Presymptomatic Testing Research Articles

AFFECT-HCM: quality of life and costs in hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, characterised by increased wall thickness. Pathogenic DNA variants in sarcomeric genes are identified in about half of HCM patients, enabling pre-symptomatic testing in family members. Since the first description of HCM tremendous progress has been made in the evaluation and management of HCM patients. However, little is known on the impact of HCM on quality of life (QoL) and costs. Purpose The AFFECT-HCM study evaluates the QoL, healthcare and societal costs in HCM patients and genotype-positive phenotype-negative (G+/P-) subjects. Methods The AFFECT-HCM is a multi-centre prospective study including genotyped HCM patients aged 18-80 years and G+/P- subjects. The study cohort is divided into three groups based on phenotype: G+/P- (wall thickness <13 mm), non-obstructive HCM (nHCM, maximal left ventricular outflow tract (LVOT) gradient <30 mmHg) and obstructive HCM (oHCM, LVOT gradient ≥30 mmHg). For QoL, the generic five-domain five-level EQ-5D-5L with the attached visual analogue scale and disease-specific Kansas City Cardiomyopathy Questionnaire are used. Healthcare and societal costs are measured via a bottom-up approach using the cost questionnaires iMCQ and iPCQ and expressed with means (the standard in healthcare cost reporting despite non-normality) in 2023 Euro per patient per year (€ PPPY). QoL and costs are compared between phenotypes. Results Results are summarised in the table. Between November 2022 - December 2023, 506 subjects (mean age 55 years, 39% female) were included in three Dutch hospitals. The study included 84 G+/P-, 307 nHCM and 115 oHCM subjects. Questionnaire response rate was 92%. Compared to G+/P- subjects; HCM patients were older (57 vs 46 yrs), more often male (67% vs 32%) and had more cardiovascular risk factors. Compared to nHCM patients, oHCM patients were more often symptomatic (58% vs 34%), more often in NYHA class III (19% vs 2%) and used more HCM-related medications (79% vs 64%). HCM patients, and particularly oHCM patients, reported decreased QoL with lower QoL-related questionnaire scores (Figure). The utilities (EQ-5D-5L) of HCM patients were lower than G+/P- subjects and the Dutch overall average (0.87±0.17), and for oHCM comparable with another study (0.82±0.18). Costs were higher for HCM patients than G+/P- subjects (€14374 vs €5888 PPPY) and higher in oHCM patients compared to nHCM patients (€19672 vs €12419 PPPY). The leading between-group difference is higher productivity losses in oHCM patients. Conclusion HCM is associated with reduced QoL and increased costs, especially in oHCM patients. The primary cost driver are healthcare costs, but the difference between oHCM and nHCM patients is mainly caused by indirect costs due to productivity losses. These data provide novel insights in the BoD of HCM and can aid in assessing cost-effectiveness analyses of new therapies for HCM in the future.Baseline characteristics and resultsQuality of life-related questionnaires

Predicting age of onset and progression of disease in late-onset genetic neurodegenerative diseases: An ethics review and research agenda.

Currently, a prognostic biomarker-based model is being developed to predict the onset and disease progression of Huntington's Disease (HD) and Spinocerebellar Ataxia (SCA) types 1 and 3, both late-onset genetic neurodegenerative diseases lacking a disease-modifying treatment (DMT). The need for more accurate predictions of onset and disease progression arises in the context of clinical trials evaluating the effectiveness of potential DMTs and identifying the optimal time to initiate such a DMT. Moreover, such a prognostic model may provide mutation carriers with personal utility. The aim of this article is to anticipate the ethical issues raised by these new prognostic models and to formulate the ethical issues that need to be addressed to facilitate an ethically responsible development and implementation of such a model. Part one of this article describes the ethical issues raised by presymptomatic genetic testing for HD and evaluates whether and how these issues may also occur by predicting onset and disease progression. Part two presents the results of a critical interpretative review into the ethical issues raised by biomarker testing in other late-onset neurodegenerative diseases lacking a DMT. The review aims to identify new ethical issues related to biomarker testing for predicting the onset and disease progression of HD and SCA. Finally, based on parts one and two, part three proposes a research agenda for the near future regarding the most pressing ethical issues that need to be addressed to ensure an ethically responsible implementation of such a prognostic model in both research settings and clinical practice.

