1st Degree Relatives Research Articles

Dietary patterns drive loss of fiber-foraging species in the celiac disease patients gut microbiota compared to first-degree relatives

BackgroundCeliac disease is an autoimmune disorder triggered by dietary gluten in genetically predisposed individuals that primarily affects the small intestine. Studies have reported differentially abundant bacterial taxa in the gut microbiota of celiac patients compared with non-celiac controls. However, findings across studies have inconsistencies and no microbial signature of celiac disease has been defined so far.ResultsHere, we showed, by comparing celiac patients with their non-celiac 1st-degree relatives, that bacterial communities of related individuals have similar species occurrence and abundance compared with non-relatives, regardless the disease status. We also found in celiac patients a loss of bacterial species associated with fiber degradation, and host metabolic and immune modulation, as ruminiclostridia, ruminococci, Prevotella, and Akkermansia muciniphila species. We demonstrated that the differential abundance of bacterial species correlates to different dietary patterns observed between the two groups. For instance, Ruminiclostridium siraeum, Ruminococcus bicirculans, and Bacteroides plebeious, recognized as fiber-degraders, appear more abundant in non-celiac 1st-degree relatives, which have a vegetable consumption pattern higher than celiac patients. Pattern of servings per day also suggests a possible link between these species’ abundance and daily calorie intake.ConclusionsOverall, we evidenced that a kinship approach could be valuable in unveiling potential celiac disease microbial traits, as well as the significance of dietary factors in shaping microbial profiles and their influence on disease development and progression. Our results pave the way for designing and adopting novel dietary strategies based on gluten-free fiber-enriched ingredients to improve disease management and patients' quality of life.

Prevalence of CDKN2A, CDK4, POT1, BAP1, MITF, ATM, and TERT Pathogenic Variants in a Single-Center Retrospective Series of Patients With Melanoma and Personal or Family History Suggestive of Genetic Predisposition.

Approximately 20%-45% of familial melanoma (FM) cases are associated with genetic predisposition. This single-center retrospective study aimed to assess the frequency of pathogenic variants (PV) in the main melanoma-predisposing genes in patients with cutaneous melanoma and investigate the clinical predictors of genetic predisposition. Patients included were those diagnosed with cutaneous melanoma at the Dermatology Unit of the University Hospital of Verona, Italy, from 2000 to 2022, presenting at least one of the followings: multiple melanomas (≥ 3); personal/family history of pancreatic cancer (PC) (up to 2nd-degree relatives); ≥ 2 1st-degree relatives with melanoma; ≥ 1 1st-degree relatives with early-onset (<45 years) melanoma and tested for CDKN2A, CDK4, POT1, BAP1, MITF, ATM, and TERT. During the study period, 35 out of 1320 patients (2.7%) underwent genetic testing. Four patients (11.4%) harbored a PV in a melanoma-predisposing gene, three in CDKN2A (8.6%), and one in MITF (2.9%). Variants currently classified as being of unknown clinical significance (VUS) were detected in CDKN2A (N = 1), MITF (N = 1), and ATM (N = 2). Family history of PC and ≥5 melanomas, personal history of ≥50 nevi, and ≥4 melanomas were significantly associated with PV in tested genes (P < 0.05). The prevalence of PV in predisposing genes in FM was lower than previously reported in Italian registries. Possible reasons include deleterious variants in untested intermediate/low-penetrance genes or yet-to-be-discovered high-penetrance genes and environmental risk factors. A family history of PC, a high number of nevi and melanomas predict a monogenic predisposition to melanoma.

Association of type 2 diabetes with family history of diabetes, diabetes biomarkers, mental and physical disorders in a Kenyan setting

This study aimed to determine the degree of family relations and associated socio-demographics characteristics, clinical/physical and mental disorders in type 2 diabetes mellitus in a Kenyan diabetes clinic. This study was part of a large multicentre study whose protocol and results had been published. It took place at the outpatient diabetes clinic at a County Teaching and Referral Hospital in South East Kenya involving 182 participants. We used a socio-demographic questionnaire, the Hamilton Depression (HAM-D) and PHQ-9 rating scales for depression, the MINI International Neuropsychiatric Interview (MINI; V5 or V6) for DSM-5 diagnoses, the WHO-5 Well-being scale and Problem Areas in Diabetes Scale (PAID). We extracted from the notes all physical conditions. We enquired about similar conditions in 1st and 2nd degree relatives. Descriptive, Chi-square test, Fisher’s exact test, one way ANOVA, and Multinomial logistic regression analysis were conducted to test achievements of our specific aims. Of the 182 patients who participated in the study, 45.1% (82/182) reported a family history of diabetes. Conditions significantly (p < 0.05) associated with a degree of family history of diabetes were retinopathy, duration of diabetes (years), hypertension, and depressive disorder. On average 11.5% (21/182) scored severe depression (≥ 10) on PHQ-9 and 85.2% (115/182) scored good well-being (≥ 13 points). All DSM-5 psychiatric conditions were found in the 182 patients in varying prevalence regardless of relations. In addition, amongst the 182 patients, the highest prevalence was poor well-being on the WHO quality of life tool. This was followed by post-traumatic disorders (current), suicidality, and psychotic lifetime on DSM-5. The least prevalent on DSM-5 was eating disorders. Some type 2 diabetes mellitus physical disorders and depression have increased incidence in closely related patients. Overall, for all the patients, the prevalence of all DSM-5 diagnoses varied from 0.5 to 9.9%.

