Carriers Of Pathogenic Mutations Research Articles

Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families.

RAD51C and RAD51D are crucial in homologous recombination (HR) DNA repair. The prevalence of the RAD51C and RAD51D mutations in breast cancer varies across ethnic groups. Associations of RAD51C and RAD51D germline pathogenic variants (GPVs) with breast and ovarian cancer predisposition have been recently reported and are of interest. We performed multi-gene panel sequencing to study the prevalence of RAD51C and RAD51D germline mutations among 3728 patients with hereditary breast and/or ovarian cancer (HBOC). We identified 18 pathogenic RAD51C and RAD51D mutation carriers, with a mutation frequency of 0.13% (5/3728) and 0.35% (13/3728), respectively. The most common recurrent mutation was RAD51D c.270_271dupTA; p.(Lys91Ilefs*13), with a mutation frequency of 0.30% (11/3728), which was also commonly identified in Asians. Only four out of six cases (66.7%) of this common mutation tested positive for homologous recombination deficiency (HRD). Taking the family studies in our registry and tumor molecular pathology together, we concluded that this relatively common RAD51D variant showed incomplete penetrance in our local Chinese community. Personalized genetic counseling emphasizing family history for families with this variant, as suggested at the UK Cancer Genetics Group (UKCGG) Consensus meeting, would also be appropriate in Chinese families.

Precision Dopaminergic Treatment in a Cohort of Parkinson's Disease Patients Carrying Autosomal Recessive Gene Variants: Clinical Cohort Data and a Mini Review.

Parkinson's disease (PD) patients harboring recessive gene variants exhibit a distinct clinical phenotype with an early disease onset and relatively mild symptoms. Data concerning individualized therapy for autosomal recessive PD forms are still scarce. Demographic and treatment data of a cohort of PD carriers of recessive genes (nine homozygous or compound heterozygous PRKN carriers, four heterozygous PRKN carriers, and three biallelic PINK1 carriers) were evaluated. The average levodopa equivalent daily dose (LEDD) was 806.8 ± 453.5 (range 152-1810) in PRKN carriers and 765 ± 96.6 (range 660-850) in PINK1 carriers. The majority responded to low/moderate doses of levodopa. The response to dopamine agonists (DAs) was often favorable both as initial and longitudinal therapy. In total, 8/13 PRKN and 1/3 PINK1 carriers were treated with amantadine successfully, and this also applied to patients who could not tolerate levodopa or DAs. In the era of personalized treatment, the therapeutic approach in recessive PD gene carriers might differ as compared to idiopathic PD. Lower LEDD doses were efficient even in patients with a very long disease duration, while a few patients were doing well without any levodopa treatment decades after disease initiation. DAs or amantadine could be used as a first and main line treatment regimen if well tolerated. Literature data on therapeutic strategies in carriers of pathogenic mutations in recessive PD genes, including device-aided treatments, will be further discussed.

Meta-analysis of breast cancer risk for individuals with PALB2 pathogenic variants.

Multigene panel testing now allows efficient testing of many cancer susceptibility genes leading to a larger number of mutation carriers being identified. They need to be counseled about their cancer risk conferred by the specific gene mutation. An important cancer susceptibility gene is PALB2. Multiple studies reported risk estimates for breast cancer (BC) conferred by pathogenic variants in PALB2. Due to the diverse modalities of reported risk estimates (age-specific risk, odds ratio, relative risk, and standardized incidence ratio) and effect sizes, a meta-analysis combining these estimates is necessary to accurately counsel patients with this mutation. However, this is not trivial due to heterogeneity of studies in terms of study design and risk measure. We utilized a recently proposed Bayesian random-effects meta-analysis method that can synthesize estimates from such heterogeneous studies. We applied this method to combine estimates from 12 studies on BC risk for carriers of pathogenic PALB2 mutations. The estimated overall (meta-analysis-based) risk of BC is 12.80% (6.11%-22.59%) by age 50 and 48.47% (36.05%-61.74%) by age 80. Pathogenic mutations in PALB2 makes women more susceptible to BC. Our risk estimates can help clinically manage patients carrying pathogenic variants in PALB2.

A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

BackgroundPathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations.MethodsPublished data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data.ResultsWe established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers.ConclusionsThese results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Bayesian meta-analysis of penetrance for cancer risk.