“Living with a question mark”: psychosocial experience of Portuguese young adults at risk for hereditary amyloid transthyretin amyloidosis with polyneuropathy

This study is the first to explore the psychosocial experience of young Portuguese adults at genetic risk for hereditary amyloid transthyretin amyloidosis with polyneuropathy (hATTR-PN). The work focuses on the developmental peculiarities of their experience with the disease. Sixteen semi-structured interviews were conducted with young adults coming for pre-symptomatic testing (PST) at a single genetics outpatient center in Portugal. The data were analyzed qualitatively. The main findings suggest that four themes mark the psychosocial experience of the young adults interviewed. The first refers to the development of psychological representations, namely beliefs, mental representations, and social perceptions about hATTR-PN. The second regards the experienced and anticipated psychosocial impacts, namely, suffering, anxiety, and relief related to the disease. The third is related to using strategies such as performing PST, strategies focused on emotional regulation and the meaning of hATTR-PN, and social strategies to deal with these impacts over time. Finally, the fourth aspect concerns the perceived and expected support for the participants’ needs provided by social contexts, that is, family and genetic counseling. In a period of life also marked by qualitatively different characteristics and developmental tasks from other life cycle stages (e.g., identity explorations, instability, and independent decision-making), experience with the disease can add psychosocial challenges to young adults at risk for hATTR-PN. Genetic counseling practices and health policies can be optimized to respond to the psychosocial needs of young adults. Future research should deepen the understanding of the psychosocial experience of individuals and families with late-onset hATTR-PN to improve the clinical response in this population.

Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis.

Amyloid neuropathy is caused by deposition of insoluble β-pleated amyloid sheets in the peripheral nervous system. It is most common in: (1) light-chain amyloidosis, a clonal non-proliferative plasma cell disorder in which fragments of immunoglobulin, light or heavy chain, deposit in tissues, and (2) hereditary transthyretin (ATTRv) amyloidosis, a disorder caused by autosomal dominant mutations in the TTR gene resulting in mutated protein that has a higher tendency to misfold. Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia, leading to atrophy of Schwann cells in proximity to amyloid fibrils and blood-nerve barrier disruption. Clinically, amyloid neuropathy is manifested as a length-dependent sensory predominant neuropathy associated with generalized autonomic failure. Small unmyelinated nerves are involved early and prominently in early-onset Val30Met ATTRv, whereas other ATTRv and light-chain amyloidosis often present with large- and small-fiber involvement. Nerve conduction studies, quantitative sudomotor axon testing, and intraepidermal nerve fiber density are useful tools to evaluate denervation. Amyloid deposition can be demonstrated by tissue biopsy of the affected organ or surrogate site, as well as bone-avid radiotracer cardiac imaging. Treatment of light-chain amyloidosis has been revolutionized by monoclonal antibodies and stem cell transplantation with improved 5-year survival up to 77%. Novel gene therapy and transthyretin stabilizers have revolutionized treatment of ATTRv, improving the course of neuropathy (less change in the modified Neuropathy Impairment Score + 7 from baseline) and quality of life. With great progress in amyloidosis therapies, early diagnosis and presymptomatic testing for ATTRv family members has become paramount. ANN NEUROL 2024;96:423-440.