Abstract P398: Family History of Cardiovascular Disease and Hypertension Are Associated With Prevalent Disease in US Americans of South Asian Origin

Introduction: Cardiovascular disease (coronary artery disease and stroke, CVD) is a major health risk among the South Asian diaspora in the US. Factors like genetics and acculturation can influence the onset and progression of these diseases. Our study investigated the associations of acculturation and family history with CVD and a major CVD risk factor of hypertension (HTN) in US South Asians. Methods: We surveyed 105 US South Asian adult participants recruited at a community event. Respondents provided information on acculturation (measured by the adoption of English spoken at home), and family history of CVD and HTN in parents and siblings. Prevalence of CVD and HTN were compared between those with or without factors of interest. Multivariate logistic regression models were run for family history variables of interest, adjusted for age, gender, and English speaking at home. Results: Participants had median age 54 (range 20-75) years, and 69.2% were male. The Table shows the association of parental and sibling history of CVD and hypertension with having CVD or HTN personally, and the association of home language with these conditions. Multivariate adjusted logistic regression analysis found little attenuation, in that , sibling history of CVD remained significantly associated with personal CVD (p = 0.026), parental history of HTN remained significantly associated with personal HTN (p=0.004) and sibling history of HTN remained significantly associated with personal HTN (p=0.014). Conclusion: Among South Asians in the US, family history in 1st degree relatives, rather than language acculturation, is associated with personal CVD and HTN, suggesting a genetic burden. The stronger association of sibling history rather than parental history of CVD suggests a possible role of environmental or secular factors that siblings may share more than parents and offspring. In this population at high risk of CVD, careful recording of family history may help early prevention strategies.

Identifying gestational diabetes mellitus and assessing risk factors in affected women: a comprehensive study.

Gestational diabetes mellitus (GDM) is a prevalent pregnancy complication associated with adverse health outcomes for both mothers and offspring. This study aimed to identify risk factors for GDM, a condition with a rapidly increasing global prevalence. We conducted a study involving 474 pregnant women who attended the obstetrics outpatient clinic of Kafkas University Faculty of Medicine Hospital between January 2022 and June 2023. Risk factors for GDM were assessed based on criteria recommended by the American Diabetes Association and the Committee on Practice of the American College of Obstetricians and Gynecologists. Statistical analyses, including descriptive statistics, Chi-square tests, Mann-Whitney U tests, and multivariate logistic regression. Individuals with GDM (mean age: 31.26±6.09 years) were significantly older than those without GDM (mean age: 28.36±4.89 years; p<0.001). Obesity prevalence was higher in the GDM group (32.5%) compared to the non-GDM group (14.3%; p<0.001). Individuals with GDM had higher rates of pre-diabetes (3.3% vs. 0.3%; p=0.007), a history of gestational diabetes (25.2% vs. 5.7%; p<0.001), high blood sugar in previous pregnancies (13.8% vs. 1.4%; p<0.001), and diabetes mellitus in 1st-degree relatives (40.7% vs. 20.3%; p<0.001). GDM was associated with increased pregnancies (p<0.001), preterm births (p<0.001), macrosomic babies (p=0.026), congenital anomalies (p=0.011), high cholesterol (p=0.036), and polyhydramnios (p=0.001) in previous pregnancies, as well as polyhydramnios in the index pregnancy (p=0.008). Regular exercise in previous pregnancies differed significantly based on GDM presence (p=0.037). Recognizing modifiable risk factors is crucial for preventing GDM and reducing associated health risks. Healthcare providers should be vigilant, especially among those with a family history of GDM, previous GDM, advanced maternal age, and other risk factors. Early lifestyle interventions show promise. Further research is needed for accurate GDM prediction.

Uptake of genetic testing among patients seeking cancer genetic counseling in Taiwan.