Multi-gene panel testing allows many cancer susceptibility genes to be tested quickly at a lower cost making such testing accessible to a broader population. Thus, more patients carrying pathogenic germline mutations in various cancer-susceptibility genes are being identified. This creates a great opportunity, as well as an urgent need, to counsel these patients about appropriate risk-reducing management strategies. Counseling hinges on accurate estimates of age-specific risks of developing various cancers associated with mutations in a specific gene, ie, penetrance estimation. We propose a meta-analysis approach based on a Bayesian hierarchical random-effects model to obtain penetrance estimates by integrating studies reporting different types of risk measures (eg, penetrance, relative risk, odds ratio) while accounting for the associated uncertainties. After estimating posterior distributions of the parameters via a Markov chain Monte Carlo algorithm, we estimate penetrance and credible intervals. We investigate the proposed method and compare with an existing approach via simulations based on studies reporting risks for two moderate-risk breast cancer susceptibility genes, ATM and PALB2. Our proposed method is far superior in terms of coverage probability of credible intervals and mean square error of estimates. Finally, we apply our method to estimate the penetrance of breast cancer among carriers of pathogenic mutations in the ATM gene.

A 15-year consolidated overview of data in over 6000 patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS)

BackgroundTransthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in various tissues and organs.MethodsEstablished in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal, observational study of patients with ATTR amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This analysis describes the baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2022), providing a consolidated overview of 15-year data from the THAOS registry.ResultsThis analysis included 4428 symptomatic patients and 1707 asymptomatic gene carriers. The majority of symptomatic patients were male (70.8%) with a mean (standard deviation [SD]) age at symptom onset of 56.6 (17.9) years. Compared with the 14-year analysis, V30M remained the most prevalent genotype in Europe (62.2%), South America (78.6%), and Japan (74.2%) and ATTRwt remained most common in North America (56.2%). Relative to the 14-year analysis, there was an increase of mixed phenotype (from 16.6 to 24.5%) and a reduction of predominantly cardiac phenotype (from 40.7 to 31.9%). The proportion of patients with predominantly neurologic phenotype remained stable (from 40.1 to 38.7%). Asymptomatic gene carriers were 58.5% female with a mean age at enrollment of 41.9 years (SD 15.5).ConclusionsThis overview of > 6000 patients enrolled over 15 years in THAOS represents the largest registry analysis of ATTR amyloidosis to date and continues to emphasize the genotypic and phenotypic heterogeneity of the disease. Nearly a quarter of the symptomatic population within THAOS was mixed phenotype, underscoring the need for multidisciplinary management of ATTR amyloidosis.Trial registrationClinicalTrials.gov Identifier: NCT00628745.

Influence of left ventricular ejection fraction, type of mutation and sex on malignant ventricular arrhythmias in dsp and flnc mutations

Abstract Introduction Pathogenic mutations in FLNC and DSP are a common cause of arrhythmogenic left ventricular cardiomyopathy and "arrhythmic dilated cardiomyopathy". We aimed to study demographic and clinical differences amongst these carriers. Purpose 1. To study the prevalence of malignant ventricular arrhythmias in DSP and FLNC mutation carriers in the studies and reports published in the literature. 2. To analyse the effect of age, left ventricular ejection fraction (LVEF), and sex on ventricular arrhythmias in both groups. Methods A systematic review of the human studies published in Medline and EMBASE until September 2022 was carried out. "Desmoplakin Mutations", "Filamin Mutations", "Arrhythmogenic Cardiomyopathy" and "Dilated Cardiomyopathy" were the keywords included in the search queries. Studies, family reports, and registries reporting on individual data of pathogenic or likely pathogenic mutation carriers were selected for analysis. Results Twenty-four articles published between 2002 and 2020 were selected from a total of 430 entries. 171 DSP carriers (from 16 studies) and 169 FLNC carriers (from 7 studies) were included in the analysis. Mean age was similar in both groups: 39.45±19.23 years in DSP vs 42.02±16.27 in the FLNC group (p:0.201). The proportion of females was higher among DSP carriers than that found among FLNC carriers: 101 (59%) vs 76 (45%), p: 0.012. Non-missense mutations were more frequent in both groups: 98 DSP carriers (57%) and 157 FLNC carriers (97%). LVEF was slightly more depressed amongst FLNC carriers: 47.75±14.94% vs 52.37±14.64%, p:0.014. A total of 81 major arrhythmic events (sudden death, ventricular fibrillation, sustained ventricular tachycardia were reported. The LVEF of the male patients that had suffered a major event was similar in both groups (39.13±18.20% in DSP vs 39.03±12.24% in FLNC, p:0.987). On the contrary, LVEF was significantly lower in female carriers of DSP mutations (32.33±15.65% in DSP vs 47.60±15.88% in FLNC, p:0.050). Male carriers show a worse prognosis than their female counterparts (log-rank 0.005) (Figure). The difference was not significant after adjusting for LVEF and type of mutation (missense vs non-missense). LVEF (HR 0.94 per percentage unit (0.91-0.96), p <0.001) and non-missense mutations (HR 0.21 (0.07-0.66), p:0.008) were inversely associated with adverse outcomes in DSP carriers in a multivariate analysis. LVEF was also associated with a better outcome in FLNC carriers (HR 0.97 (0.95-0.99), p: 0.019. Conclusion Moderate systolic dysfunction is a risk factor for malignant arrhythmias amongst DSP and FLNC mutation carriers. Female FLNC carriers with mild systolic dysfunction are at risk for sustained ventricular arrhythmias. Missense DSP mutations are associated with poor arrhythmic prognosis.Sex differences in survival