Presymptomatic Testing for Huntington's Disease in Mexico: 28 Years of Experience

IntroductionHuntington's disease (HD) is a genetic neurodegenerative disorder with dominant inheritance. Our center in Mexico City has offered presymptomatic testing (PT) since 1995. ObjectiveTo describe the main clinical and demographic characteristics of at-risk HD individuals who applied to the PT program, the reasons for seeking it, and the molecular results. MethodsA cross-sectional study was conducted with sociodemographic and clinical data of all PT applicants from 1995–2023. Reasons for seeking PT were assessed using a modified questionnaire. In addition, anxiety, and depressive symptoms before and after PT were evaluated with Beck's instruments; cognitive impairment (CI) was assessed with the Mini-Mental State Examination (MMSE) and molecular results. Results214 people applied for PT (2.1% of the at-risk population identified in our center); 63% were women (mean age of 37.11 years). 204 (95.3%) were accepted and 190 received results. 70% indicated that the main reason for applying for PT was to inform their offspring about the risk of inheriting HD. Significant differences were observed in the reasons for seeking PT by age group. Although some subjects received treatment, Beck's instrument scores did not indicate special attention or pharmacological treatment. The MMSE showed probable CI in 20 subjects. Of those who received results, 37% were carriers of a full penetrance allele. ConclusionOur center has the only formal PT program for HD in Mexico. The reasons for seeking PT are varied and age-related. Although PT is offered to all subjects at risk for HD, uptake remains low.

Predictors of SARS-CoV-2 transmission in congregate living settings: a multicenter prospective study.

Older adults residing in congregate living settings (CLS) such as nursing homes and independent living facilities remain at increased risk of morbidity and mortality from coronavirus disease 2019. We performed a prospective multicenter study of consecutive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) exposures to identify predictors of transmission in this setting. Consecutive resident SARS-CoV-2 exposures across 17 CLS were prospectively characterized from 1 September 2022 to 1 March 2023, including factors related to environment, source, and exposed resident. Room size, humidity, and ventilation were measured in locations where exposures occurred. Predictors were incorporated in a generalized estimating equation model adjusting for the correlation within CLS. Among 670 consecutive exposures to SARS-CoV-2 across 17 CLS, transmission occurred among 328 (49.0%). Increased risk was associated with nursing homes (odds ratio (OR) = 90.8; 95% CI, 7.8-1047.4), Jack and Jill rooms (OR = 2.2; 95% CI, 1.3-3.6), from source who was pre-symptomatic (OR = 11.2; 95% CI, 4.1-30.9), symptomatic (OR = 6.5; 95% CI, 1.4-29.9), or rapid antigen test positive (OR = 35.6; 95% CI, 5.6-225.6), and in the presence of secondary exposure (OR = 6.3; 95% CI, 1.6-24.0). Exposure in dining room was associated with reduced risk (OR = 0.02; 95% CI, 0.005-0.08) as was medium room size (OR = 0.3; 95% CI, 0.2-0.6). Recent vaccination of exposed resident (OR = 0.5; 95% CI, 0.3-1.0) and increased ventilation of room (OR = 0.9; 95% CI, 0.8-1.0) were marginally associated with reduced risk. Prospective assessment of SARS-CoV-2 exposures in CLS suggests that source characteristics and location of exposure are most predictive of resident transmission. These findings can inform risk assessment and further opportunities to prevent transmission in CLS.

Human Genetics Society of Australasia Position Statement: Predictive and Presymptomatic Genetic Testing in Adults and Children.

This Position Statement provides guidelines for health professionals who work with individuals and families seeking predictive genetic testing and laboratory staff conducting the tests. It presents the major practical, psychosocial and ethical considerations associated with presymptomatic and predictive genetic testing in adults who have the capacity to make a decision, children and young people who lack capacity, and adults living with reduced or fluctuating cognitive capacity.Predictive Testing Recommendations: (1) Predictive testing in adults, young people and children should only be offered with pretest genetic counseling, and the option of post-test genetic counseling. (2) An individual considering whether to have a predictive test should be supported to make an autonomous and informed decision. Regarding Children and Young People: (1) Predictive testing should only be offered to children and young people for conditions where there is likely to be a direct medical benefit to them through surveillance, use of prevention strategies, or other medical interventions in the immediate future. (2) Where symptoms are likely to develop in childhood, in the absence of direct medical benefit from this knowledge, genetic health professionals and parents/guardians should discuss whether undertaking predictive testing is the best course of action for the child and the family as a whole. (3) Where symptoms are likely to develop in adulthood, the default position should be to postpone predictive testing until the young person achieves the capacity to make an autonomous and informed decision. This is applicable regardless of whether there is some action that can be taken in adulthood.