Genetic testing is becoming increasingly available and affordable. Understanding the reasons for individual decisions about genetic testing may assist in the identification of clinically appropriate use of genetic counseling and genetic testing resources. With the ongoing development of cancer genetic counseling services in Taiwan, we conducted this study to understand the characteristics of those seeking cancer genetic counseling and genetic testing and the predictors for undergoing genetic testing after counseling. Cross-sectional with correlational design was used in this study. Surveys completed by patients visiting the genetic counseling clinic at the cancer center included demographics, personal and family history of cancer, and questions on attitudes toward genetic counseling and genetic testing. Multinomial logistic regression was used to analyze the predictors of decision to undergo genetic testing. A total of 120 participants between the years 2018 and 2021 were analyzed, of which 54.2% were referred by health care professionals. The majority (76.7%) had a personal history of cancer and 50% had breast cancer. Over half (53.3%) had a strong family history of cancer defined as two or more 1st-degree relatives having cancer at a young age. Only 35.8% decided to receive genetic testing right after counseling and 47.5% were undecided. The main reason for hesitation or not pursuing testing was cost (41.4%). Multivariate logistic regression analysis showed that a positive attitude toward genetic counseling was significantly associated with the uptake of genetic testing (Odds ratio 7.60, 95% CI 2.34-24.66, p < 0.001). Given the significant number of individuals undecided about genetic testing after counseling, decision aid could be developed to support genetic counseling and increase satisfaction with the testing decision.

Knowledge Beliefs and Barriers of Healthcare Workers about Human Papilloma Virus (HPV) and HPV Vaccination

Background/Purpose: HPV vaccine is critical in the primary prevention of HPV infection and related diseases. HPV vaccination alone reduces HPV infection by 70% and cervical cancer by 48%. Healthcare workers are expected to have sufficient knowledge and positive attitudes and behaviours about the HPV vaccine. This study aimed to determine the knowledge level of healthcare workers about HPV and HPV vaccination and their beliefs and barriers towards HPV vaccination. Methods: In this cross-sectional study, 339 healthcare workers were reached by snowball sampling. Sociodemographic form, 'Human Papilloma Virus Knowledge Scale (HPV-KS)', 'Health Belief Model Scale for Human Papilloma Virus (HPV) and Its Vaccination (HBMS-HPVV)' were applied online. Results: 254 female (74.9%) and 85 male (25.1%) healthcare workers participated in this study, and 60.5% of the participants were physicians. 94.4% of participants have heard of the HPV vaccine. The most frequently consulted information sources are specialist physicians (57%), social media/TV/Websites (24.4%), and other health workers (23.7%). Twenty-six participants (7.7%) have had at least one dose of the HPV vaccine, and 58% completed three doses. 6.7% of the participants having daughters, and 0.7% of those having sons vaccinated their children against HPV. Women who have had HPV screening (p=0.016), HPV positive results (p=0.033) and pathological cervical cancer screening results (p=0.004), those having 1st-degree relatives or close friends who had HPV vaccine (p

Feasibility and early clinical impact of precision medicine for late-stage cancer patients in a regional public academic hospital

AimOur goal was to describe a precision medicine program in a regional academic hospital, characterize features of included patients and present early data on clinical impact.Materials and methodsWe prospectively included 163 eligible patients with late-stage cancer of any diagnosis from June 2020 to May 2022 in the Proseq Cancer trial. Molecular profiling of new or fresh frozen tumor biopsies was done by WES and RNAseq with parallel sequencing of non-tumoral DNA as individual reference. Cases were presented at a National Molecular Tumor Board (NMTB) for discussion of targeted treatment. Subsequently, patients were followed for at least 7 months.Results80% (N = 131) of patients had a successful analysis done, disclosing at least one pathogenic or likely pathogenic variant in 96%. A strongly or potentially druggable variant was found in 19% and 73% of patients, respectively. A germline variant was identified in 2.5%. Median time from trial inclusion to NMTB decision was one month. One third (N = 44) of patients who underwent molecularly profiling were matched with a targeted treatment, however, only 16% were either treated (N = 16) or are waiting for treatment (N = 5), deteriorating performance status being the primary cause of failure. A history of cancer among 1st degree relatives, and a diagnosis of lung or prostate cancer correlated with greater chance of targeted treatment being available. The response rate of targeted treatments was 40%, the clinical benefit rate 53%, and the median time on treatment was 3.8 months. 23% of patients presented at NMTB were recommended clinical trial participation, not dependent on biomarkers.ConclusionsPrecision medicine in end-stage cancer patients is feasible in a regional academic hospital but should continue within the frame of clinical protocols as few patients benefit. Close collaboration with comprehensive cancer centers ensures expert evaluations and equality in access to early clinical trials and modern treatment.