Prophylactic effect of chronic immunosuppression in a mouse model of CSF-1 receptor-related leukoencephalopathy.

Mutations leading to colony-stimulating factor-1 receptor (CSF-1R) loss-of-function or haploinsufficiency cause CSF1R-related leukoencephalopathy (CRL), an adult-onset disease characterized by loss of myelin and neurodegeneration, for which there is no effective therapy. Symptom onset usually occurs in the fourth decade of life and the penetrance of disease in carriers is high. However, familial studies have identified a few carriers of pathogenic CSF1R mutations that remain asymptomatic even in their seventh decade of life, raising the possibility that the development and severity of disease might be influenced by environmental factors. Here we report new cases in which long-term glucocorticoid treatment is associated with asymptomatic status in elder carriers of pathogenic CSF-1R mutations. The main objective of the present study was to investigate the link between chronic immunosuppression initiated pre-symptomatically and resistance to the development of symptomatic CRL, in the Csf1r+/- mouse model. We show that chronic prednisone administration prevents the development of memory, motor coordination and social interaction deficits, as well as the demyelination, neurodegeneration and microgliosis associated with these deficits. These findings are in agreement with the preliminary clinical observations and support the concept that pre-symptomatic immunosuppression is protective in patients carrying pathogenic CSF1R variants associated with CRL. Proteomic analysis of microglia and oligodendrocytes indicates that prednisone suppresses processes involved in microglial activation and alleviates senescence and improves fitness of oligodendrocytes. This analysis also identifies new potential targets for therapeutic intervention.

P-069 A male factor panel of NGS can identify the genetic cause of more than half patients with seminal alterations