Cascade screening in HBOC and Lynch syndrome: guidelines and procedures in a UK centre

In the 33 years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of healthcare Evidence and these have impacted on the thresholds for testing BRCA1/2 in Hereditary Breast Ovarian Cancer (HBOC) and in determining that all cases of colorectal and endometrial cancer should undergo screening for Lynch syndrome. Gaps for testing other CPGs relevant to HBOC have been filled by the UK Cancer Genetics Group and CanGene-CanVar project (web ref. https://www.cangene-canvaruk.org/). We present time trends (1990–2020) of identification of index cases with germline CPG variants and numbers of subsequent cascade tests, for BRCA1, BRCA2, and the Lynch genes (MLH1, MSH2, MSH6 and PMS2). For BRCA1/2 there was a definite increase in the proportion of index cases with ovarian cancer only and pre-symptomatic index tests both doubling from 16 to 32% and 3.2 to > 8% respectively. A mean of 1.73–1.74 additional family tests were generated for each BRCA1/2 index case within 2 years. Overall close to one positive cascade test was generated per index case resulting in > 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 (p < 0.0001).

Clinically-relevant Germline Variants in Children with Non-Medullary Thyroid Cancer.

The underlying genetic cause of non-medullary thyroid cancer (NMTC) in children is often unknown, hampering both predictive testing of family members and preventive clinical management. Our objectives were to investigated the potential heritability in the largest childhood NMTC cohort that has been genotyped to date. Nationwide retrospective cohort study. Tertiary referral centers. In total, 97 patients diagnosed with pediatric NMTC between 1970-2020 were included in this study. Germline whole genome sequencing (WGS). The main outcome measures were mutation detection yield in 1) clinically-relevant tumor predisposition genes, and 2) genes previously associated with NMTC. In total, 13 of 97 patients (13%) carried a germline (likely) pathogenic (P/LP) variant in a well-known tumor predisposition gene: APC (n=1), BRCA2 (n=2), CHEK2 (n=4), DICER1 (n=4), HOXB13 (n=1), , and MITF (n=1). In addition, one patient was diagnosed with Pendred syndrome (SLC26A4) and nine variants of high interest were found in other NMTC candidate susceptibility genes. The reported prevalence (13%) of germline variants in well-known tumor predisposing genes and the added value of a revised personal-/family history and histology led us to recommend genetic counseling for all childhood NMTC patients.The detected tumor predisposition syndromes are associated with a risk for second cancers which necessitates additional surveillance of the index patients and pre-symptomatic genetic testing of at risk family members.

Symptom Screenings and Surveillance Testing for COVID-19 in University Athletes

The Coronavirus disease (COVID-19) pandemic presented prevention, screening, and mitigation challenges for public and primary healthcare, including university athletics. During 2020-21, student-athletes at a medium-sized university were required to undergo a COVID-19 screening program [symptom screening/surveillance testing] as a condition of athletic participation.To determine the effectiveness of the screening program in identifying athletes in this population with a COVID-19 diagnosi, prior to every athletic encounter, all 334 student-athlete participants reported any COVID-19 symptoms to the athletic training staff, body temperature was measured, and participants from three teams were randomly selected for an additional anosmia screening. All participants were subject to COVID-19 surveillance testing. For each participant, results of each element of the screening and testing processes were recorded in their electronic medical record and cross-referenced with any positive COVID-19 medical diagnosis. From 2025 surveillance tests conducted, only 32 participants tested positive. Of those, 25 (78%) experienced and reported COVID-19 symptoms to the athletic trainer immediately before testing. Onlyseven (.035%) were captured as pre-symptomatic positive tests. One hundred ten athletes who experienced symptoms, however, did not participate in an athletic encounter that day but instead self-admitted to the university health center for testing. All 110 tested positive at the health center. Experiencing and reporting COVID-19 symptoms appeared effective, and COVID-19 surveillance testing appeared ineffective, as detection measures in this study. Due to the extensive and costly resources needed, the decision to continue to implement these processes in the future will be difficult.