The Effectiveness of Course Therapy with Actovegin of Minimal Cognitive Dysfunction in 1st-Degree Relatives of Patients with Alzheimer’s Disease: the Role of ApoE Genotype

The aim of the study: evaluation of the impact of long-term effects of repeated courses of Actovegin therapy on indicators of minimal cognitive dysfunction (MCD) in relatives of patients with Alzheimer’s disease (AD).Study participant: 76 people with signs of minimal cognitive dysfunction objectively confirmed by clinical and neuropsychological examination, who are relatives of the 1st degree of relatives of patients with AD.Study design: a prospective comparative study of the effects of repeated courses (4 courses in total) of three-month oral therapy with Actovegin (at a daily dose of 600 mg divided into three doses of 200 mg) every 1.5 years in groups of relatives with ApoE4(+) and ApoE4(–) genotypes.Methods: psychometric, neuropsychological, molecular genetic, statistical.Results: in the study, the effectiveness of 4 repeated courses of Actovegin therapy in relatives with manifestations of MСD was established. According to the CGI-I subscale, no deterioration was found over a period of 4 years and 9 months. By the end of the study, in 86.9% of all cases, a pronounced and moderate improvement was achieved.Conclusion: minimal cognitive dysfunction in first-degree relatives of AD patients, both in carriers of the ApoE4(–) genotype and especially in carriers of the ApoE4(+) genotype, is the basis for special attention to measures to prevent cognitive deficits.

Abstract P6-05-47: Preimplantation genetic testing for BRCA gene mutation carriers - the future of health care in Poland?

Abstract Introduction Genetic background is rarely the cause of breast cancer incidence. Mutations in genes that increase the risk of breast cancer (most commonly BRCA1/2) are diagnosed in about 5-10% of patients. The lifetime risk of breast cancer in BRCA1/2 gene mutation carriers is 80%, and for ovarian cancer from 40-60%, while the chance of passing the mutation to offspring is 50%. The use of pre-implantation genetic testing (PGT-M) of the embryo during in vitro treatment prevents the transfer of mutated gene associated with an increased risk of cancer to the child. The significantly limited availability and high cost of PGT-M in Poland prevent its widespread use. The aim of the survey was to assess interest in PGT-M by female carriers of mutations in genes that increase cancer risk in Poland. Material and Methods The survey covered 103 persons, 102 with diagnosed mutations in genes that increase cancer risk. The questionnaire consisted of 22 questions regarding: age and gender of the patients, carriage of mutations in genes that increase the risk of cancer (age of mutation diagnosis, type of mutation, preventive measures taken, carriage of mutations in the family, incidence of cancer among relatives, and care of relatives during illness), and knowledge of pre-implantation diagnosis and attitudes regarding the use of PGT-M to avoid passing the defective gene to offspring. Results The study included 101 women (98.1%) and 2 men (1.9%), with a median age of 38 years (22-74). Fifty-two (50.5%) were diagnosed with cancer: 50 with breast cancer and 2 with ovarian cancer. Eighty-one subjects (78.6%) were diagnosed with a mutation in the BRCA1 gene, seventeen (16.5%) in the BRCA2 gene, three (2.9%) in the CHEK2 gene, two (1.9%) in the TP53 gene and one (1%) in the PALB gene. The median age of mutation diagnosis was 34 years (18-66). A significant proportion of patients took prophylactic measures, sixty-one (59.2%) underwent risk-reducing mastectomy (RRM), and forty-six (44.7%) risk-reducing salphingo-oophorectomy (RRSO). Ninety-five subjects (92.2%) declared regular visits to a genetic counseling center. Thirty-two persons (31.1%) had a family history of cancer (1-5 members in the family), mainly in 1st degree relatives – parents and siblings (about 60% of cases), the predominant cancers were breast cancer (106 cases), ovarian cancer (38 cases) and prostate cancer (7 cases); eighty-two family members died of cancer, seventy-five (72.8%) respondents accompanied family members in the dying process. Twenty-six individuals (25.2%) knew what PGT-M was, information was obtained from an oncologist (11), gynecologist (7), geneticist (6), other patients (6) and most often from the Internet (17). Seventy-four respondents (71.8%) had children. Thirty-three (32%) declared that information about carrying a mutation in a gene that increases cancer risk influenced their decision to have offspring. Sixty-eight (64.1%) of the respondents, with prior knowledge of PGT-M and with the availability of the method, would have used the diagnosis in combination with in vitro fertilization to avoid passing the defective gene to offspring. Fifty subjects (48.5%) were willing to cover the costs of this procedure. Conclusions PGT-M in combination with in vitro fertilization is a safe and effective method of preventing the transfer of a defective gene to offspring. Due to the lack of availability and high cost of the procedure, it is not available in daily clinical practice among carriers of mutations in genes that increase the risk of cancer in Poland. Their own incidence of cancer, multiple incidences in family members and involvement in the dying process may influence patients’ decisions to have offspring and motivate them to seek out centers offering PGT-M. The results of this survey indicate the need to offer pre-implantation testing to patients despite the lack of reimbursement and to increase its availability in Poland. Citation Format: Joanna Kufel-Grabowska, Amira Podolak, Mikołaj Bartoszkiewicz, Daniel Maliszewski, Dominika Ossowska, Robert Spaczynski. Preimplantation genetic testing for BRCA gene mutation carriers - the future of health care in Poland? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-47.