Abstract Study question Is Next Generation Sequencing (NGS) an effective diagnostic tool for sperm abnormalities? Summary answer NGS male factor gene panel can be a potent diagnostic tool for discovering pathogenic variants linked to sperm abnormalities. What is known already Male infertility, responsible for half of infertility cases, often shows as absence or decreased sperm count (azoospermia, criptozoospermia or oligozoospermia), poor motility (asthenozoospermia) or a higher proportion of morphologically abnormal sperm (teratozoospermia). While the spermiogram remains the gold standard for evaluating male fertility, the potential to identify the molecular basis of sperm abnormalities may make NGS a valuable approach for such patients. The aim of our study was to assess NGS panel's effectiveness in diagnosing patients with abnormal sperm count, motility and morphology. Study design, size, duration A prospective study was conducted from May 2021 to May 2022 in 82 patients including 20 patients with oligozoospermia, 19 with asthenozoospermia and 23 with teratozoospermia. No other sperm alterations were taken into account in each group. The control group consisted of 20 normozoospermic healthy donors selected on the basis of normal sperm parameters according to the WHO criteria (2010). Patients carrying Y-chromosome microdeletions or abnormal karyotype were excluded. Participants/materials, setting, methods Genomic DNA extraction from blood-EDTA of the patients was performed using the commercial MagMax DNA MultiSample Ultra kit and the King-Fisher automated extractor (ThermoFisher®). Next Generation Sequencing (NGS) was done using a panel with 426 genes involved in the spermatogenesis process. Panel sequencing for identification of genetic variants was performed using Nextera Enrichment technology (Illumina®). FASTAQ data were processed using BWA and GATK algorithms. VCF files were analysed using Variant Interpreter software and in silico predictors. Main results and the role of chance Data analysis showed that thirty-seven of the sixty-two patients were carriers of pathogenic mutations in at least one of the genes included in the panel (37/62,59.6%). In the oligozoospermic group, eleven patients (11/20,55%) were carriers of pathogenic mutations in:CFTR, CEP290, WDR66, ESR1, DNAI2, POLG, PIWIL3, GNRHR, MSH5 and CTNS. In the asthenozoospermic group, ten out of nineteen patients (10/19,52.6%) were carriers of pathogenic mutations in:HS6ST1, PMS2, CYP19A1, DNAI2, POLG, LRRC6, G6PD, CCDC39 and PIWIL3. In the teratozoospermic group, six of the twenty-three patients (6/23,26%) were carriers of pathogenic mutations in:CFTR, PIWIL3, CYP21A2, SRD5A. No pathogenic mutations were detected in the control group. The analysis showed comparable results among the various spermiogram alterations with no significant difference (p > 0.05). Each variant was found in a single patient per group, except POLG and CCDC39, which were found in two cases in the oligozoospermic and asthenozoospermic group, respectively, also CFTR and PIWIL3 in two teratozoospermic patients. Besides, it is remarkable that some of the pathogenic variants were present in genes in more than one group:CFTR (3/62), DNAI2 (2/62), POLG (3/62) and PIWIL3 (4/62). All identified variants were linked with processes of spermatogenesis such as dynein assembly and DNA integrity. Limitations, reasons for caution The main limitation of this study is the limited number of patients included. Functional studies with a larger cohort of males with seminal disorders is warranted to confidently correlate the genetic variants identified in this analysis with spermatogenic failure. Wider implications of the findings The gene list included in our panel represents a step-forward in the screening of males with altered sperm parameters. Our results may add in the knowledge of male factor infertility to provide etiologic factors towards a personalized treatment and adequate genetic counselling. Trial registration number Not applicable

BRCA1 and BRCA2 carriers with breast, ovarian and prostate cancer demonstrate a different pattern of metastatic disease compared with non-carriers: results from a rapid autopsy programme.

To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n=3, range=1-3) compared with non-carriers (median n=9, range=1-7) (P=0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n=10, range=3-8) than non-carriers (median n=5, range=3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P=1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant.

Characterization of CDR® plus NACC FTLD at Phenoconversion from Asymptomatic to Mild Behavioral and/or Cognitive Impairment in Familial Frontotemporal Lobar Degeneration: Data from the ALLFTD Consortium

AbstractBackgroundThe three most common genes responsible for the familial Frontotemporal Lobar Degeneration (f‐FTLD) are MAPT, GRN, and C9orf72, with the C9orf72 mutation being the most common cause of f‐FTLD. The ALLFTD Consortium targets to characterize f‐FTLD, including its preclinical stage, to prepare for clinical trials in FTLD. We sought to investigate the initial symptoms and clinical picture of f‐FTLD and compare them among the common pathogenic genes using longitudinal CDR® plus NACC FTLD.MethodWe longitudinally assessed the CDR® plus NACC FTLD among 292 asymptomatic participants of the ALLFTD Consortium who are family members of f‐FTLD caused by MAPT (n = 99), GRN (n = 67), or C9orf72 (n = 126) mutations, and described the detailed profiles of the CDR® plus NACC FTLD in the participants who developed Mild Behavioral and/or Cognitive Impairment (MBCI).ResultForty‐one participants (17 MAPT, 11 GRN, 13 C9orf72) developed MBCI during follow‐up visits . Age at the diagnosis of MBCI was 52.3±13.0 years (GRN 63.2±11.8, MAPT 43.5±8.6, C9orf72 54.7±10.7). Frequencies of abnormal rating on the eight CDR® plus NACC FTLD domains at the time of MBCI diagnosis were: “Memory” 44% (MAPT 47%, GRN 55%, C9orf72 31%); “Orientation” 7% (MAPT 6%, GRN 9%, C9orf72 8%); “Judgment and Problem Solving” 39% (MAPT 41%, GRN 55%, C9orf72 23%); “Community Affairs” 22% (MAPT 24%, GRN 18%, C9orf72 23%); “Home and Hobbies” 22% (MAPT 35%, GRN 0%, C9orf72 23%); “Personal Care” 0%; “Behavior/Comportment/Personality” 51% (MAPT 59%, GRN 55%, C9orf72 38%); “Language” 29% (MAPT 18%, GRN 55%, C9orf72 23%).ConclusionInitial symptoms and clinical picture of f‐FTLD in MBCI stage differ among responsible FTLD genes, which could be useful in detecting very early features of f‐FTLD in pathogenic mutation carriers.