Human Genetics of Cardiomyopathies.

The identification of a disease-causing variant in a patient diagnosed with cardiomyopathy allows for presymptomatic testing in at risk relatives. Carriers of a pathogenic variant can subsequently be screened at intervals by a cardiologist to assess the risk for potentially life-threatening arrhythmias which can be life-saving. In addition, gene-specific recommendations for risk stratification and disease specific pharmacological options for therapy are beginning to emerge. The large variability in disease penetrance, symptoms, and prognosis, and in some families even in cardiomyopathy subtype, makes genetic counseling both of great importance and complicated.

The value of pre-symptomatic genetic risk assessment for age-related macular degeneration: the Moran AMD Genetic Testing Assessment (MAGENTA) study—a study protocol for a randomized controlled trial

BackgroundAge-related macular degeneration (AMD) is an irreversible blinding eye condition with complex genetic and environmental etiologies. Genetic testing for AMD for previously identified multiple-risk single nucleotide polymorphisms can help determine an individual’s future susceptibility. However, such testing has been discouraged until evidence shows that providing such information to symptomatic or pre-symptomatic individuals will alter their disease course. Therefore, we designed this study to investigate whether knowledge of AMD risk could stimulate the adoption of a healthier lifestyle that could lower the incidence of AMD later in life. We hypothesize that pre-symptomatic individuals informed of a high genetic risk of AMD are more likely to make quantifiable, positive lifestyle changes relative to participants informed of lower genetic risk or randomized to deferred disclosure of genetic testing results.MethodsThe Moran AMD Genetic Testing Assessment (MAGENTA) study is a phase 2, single-center, prospective, double-masked, randomized controlled trial conducted at the John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. Participants are randomized by a 3:1 allocation ratio to immediate and deferred disclosure groups and followed for 12 months. Skin, ocular, and serum carotenoid status, as well as nutritional and social surveys, are assessed at study visits. Skin carotenoid assessment is by resonance Raman spectroscopy and reflectance spectroscopy, ocular carotenoids are measured with Heidelberg Spectralis autofluorescence imaging and fluorescence lifetime imaging ophthalmoscopy (FLIO), and serum carotenoids are quantified using high-performance liquid chromatography. The primary outcome evaluates changes in skin carotenoid status in response to genetic risk disclosure. The secondary outcomes examine changes in ocular and serum carotenoid status in response to genetic risk disclosure. Also, we will correlate AMD genetic risk with baseline ocular and systemic carotenoid status and FLIO.DiscussionMAGENTA will provide much-needed evidence on whether pre-symptomatic testing for AMD risk can lead to quantifiable long-term changes in behavior and lifestyle associated with a lower incidence of AMD later in life. Findings from the MAGENTA trial will facilitate the design of a future larger, longer-term, multicenter phase 3 trial that could feature subgroup analysis, expanded measures of lifestyle modification, and potential active nutritional interventions.Trial registrationClinicalTrials.gov NCT05265624. Registered on March 3, 2022.