Correlation of Family History of Diabetes Mellitus With Hyperglycaemia in Acute Stroke in Non Diabetic Patient

Background: Raised blood glucose is common in diabetic patients in early phase of stroke. It is also known that blood glucose level increases during acute stroke in non diabetic patients. Objective: Objective of this study was to assess the association between family history of diabetes and newly developed diabetes, impaired fasting glucose, impaired glucose tolerance during acute stroke in non diabetic patients. Methods: The purposive sampling method was applied to identify the patients by appropriate history taking about diabetes among the patients and their 1st degree relatives, documentary papers and laboratorial support evidenced by HbA1c level less than 6.5% (This means patient to be non diabetic). Data were collected from 100 patients. The data were collected by questionnaire, pre-tested earlier and data collection sheet illustrating the family history of diabetes mellitus and glycemic status during acute stroke among the nondiabetic patients. It was conducted from January, 2021 to July, 2021 in the Department of Medicine of Dhaka Medical College Hospital. Results: The study found that, mean age of the patents was 61.76±7.33 years. Family history of Diabetes Mellitus (first degree relative) was found among 48% patients.52% patients did not give family history of Diabetes Mellitus. During analysis of the lab investigations among the participants, mean HbA1c level was found 5.69± 0.65 mmol/L which was found normal among the entire patient group. Patients Fasting Blood Sugar (FBS) was tested and mean FBS level was 5.94±0.86.Among the respondents 48% gave family history(1st degree relative) of Diabetes of which 8.3% revealed normal glycemic status , 66.7% showed IGT and 25.0% were diabetic. On the other hand 52% respondents had no family history of Diabetes, among them 50% showed no glycemic abnormality, 42.3% showed IGT and only 7.7% were diabetic. Conclusion: In a nutshell, the study finds that, in patients with no history of diabetes who have acute stroke, may develop moderately elevated glucose levels and it is significantly higher in those who have family history of diabetes mellitus. J Dhaka Med Coll. 2021; 29(1): 38-42

Early-onset grade 2-3 diffuse gliomas and schwannomas increase the risk of central nervous system tumors among the patients' relatives.

Central nervous system (CNS) tumors are a heterogeneous group of tumors that include several aggressive malignancies with a high mortality rate. This study aimed to evaluate the familial relative risk of CNS tumors in family members of early-onset index cases (probands) in and between diffuse glioma, non-diffuse glioma, meningioma, and other CNS tumors. We retrieved tumor data from the Finnish cancer registry and familial relationships data from the population information system. We ascertained 5408 probands diagnosed with primary CNS tumors (age ≤40 years) between 1970 and 2012 in Finland. We report the standardized incidence ratios as a measure of familial aggregation using Poisson regression. The risk of early-onset diffuse glioma increased among siblings of probands with the same tumor [SIR 3.85, 95% confidence interval (CI): 1.66-7.59], with association mainly returning to grade 2-3 diffuse gliomas. Early-onset other CNS tumors were associated with an increased risk of other CNS tumors, early-onset meningioma, and late-onset diffuse glioma in 1st-degree relatives. The elevated risk of other CNS tumors was largely caused by schwannomas (SIR 59.44, 95% CI: 27.18-112.84 for 1st-degree relatives) and associated with neurofibromatosis. No tumor syndrome was associated with an increased risk of diffuse gliomas. The early onset of grade 2-3 diffuse gliomas is associated with an increased risk of similar tumor entities. Early-onset schwannomas dramatically increase CNS tumor risk with a broader tumor-type profile. In future studies, it would be important to identify the underlying shared hereditary factors that contribute to the development of familial diffuse gliomas.