Genetic and glial heterogeneity in Alzheimer disease

AbstractBackgroundAlzheimer disease (AD) has substantial genetic, molecular, and cellular heterogeneity associated with its etiology. However, much of the downstream cell‐type‐specific transcriptional and functional ramifications of familial mutations and high‐risk variants for AD are still poorly understood.MethodsWe generated unsorted single‐nuclei transcriptomic profiles (snRNA‐seq) of parietal lobes from 67 donors from the Knight ADRC and DIAN cohorts [1] to investigate altered molecular pathways in healthy and AD individuals, including carriers of pathogenic mutations in APP and PSEN1 and risk variants in TREM2. We validated our findings using snRNA‐seq from the DLPFC from the ROS‐MAP cohort [2]. We analyzed ∼294K high‐quality nuclei and identified six major cell populations. We performed deep subclustering analysis for the distinct cell types to reveal and characterize transcriptional states associated with AD genetic variants.ResultsCarriers of TREM2 AD risk variants p.R47H, p.R62H, and p.H157Y showed significantly increased proportions of nuclei in a reduced activation state (p = 3·29×10−2), consistent with in vitro experiments showing reduced microglial activation associated with these variants. [2, 3] (Figure). This state was replicated in the ROSMAP cohort (p = 7·4×10−107), and TREM2 p.R62H carriers showed a higher proportion of nuclei (p = 2·26×10−2). TREM2 risk variant carriers also showed an increased proportion of oligodendrocytes (Figure) exhibiting upregulation of 1,124 genes including TFEB (Knight ADRC p = 4·66×10−2; ROSMAP p = 2·48×10−2). Altered TFEB expression may be driven by the interaction of TREM2 with mTOR[4, 5]. TFEB is a central regulator of lysosomal biogenesis[6, 7] and represses myelination at different developmental stages.[8] Altered TFEB signaling has been implicated in several neurodegenerative diseases.[6, 9]ConclusionsAD pathogenic and risk variants are sufficient to alter human brains' transcriptional and cellular landscape. While TREM2 is mainly expressed in microglia, and its loss of function mutations cause Nasu‐Hakola disease, which is characterized by loss of myelination, suggesting TREM2‐linked oligodendrocyte‐microglia crosstalk.[10] Here, we found that AD patients with TREM2 variants showed upregulation of TFEB and lysosomal pathways in a subset of oligodendrocytes likely driven by altered microglia transcriptional states. The integration of genetic and single‐cell molecular data facilitates our understanding of the heterogeneity of pathways, biological processes, and cell types affected in AD.