Measuring attitudes, motivations and barriers to presymptomatic dementia testing

AbstractBackgroundThe increasing biomarkers testing and new methods of presymptomatic screening for dementia have risen questions like: Should people get tested? Would they want to know whether they will get this fatal, untreatable disease? This has picked the demand for a well‐structured counseling program for dementia screening. In this direction, it is important to meet the needs of the target group; however, not much is known about people with a family history of dementia attitudes about testing, the motivations and barriers, and the expectations relevant to future counseling programs about testing for dementiaMethodThis study was comprised of a validation study of a new psychometric tool and a cross‐sectional survey to assess the attitudes, buries and motivations to dementia testing. The content of the questionnaire was based on (1) a literature review, (2) the Perceptions Regarding Investigational Screening for Memory in Primary Care (PRISM‐PC) Questionnaire (M. Boustani et al., 2008), (3) a board of Clinical expert opinions. Two hundred eight (208) people enrolled in this cross sectional study. Participants came from Greece, ages ranged from 18‐70 (M = 35.5, SD = 5.7). and the majority of the sample was female (93.3%). Psychometric properties were assessed through construct validity (principal component analysis) and internal consistency (Cronbach’s alpha).ResultExploratory factor analyses revealed the presence of four factors. The first factor labelled as “Perceived harms of testing”, the second “Acceptance of testing”, the third “Perceived benefits of testing”) and the fourth factor “Need of knowledge”. The reliability of each factor separately was satisfactory to very satisfactory (.70‐.87). Cronbach’s alpha coefficient for all the final 25 items of the initial questionnaire was good (Cronbach’s α = 0.82), suggesting very satisfactory internal consistency.ConclusionThis is the first study that created a questionnaire for measuring the attitudes of Greek people towards dementia and genetic screening. Capturing data via this questionnaire might help clinicians, policymakers, and health services researchers in dementia understand better peoples’ perspectives related to the pros and cons of dementia screening and develop effective counseling programs and prevention strategies.

Randomized Trial of Telegenetic Counseling for Gene Testing in Huntington’s Disease (P1-11.011)

<h3>Objective:</h3> To determine the feasibility and patient satisfaction of telegenetic counseling for Huntington’s Disease (HD). <h3>Background:</h3> Genetic counseling is necessary for pre-symptomatic or symptomatic HD genetic testing, but the lack of access to counseling due to geography or expense is a critical gap for many patients. The hypothesis of this study was that there would be no difference in patient satisfaction between telegenetic counseling (teleGC) or in-person counseling (in-personGC) for HD testing. <h3>Design/Methods:</h3> This was a prospective, randomized, unblinded study of either teleGC or in-personGC for HD gene testing. Participants had standardized genetic counseling from a certified genetic counselor in the clinic or via HIPPA appropriate telemedicine platform first, then crossed over. A study coordinator interviewed the participant using a telehealth survey after each encounter. <h3>Results:</h3> 19 in-personGC and 15 teleGC participants were included: 68% women, 41±15 yrs, 80% white, 10% Hispanic, and +CAG=45±4.4 (n=15) (P&gt;0.1). All participants were satisfied with their initial counseling experience when asked to rate on a scale of 1–10 (median 10/10, p=0.94). The majority of symptomatic HD participants (5/7) preferred in-person GC. The main advantage of teleGC was reduction in travel time for the in-personGC first (n=16) and teleGC first (n=11) groups. Technical challenges were reported (n=11) and the counseling slide deck was difficult to see (n=4) with teleGC. Visually seeing the genetic counselor improved understanding for both in-personGC (n=10) and teleGC (n=8) participants. Participants felt they were able to pick up on emotional cues (n=33) and were comfortable asking questions (n=34). <h3>Conclusions:</h3> Telegenetic counseling is a feasible option for HD gene testing, if patients are able to overcome technical issues. Having a video visit, rather than a phone call, should be considered when using telegenetic counseling for HD gene testing. In-person counseling may be preferred to increase understanding of the material in some patients, such as motor manifest HD. <b>Disclosure:</b> Dr. Hall has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier - Parkinsonism and Related Disorders. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology. The institution of Dr. Hall has received research support from Parkinson’s Foundation. The institution of Dr. Hall has received research support from CHDI. The institution of Dr. Hall has received research support from Biohaven. The institution of Dr. Hall has received research support from Neurocrine. The institution of Dr. Hall has received research support from Uniqure. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as a Study section with NIH. Dr. Rosenbaum has nothing to disclose. Jacob Hawkins has nothing to disclose. Bichum Ouyang has nothing to disclose. Christa Suzanne Cooper, PA has nothing to disclose. Dr. Patel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott Laboratories. Dr. Patel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie Pharmaceuticals. Dr. Patel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva Pharmaceuticals.