Cerebrolysin Treatment Reduces the Risk of Mild Cognitive Decline to Dementia in 1st-Degree Relatives of Alzheimer's Patients: A Prospective Comparative Study

To evaluate the long-term effects of annual course therapy with Cerebrolysin on cognitive functioning and the risk of transition to dementia in relatives of patients with Alzheimer's disease (AD) with amnestic-type mild cognitive decline syndrome (aMCI) in comparison with the same group untreated relatives. The cohort included 88 first-degree relatives of BA patients with aMCI syndrome aged 50 to 82 years (mean age 65.0±9.9 years) of which 46 people received course therapy with Cerebrolysin and 42 people were not treated. Clinical, neuropsychological, statistical methods were used. Conducted annual course therapy with Cerebrolysin (a total of 3 courses of infusion therapy: for a course of 20 intravenous infusions of 20 ml of Cerebrolysin in 100 ml of isotonic saline) followed by a follow-up study after 3 months after the end of the therapeutic period. The dynamics of cognitive functioning in the therapeutic group was compared with the corresponding dynamics in the comparison group over the same period. The assessment was carried out on day 0, by the end of 1, 14, 27 and 30 months research. In the therapeutic group, according to the CGI-I scale, by the end of the 3rd course of therapy, in 95.7% of cases, a pronounced or moderate improvement was achieved after each of the courses on all scales and tests. In this group, by the end of the therapeutic period, a significant improvement in the initial mean group scores was established. According to the all scales and tests, a significant improvement of the initial average group scores was found after each course of therapy (p<0.05). In the comparison group there was a significant deterioration (p<0.05) of the average group scores of most of the cognitive scales and test by the end of the observation. The annual conversion from aMCI to dementia due to probable AD was 9.5% only in the comparison group. The average group indicators of all scales and tests significantly worsened starting from the 14th month of observation in the comparison group. The absence of cases of aMCI conversion to dementia in the treated patients for 2.5 years of observation can serve as confirmation of a disease-modifying effect in Cerebrolysin. These results indicate the need for more extensive clinical studies of the preventive effects of Cerebrolysin and to explore the possibility of including such therapy in drug prevention programs for AD in people at high risk for this disease.

Autism Spectrum Disorder May Be Highly Prevalent in People with Functional Neurological Disorders

Recent observations suggest that autism spectrum disorder (ASD) co-occurs in people with a functional neurological disorder (FND), but little systematic data are available on the relationship between FND and autism. The study aimed to assess the self-reported autistic traits via a standardized questionnaire and the prevalence of previously diagnosed ASD among people with FND and their 1st-degree relatives. We performed a survey of members of the patient organization FNDHope, using a self-completed questionnaire for screening for autistic traits and ASD: the adult autism subthreshold spectrum (AdAS spectrum). There were 344 respondents diagnosed with FND with a mean age of 39.8 ± 11.6 years (female sex 90%). Eight per cent of respondents volunteered a previous diagnosis of ASD, and 24% reported a 1st-degree relative with a formal diagnosis of ASD, mostly their children. We found that 69% of respondents had scores in the AdAS spectrum indicating a clinically significant ASD and 21% indicating autistic traits. Further studies are needed to provide more evidence regarding the prevalence of ASD in people with FND and how this may influence the aetiology, treatment selection and prognosis.

A comparative cost analysis of two screening strategies for colorectal cancer in Lynch Syndrome in a South African tertiary hospital.

Lynch Syndrome (LS) individuals have a 25-75% lifetime risk of developing colorectal cancer. Colonoscopy screening decreases this risk. This study compared the cost of Strategy 1: screening colonoscopy for 1st degree relatives of patients that met the Revised Bethesda Criteria (i.e., probands) to Strategy 2: screening colonoscopy for 1st degree relatives of probands with genetic mutations for Lynch Syndrome based in a resource-constrained health care system. A comparative, health care provider perspective, cost analysis was conducted at a tertiary hospital, using a micro-costing, ingredient approach. Forty probands that underwent genetic testing between November 01, 2014 and October 30, 2015 and their first-degree relatives were costed according to Strategy 1 and Strategy 2. Unit costs of colonoscopy and genetic testing were estimated and used to calculate and compare the total costs per strategy in South African rand (R) converted to UK pounds (£). Sensitivity analyses were performed on colonoscopy adherence, relatives' positivity, and variable discount rates. The cost for Strategy 1 amounted to £653 344/R6 161 035 compared to £49 327/R 465155 for Strategy 2 (Discount rate 3%; Adherence 75%; and Positivity rate of relatives 45%). Base case analysis indicated a difference of 92% less in the total cost for Strategy 2 compared to Strategy 1. Sensitivity analyses showed that the difference in cost between the two strategies was not sensitive to variations in adherence, positivity or discount rates. Colonoscopy screening for LS and at-risk family members was tenfold less costly when combined with genetic analysis. The logistics of rolling out this strategy nationally should be investigated.