Natural History of Patients with Typical and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract Background Recently, a novel genetic-based classification for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) has been proposed to distinguish “typical” (RYR2 and CASQ2 genes) and “atypical” (TRDN, TECRL, CALM1–3, RYR2 loss-of-function [RYR2-LoF]) CPVT variants. Although some genetic forms were reported as malignant forms of CPVT, natural history data comparing typical and atypical CPVT variants are lacking. Purpose We compared the natural history of “typical” and “atypical” forms of CPVT in a large cohort of patients with genetically confirmed CPVT. Methods CPVT was diagnosed according to the criteria defined in the 2015 European Society of Cardiology Guidelines. Based on the genetic background, we classified the patients in two groups: 1) “Typical” CPVT (i.e., carriers of pathogenic or likely pathogenic mutations in RYR2 and CASQ2 genes); 2) “Atypical” CPVT (i.e., carriers of pathogenic or likely pathogenic mutations in TRDN, TECRL, CALM1–3 and RYR2-LoF). Patients with mutations in the CALM1, CALM2 or CALM3 were not identified in our cohort. The outcome was the occurrence of a life-threatening arrhythmic event (LAE), defined as: sudden cardiac death, aborted cardiac arrest or hemodynamically non-tolerated ventricular tachycardia. The Kaplan-Meier life-table method was used to determine the cumulative probability of experiencing a first LAE before the age of 40 years and in the absence of treatment. Outcomes in two groups were compared using the log-rank test. Results The study cohort included 238 patients (56% females, median age at diagnosis 14 years [IQR: 9–28 years]), of whom 226/238 (95%) patients with “typical” CPVT (216 RYR2, 10 CASQ2), and 12/238 (5%) patients with “atypical” CPVT (5 RYR2-LoF, 4 TRDN, 3 TECRL). In the entire population, the cumulative probability of experiencing a first LAE between birth and the diagnosis of CPVT was 2.3%, 21.2 and 40.8% at 5, 20, and 40 years, respectively. At any given age, the probability of a first LAE in the absence of therapy was significantly higher in patients with atypical CPVT (25%, 36%, and 100% at 5, 20, and 40 years, respectively), as compared to patients with typical CPVT (1%, 20%, and 39% at 5, 20, and 40 years, respectively; p=0.003, Figure 1). Patients with atypical CPVT suffered LAEs in early childhood (i.e., by the age of 5 years) significantly more often than patients with typical CPVT (3/5 patients [60%] in atypical CPVT vs. 2/43 patients [5%] in typical CPVT, p&amp;lt;0.001; Figure 2). Conclusions The natural history of CPVT is modulated by the genetic cause. Atypical CPVT variants are rare but are characterized by a worse outcome and a greater likelihood of experiencing an LAE since the early childhood, as compared to typical CPVT. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ricerca Corrente funding scheme of the Italian Ministry of Health

Promise or peril: the ECG in HCM

Abstract Introduction Hypertrophic cardiomyopathy is a complex disease of the myocardium characterised by left ventricular hypertrophy &amp;gt;15mm in any one segment, in the absence of loading conditions. The phenotypic variability and inhomogeneous nature of the condition have resulted in difficulties with diagnosis. Despite the significant progression in cardiac imaging and genetics, the electrocardiogram (ECG) remains the cornerstone of initial evaluation of patients with HCM and in the screening of families. Moreover, the ECG is in widespread use for pre-participation sports screening. Purpose Original and contemporary studies indicate that the ECG is normal in only 6–10% of patients with echocardiographic evidence of HCM. We hypothesised that the ECG may be normal in a significant proportion of HCM patients. This study sought to reassess the ECG as a screening tool in a HCM cohort. Methods 112 patients were selected randomly from the database of a specialist cardiomyopathy clinic. Their most recent ECG, clinical and imaging data were reviewed. All patients had echocardiographic HCM and were carriers of pathogenic sarcomere gene mutations. Patients with phenocopies were excluded. ECG data for 100 age and sex-matched controls was also analysed. ECG interpretation was performed using international criteria. Results 18% of patients with a clinical diagnosis of HCM by conventional diagnostic standards (LV wall thickness &amp;gt;15mm) had a normal ECG. A further 7% had a normal ECG with a mild HCM phenotype (LV wall thickness of 13–14mm). The most common abnormality observed was T wave inversion (TWI) in 28%. An additional unexpected finding in the HCM group was isolated TWI in lead aVL. This occurred in 27% of patients in the absence of any other repolarisation abnormalities, compared with 1% of controls. The significance of this finding is unclear. 27% of HCM patients displayed voltage criteria for left ventricular hypertrophy by either Cornell or Sokolow-Lyon criteria, with just 4% meeting criteria for both. 13% of HCM patients had corrected QT prolongation, in the absence of medications responsible for this. Conclusion The ECG continues to play a pivotal role in HCM diagnosis but its sensitivity to detect disease has been over-estimated. Up to a quarter of patients with HCM have a normal ECG. This is significantly higher than previously reported. The ECG in isolation therefore is not a reliable tool for screening for HCM in the general population and especially unreliable in at-risk subjects. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Mater Foundation

