance at the age of 50 years was 47% (95% CI 38%-56%). One hundred and fifty three (47.7%) individuals underwent cardiac magnetic resonance (CMR) imaging; among those diagnosed with HCM, 22/89 (24.7%) fulfilled criteria on CMR but not echocardiography. In a multivariable model adjusted for genotype, follow up duration and evaluation with CMR, independent predictors of HCM development were male sex (HR 3.11; CI 1.82–5.32) and abnormal ECG (HR 7.87; CI 4.43–13.97). Patients with MYH7 and multiple mutations were more likely to develop HCM than those with MYBPC3 mutations (HR 2.03; CI 1.04–3.96 and HR 10.13; CI 1.40–72.92, respectively). Disease penetrance was lowest in carriers of TNNI3 mutations (HR 0.13; CI 0.03–0.48). There were no major adverse events in individuals without HCM. Following the diagnosis of HCM, the combined rate of all-cause death, appropriate defibrillator shock or resuscitated cardiac arrest was 1.1%/year [median follow up 4.0 years (IQR 2.1–8.9)]. Conclusions Approximately 50% of SP mutation carriers develop HCM by the age of 50 and become prone to disease complications during long-term follow-up. Sex, MYH7 mutations and the presence of an abnormal ECG are associated with a higher risk of disease development. CMR should be employed systematically in long-term screening. HCM penetrance by sex Funding Acknowledgement Type of funding source: None