A pilot study to increase cascade genetic risk education and testing in families with hereditary cancer syndromes.

378 Background: There is great need to build and evaluate tools and strategies to improve cascade genetic risk evaluation in families at high risk for hereditary cancer. The Genetic Information and Family Testing (GIFT) Trial is a population-based intervention that will examine features of a virtual platform that provides genetic risk education (GRE) and low-cost genetic testing (GT) to relatives of 5000 adult patients diagnosed with cancer in 2018-19 in Georgia and California and who tested positive for a clinically actionable germline pathogenic variant (PV). We present findings of a pilot study that informed the GIFT Trial protocol and platform features. Methods: We surveyed 277 women diagnosed with breast cancer in 2017, reported to the Georgia SEER registry, and who tested positive for a clinically actionable PV in a cancer-associated gene. We then invited respondent patients to enroll in the intervention phase which provided online GRE, human pretest genetic navigator support, and an offer of low-cost GT through Color Health, Inc. to all untested 1st or 2nd degree relatives. Respondent patients were eligible for the intervention if they reported a PV on genetic testing and had at least one relative who had not received GT. Enrolled patients invited relatives through the platform by providing email addresses. Family clusters were block randomized to free vs $50 test costs at the time of the initial patient invitation. Results: 125 of 277 patients (45.2%) returned surveys: median age was 51 and 22% were African American. The most common PV reported by patients were BRCA2 (25.7%), BRCA1 (19.5%), CHEK2 (20.4%), ATM (8.8%) and PALB2 (7.1%). Disclosure of genetic test results to relatives was quite high: 83.6% of patients reported that they discussed results with all their daughters vs 69.4% with sons; 78.1% discussed their results with all sisters vs 61.8% with all brothers. The median number of patient-reported untested relatives in a family was 9 (25th-75th percentile: 4-14). Most respondents were eligible for the trial offer (113 of 125, 90.4%). Overall, results were similar between the free test arm and $50 test arm: In the free testing arm, 20 patient participants invited 28 relatives; 12 relatives enrolled, and all 12 relatives ordered testing. In the $50 arm, 16 patient participants invited 38 relatives of whom 18 enrolled and all 18 ordered testing. For the 66 relatives invited by the patient participants: 47 (71.2%) were first degree (8 parents, 22 siblings, and 17 children) and about half of the relatives were men (47.0%). Conclusions: Breast cancer patients with PVs make substantial efforts to communicate with family members about genetic risk but most relatives do not receive GT. Our study findings suggest that a low-cost online navigator-supported intervention can directly engage relatives to increase cascade genetic risk education and testing with little difference in uptake by test cost arms.

S3558 A Tale of Two Sisters: Two Pediatric Cases Within a Familial Cluster of Hereditary Diffuse Gastric Carcinoma

Introduction: We report a case of HDGC in two sisters, (10 and 15 years old) and their father (41 years old). Case Description/Methods: Our patient is a 15-year-old Caucasian female who initially presented to our clinic with a 4-month history of right lower quadrant tenderness and generalized abdominal pain, which she characterized as “stabbing pain.” Review of systems was significant for intermittent diarrhea and constipation. Family history was significant for a paternal great-aunt who reportedly died from gastric cancer at age 28. Abdominal ultrasound showed no significant abdominal pathology and no appreciable stomach wall thickening. EGD revealed diffuse mild inflammation of the stomach with normal appearing rugae without ulceration or masses and normal proximal duodenum. Biopsy results from the antrum revealed poorly differentiated signet ring cell carcinoma. The patient underwent a second EGD and imaging to confirm and stage the cancer. The patient subsequently underwent a laparoscopic roux-en-Y esophagojejunostomy, jejunojejunostomy with exploratory laparoscopy. Based upon the unusual occurrence of SRCC in a young female, the patient and her family underwent genetic testing. The patient was found to be positive for a CDH1/E-cadherin mutation. It was found that the patient’s father and her 10-year-old sister also carried this mutation. The 10-year-old sister and the father underwent screening EGD with greater than 40 biopsies taken throughout the stomach, esophagus, and duodenum in representative areas. Surprisingly, both patients were found also to have gastric SRCC. The father has since undergone chemotherapy, radiation, and a laparoscopic roux-en-Y esophagojejunostomy, jejunojejunostomy. The family is opting for conservative management at this time for the 10-year-old patient with plans to undergo the same surgery when she is older (Figure). Discussion: Gastric carcinoma in the pediatric population is exceedingly rare. HDGC should be considered when a patient presents with gastrointestinal symptoms and has a positive family history of gastric cancer among 1st and 2nd degree relatives, particularly if a relative was diagnosed before the age of 50. For carriers of the CDH1 mutation, prophylactic total gastrectomy is recommended with intraoperative confirmation of squamous epithelium in the esophagus at the proximal margin and duodenal mucosa at the distal margin. If gastrectomy is contraindicated, yearly endoscopic surveillance with random biopsies is recommended.Figure 1.: Biopsy from gastric antrum demonstrating poorly differentiated signet ring cell carcinoma present in the lamina propria.