Hereditary diffuse gastric cancer in a Japanese family with CDH1 mutation three case reports

BackgroundGermline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1–3% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan.MethodIn this study we report the clinical courses of three cases with HDGC from a single Japanese family.ResultsThe proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in these relatives revealing abnormal small pale mucosal patches, small ulcerative lesion and no abnormal findings. Moreover, random and targeted biopsies were compatible with pathological diagnosis of HDGC in the three cases, all of which underwent total prophylactic gastrectomy.ConclusionIt is critical for the assessment and management of HDGC patients to be actively offered a multidisciplinary and familial-oriented approach. Notably, genetic screening in suspected individuals and familial members is a determining piece for a higher detection rate and the identification of clinical relevant mutations in both low and high-incidence gastric cancer countries.

Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing: Yield and dilemmas

PurposeExome sequencing (ES) could detect pathogenic variants that are unrelated to the test indication, including findings that may have an impact for patients considering conception/reproduction (reproduction-related findings [RRFs]), deliberately searched secondary findings (SFs), and incidental findings (IFs). We aimed to examine the detection rate of clinically actionable findings and to present counseling dilemmas in 840 parents of probands undergoing clinical trio ES testing. MethodsRRFs/IFs/SFs were actively searched for in the parents as part of ES data analysis. Variants were filtered by frequency, mode of inheritance, ClinVar classification, presence in local pathogenic variant databases, and protein-truncating effect. ResultsIn 14 of 420 families (3.3%), 15 RRFs were detected. Shared parental heterozygous status for autosomal recessive disorders was identified in 23.3% of consanguineous and 1.8% of nonconsanguineous couples. SFs were found in 22 of 840 individuals (2.6%), including 15 variants (7 founder variants) in cancer-predisposing genes and 4 in cardiac disease–related genes. IFs were found in 3 individuals without reported symptoms. Overall, variants of potential medical importance were detected in 9.3% of families. Challenges related to the decision whether to report variants included unreported parental phenotype, presymptomatic testing, variable disease expressivity, potential medical implications for children who are already born, and medicolegal aspects. ConclusionActive search for RRFs, IFs, and SFs yields a high rate of findings, which may contribute to individual medical care in parents of probands undergoing ES. A structured approach to overcome the challenges associated with reporting these findings should be considered before such an active search can be broadly adopted in clinical genomic data analysis.