S3703 A Case of Hereditary Diffuse Gastric Cancer

Introduction: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant disorder associated with pathogenic germline variants in the cadherin 1 (CDH1) or alpha-1 catenin (CTNNA1) genes. Carriers have an 80% risk of developing stomach cancer, at an average age of 38, and 60% lifetime risk of developing lobular breast cancer. This is a case of a middle-aged female diagnosed with CDH1+ HDGC. Case Description/Methods: An asymptomatic 50-year-old Bangladeshi female presented for surveillance colonoscopy given a strong family history of colon cancer in three siblings, mother and uncle and stomach cancer in her mother. She had a normal upper endoscopy three years earlier for indication of heartburn. She proceeded with colonoscopy which showed two tubular adenomas measuring 7-8 mm. Due to concern of a hereditary syndrome, she was referred to a genetics counselor and an Ambry Colonext Panel with RNA Analysis was conducted. Results were positive for pathogenic heterozygous c.1137G >A mutation in the CDH1 gene raising concern for HDGC. At the time, she opted for surveillance instead of prophylactic gastrectomy. A follow up upper endoscopy showed a few, minute pale regions on close inspection, but no masses, ulcerations or other features suggestive of malignancy. Per Cambridge protocol, 34 biopsies were collected and one gastric body biopsy returned positive for gastric adenocarcinoma with signet ring cell features and weak E-Cadherin expression. Cross sectional imaging was negative for metastatic disease. She met with oncology and surgery teams and underwent laparotomy with total gastrectomy and Roux-en-Y esophagojejunostomy. Gastrectomy biopsy confirmed a single microscopic focus of diffuse adenocarcinoma. Discussion: Diagnosis of HDGC-associated signet ring cancers is especially difficult because they are only visible on direct mucosal evaluation late in the disease process. Genetic testing is recommended for those meeting family or individual criteria. Prophylactic gastrectomy, as early as age 20, is recommended for pathogenic mutation carriers with an appropriate pedigree. Those denying surgery can be offered annual endoscopy with the understanding that frequent surveillance has not been proven to be effective in early gastric cancer detection in HDGC. During endoscopy, any visible lesion should be biopsied and a minimum of 30 biopsies are recommended to include all five anatomic gastric zones. H. pylori should be screened for and treated. Referral to a breast surgeon is also recommended.

Local treatment in patients with hereditary breast cancer: decision-making process in low-, moderate-, high-penetrance pathogenic germline mutation carriers.

We summarize recent evidence regarding commonly tested breast cancer susceptibility genes and review indications derived from recently published guidelines regarding management of carriers affected by early breast cancer (BC). Management of affected women with a known genetic predisposition to BC was matter of debate at the most relevant international conferences, such as St. Gallen International Consensus Conference and San Antonio Breast Cancer Symposium held both in 2021. At the same time, a joint Experts Panel from American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Surgical Oncology (ASCO/ASTRO/SSO) convened to develop recommendations to support clinical decision-making in this specific setting and results about administration of new systemic therapies such as poly adenosine diphosphate-ribose polymerase (PARP) inhibitors became available. Population of patients affected by BC and carriers of mutations in susceptibility genes is progressively increasing, but new mutations identified do not always have a clear clinical impact.To date, we have data to support consideration of different local management choices for affected patients carrying specific mutations, but some issues especially relating to breast-conserving surgery or administration of radiotherapy in these patients, still need to be better addressed. Opinions about the best way to treat these patients are still heterogeneous and information deriving from different sources seems to be conflicting at times. Our purpose is to offer a synopsis of the different evidence available that may be helpful in clinical decision making.

Clinical relevance and translational impact of reduced penetrance in genetic movement disorders.

Reduced penetrance is an important but underreported aspect in monogenic diseases. It refers to the phenomenon that carriers of pathogenic variants do not manifest with an overt disease. Clinical expressivity, on the other hand, describes the degree to which certain disease characteristics are present. In this article, we discuss the implications of reduced penetrance on genetic testing and counseling, outline how penetrance can be estimated in rare diseases using large cohorts and review the ethical, legal and social implications of studying non-manifesting carriers of pathogenic mutations. We highlight the interplay between reduced penetrance and the prodromal phase of a neurodegenerative disorder through the example of monogenic Parkinson's disease and discuss the therapeutic implications.

Comparative analysis of right ventricular strain in Fabry cardiomyopathy and sarcomeric hypertrophic cardiomyopathy.