632 PREVALENCE OF VARIANT GENOTYPE IN PATIENTS WITH SUSPECTED CARDIAC ATTR AMYLOIDOSIS

Abstract Background Emerging therapeutic options and availability of non-invasive diagnostic tools are increasing recognition of cardiac ATTR (transthyretin) amyloidosis worldwide. However, the relative prevalence of hereditary ATTR amyloidosis may be underestimated, particularly in aged males in whom the disease may be assumed to be wild- type and TTR genetic test not performed. TTR gene variants associated with a predominant cardiac phenotype are known to result in worse prognosis. Identification of a pathogenic variant may not only guide treatment strategy but also allow for genetic counselling and cascade testing in at risk relatives. Purpose To identify the prevalence and type of genetic mutations in patients referred to our Centre for suspected cardiac ATTR amyloidosis. Methods We evaluated consecutive patients referred to our Centre from January 2017 to December 2021 for suspected cardiac ATTR amyloidosis based on signs of heart involvement on echocardiogram or magnetic resonance, a Perugini score 2 or 3 bone scintigraphy or a tissue biopsy proving TTR amyloid deposition, no family history, no signs of neurological or other organ involvement. All patients underwent clinical evaluation and laboratory analysis including serum and urine immunofixation, serum free light chains, and TTR genetic testing. As AAPOA-I amyloidosis is reported in Northern Italy we also routinely perform APOA1 genetic test in patients with suspected cardiac amyloidosis. Diagnosis was ultimately established on a tissue biopsy in patients in which a monoclonal component (CM) was identified. Results 481 patients were included, mean age at presentation was 76 years (min-max 50-93), 40 (8%) were women. In all patients with CM (29%), tissue biopsy confirmed TTR amyloid deposition by immunoelectron microscopy or proteomics. 439 patients (91%) did not carry TTR or APOA1 variants, while 42 (9%) had a heterozygous pathogenic mutation. 41 patients have a pathogenic TTR mutation the most frequent being Ile68Leu (n=28; 67%), followed by Tyr78Phe, Val122Ile and Val94Leu (n=3/2/2 respectively). One novel mutation, namely Pro43Thr, was identified. In one patient APOA1 Leu75Pro variant was identified and diagnosis of AApoA-I amyloidosis confirmed by typing on endomyocardial biopsy. No significant differences were found between ATTRwt and ATTRv patients apart from gender distribution. Although age did not differ among the two groups, the prevalence of a variant genotype raises when considering only patients younger than 70 years (14%). 20% of women carry a pathogenic variant, irrespective of age. Interestingly, among women with ATTRwt (n=32), almost one third (31%) was diagnosed with hip dysplasia in childhood, requiring multiple orthopaedic surgeries and prothesis implantation. Conclusions In our cohort, one out of ten patients referred for suspected cardiac ATTR amyloidosis was ultimately diagnosed with ATTRv. Our results emphasize the importance of performing genetic testing irrespective of age at presentation. Diagnosis of ATTRv is relevant for monitoring disease progression, for defining treatment strategy and for offering genetic counselling and presymptomatic test in at risk relatives. Finally, the high prevalence of hip dysplasia among women with ATTRwt deserves further investigation to define whether it may represent a novel, gender-related red flag for this disease.

Reproductive choices and intrafamilial communication in neurogenetic diseases with different self-estimated severities

BackgroundLow uptake of presymptomatic testing and medically assisted reproduction in families impacted by neurogenetic diseases prompted us to investigate how reproductive options are considered and whether there is a relationship...

Functional analysis of RYR1 variants in patients with confirmed susceptibility to malignant hyperthermia

BackgroundA major bottleneck to the introduction of noninvasive presymptomatic diagnostic tests for the pharmacogenetic disorder malignant hyperthermia is the lack of functional data for associated variants. MethodsWe screened 50 genes having a potential role in skeletal muscle calcium homeostasis using the HaloPlex™ (Agilent Technologies, Santa Clara, CA, USA) target enrichment system and next-generation sequencing. Twenty-one patients with a history of a clinical malignant hyperthermia reaction together with a positive in vitro contracture test were included. Eight variants in RYR1 were subsequently introduced into the cDNA for the human ryanodine receptor gene and tested in cultured human embryonic kidney (HEK293) cells for their effect on calcium release from intracellular stores in response to the ryanodine receptor-1 agonist 4-chloro-m-cresol using fura-2 as calcium indicator. Each variant was subjected to in silico curation using the European Malignant Hyperthermia Group scoring matrix and ClinGen RYR1 variant curation expert panel guidelines. ResultsPotentially causative RYR1 variants were identified in 15 patients. Of these, two families carried two RYR1 variants, five variants had been previously reported as ‘pathogenic’, two variants had been previously reported as ‘likely benign’, and eight were of ‘uncertain significance’. Of these eight variants, four showed hypersensitivity to 4-chloro-m-cresol. Three variants were reclassified as either ‘pathogenic’ or ‘likely pathogenic’. Two were classified as ‘benign’, whilst three remained of ‘uncertain significance’. ConclusionsThree (p.Tyr1711Cys, p.Val2280Ile, and p.Arg4737Gln) additional variants can be added to the list of RYR1 disease-associated variants managed by the European Malignant Hyperthermia Group. These can therefore be used diagnostically in the future. Three variants (p.Glu2348Gly, p.Asn2634Lys, and p.Arg3629Trp) that remained classified as of uncertain significance require further family studies or a different functional test to determine clinical relevance in malignant hyperthermia.

A CHANGE OF HEART: A CASE OF CARDIAC AMYLOIDOSIS

A CHANGE OF HEART: A CASE OF CARDIAC AMYLOIDOSIS