To perform a comparative analysis of right ventricle (RV) myocardial mechanics, assessed by 2D speckle-tracking echocardiography (2D-STE), between patients with Fabry disease and patients with sarcomeric disease. Patients with Fabry cardiomyopathy (FC) (n = 28) were compared with patients with sarcomeric hypertrophic cardiomyopathy (HCM), matched for degree of left ventricle hypertrophy (LVH) and demographic characteristics (n = 112). In addition, patients with Fabry disease and no LVH [phenotype-negative carriers of pathogenic α-galactosidase gene mutations (GLA LVH-)] (n = 28) were compared with age and sex-matched carriers of sarcomeric gene mutations without LVH [Phenotype-negative carriers of pathogenic sarcomeric gene mutations (Sarc LVH-)] (n = 56). Standard echocardiography and 2D-STE were performed in all participants. Despite a subtle impairment of RV global longitudinal strain (RV-GLS) was common in both groups, patients with FC showed a more prominent reduction of RV free wall longitudinal strain (RV-FWS) and lower values of difference between RV-FWS and RV-GLS (ΔRV strain), in comparison to individuals with HCM (P < 0.001 and P = 0.002, respectively). RV-FWS and ΔRV strain demonstrated an independent and additive value in discriminating FC from HCM, over the presence of symmetric LVH, systolic anterior motion of the mitral valve and RV hypertrophy. Similar results were found in GLA LVH- patients: they had worse RV-FWS and lower values of ΔRV strain as compared to Sarc LVH- patients (both P < 0.001). Patients with FC show a specific pattern of RV myocardial mechanics, characterized by a larger impairment of RV-FWS and lower ΔRV strain in comparison to patients with HCM, which may be helpful in the differential diagnosis between these two diseases.

Jinekolojik Onkoloji Pratiğimizde Risk Azaltıcı Cerrahi Yönetimi Gerektiren Genetik Değişiklikler

Kanser, fonksiyonu hücre büyümesi ve DNA’nın bütünlüğünü koruma olan genlerdeki mutasyonlar sonucu gelişir. Mutasyonlar, germ hücrelerinde(germline)(GLM) ve diğer hücrelerde (somatik)(SM) olabilir. Kanserlerin %5-10’undan germline mutasyonlar sorumludur. Erken dönemde GLM’ların tespit edilmesi; risk altındaki bireylerin belirlenmesi, takibinin yapılması ve risk azaltıcı koruyucu stratejilerin geliştirilmesi açısından önemlidir. Ayrıca son zamanlarda tümör dokusunda SM’ların tespiti, hedefe yönelik ve adjuvan tedaviyi düzenlemede rehber olmaktadır. Over ve meme kanserlerinin yaklaşık %10-30’u ailesel kümelenme göstermekle birlikte vakaların sadece %5-10’u kalıtsaldır. Özellikle, kalıtsal over kanserlerinin yaklaşık %65-85’ini DNA onarım kusurlarına neden olan BRCA1/2 genlerinde GLM’lar sonucu oluşmaktadır. BRCA1/2 genlerinde patojenik mutasyonu olan bireyler için risk azaltıcı mastektomi (RRM) meme kanseri riskini %90-95 oranında azaltırken, salpingo-ooferektomi (RRSO) ile meme ( %50), over ve fallop tüpü kanseri insidansı da ( %70-96) azalmaktadır. Ayrıca RRSO, kansere özgü genel mortaliteyi azaltmakla ve over kanserini önlemede en etkili seçenek olarak kabul edilmektedir. BRCA1/2 dışında homolog rekombinasyon yolu DNA tamirinde rol oynayan RAD51C, RAD51D ve BRIP1 genlerdeki patojenik mutasyonlar over kanserinde rol oynamaktadır. RAD51C, RAD51D ve BRIP1, genlerinin patojenik mutasyon taşıyıcılarında rehberler, RRSO’i önermektedir. Lynch sendromu (LS), kolorektal ve endometriyal kanser gelişme riskinde artış ile karakterize otozomal dominant bir hastalıktır. LS’da endometrium ve over kanseri risk artışı en fazla olan MLH1, MSH2 ve MSH6 genlerinde patojenik mutasyon taşıyıcılarında fertilitesini tamamladıktan sonra risk azaltıcı cerrahi olarak histerektomi ve RRSO önerilmektedir. Bu derlemede amacımız, jinekolojik onkoloji pratiğimizde son zamanlarda kullanımı gittikçe artan risk azaltıcı profilaktik cerrahi uygulamaları gerektiren genetik hastalıkları son rehberler eşliğinde özetlemektir.

Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS): 14-year update

BackgroundTransthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs.MethodsEstablished in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021).ResultsThis analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation [SD]) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation.ConclusionsThis 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease.ClinicalTrials.gov Identifier: NCT00628745.