Suicidality in the geriatric population.

Suicide in older adults is a major global concern in both public and mental health. With an ageing population on the rise, a surge in suicidal deaths is predicted in the coming years. The objectives of this paper are to review the risk factors, protective factors, assessment rating scales and current prevention strategies in the geriatric population. The identification of modifiable risk factors and strengthening of protective factors as well as staging according to suicidal ideation, behaviors and/or attempt(s) are necessary to devise appropriate personalized interventions in vulnerable older adults. A history or current psychiatric illness particularly depression, physical illnesses, previous suicide attempt, substance abuse, loneliness, marital status, financial stress, a family history of psychiatric illnesses or suicide in 1st degree relatives and low social support most commonly increase suicidal susceptibility in older adults. Conversely, factors that increase resilience in older adults include a good physical health and cognitive function, religiousness, good quality of life and life satisfaction, ability to perform activities of daily living, marital status, having friends and social connectedness. While the risk factors associated with suicide in the geriatric population are complex and multidimensional in nature, the current preventive strategies have provided no substantial decline in suicidal risk. Therefore, a combination of strategies applied via a multilevel prevention program at a primary, mental healthcare, societal and community level could mitigate suicidal risk. Further research and better preventive measures are warranted to diminish suicidal risk in older adults.

1446P Barriers and facilitators for genetic/epigenetic screening trials attendance in healthy populations at high-risk for cancer: A qualitative study

For several tumors the possibility to detect suspected lesions in early stages could make a difference between life and death. New directions in research projects and cancer screening trials (CST) aimed at stratifying populations at high risk (HR) for cancer by integrating omics, imaging data and epidemiologic risk factors. A comprehensive understanding of factors that hinder or enhance participant’s adherence to these trials is needed, to also improve the criteria and approach to returning results. The aims are a) identify facilitators and barriers influencing HR populations’ adherence to CST; b) compare the effect of constructs from the Health Belief Model (HBM) and the Theory of Planned Behaviors (TPB) on the decision-making process. 3 Focus Group Discussions (FGDs) were conducted with 1st-degree relatives of cancer patients (N=18). Transcripts from the FGDs were analyzed using NVivo software to perform thematic analysis. Preliminary results identified two main facilitators and two main barriers. The facilitators were: a) the availability of a structured prevention program in association with the genetic/epigenetic returning of result; b) the reception of detailed information and counseling concerning the probabilistic/uncertain nature of genetic/epigenetic data. The barriers were: a) the psychological impact of “negative” screening results on participants and their families; b) younger age and related perception of personal risk. Social norms and perceived behavioral control (TPB) seem not crucial constructs in the decision-making process, whereas constructs such as knowledge, perceived susceptibility, perceived seriousness, preventive behaviors and cues to actions (HBM) might explain HR subject’s adherence to cancer screening trials. Technological advances in (epi)genetics, diagnostic technologies and clinical trials for cancer screening must be matched by parallel advances on how we support the informed choices, essential to public participation. Our study contributes to the promise of 4P medicine personalizing preventive screening interventions at the psychosocial dimension, as well as biological dimension.

Investigating the relationship between cancer and orofacial clefts using GWAS significant loci for cancers: A case-control and case-triad study.

BackgroundSeveral population-based case-control studies have reported concurrent presentation of cancer and congenital malformations. Many associations have been made between oral clefting and cancers, though some of these results are conflicting. Some studies have reported an increased risk of cancer among 1st-degree relatives of cleft cases and vice versa, and also an excess risk of cancers of the breast, lung, and brain among those with oral clefts. This study aimed to determine if the genetic polymorphisms found in some cancers are also associated with orofacial cleft in an African cohort.MethodsThe study was a case-control and case-triad study in which cases were 400 individuals clinically diagnosed with non-syndromic cleft lip and/or palate (CL/P), while controls were 450 individuals without CL/P. Samples were obtained from three African countries while DNA extraction, PCR, and genotyping were carried out at the University of Iowa, US. Eleven SNPs in genes coding for SWI/SNF subunits and 13 GWAS significant SNPs for cancers associated with orofacial cleft were selected. Case-control analysis, transmission disequilibrium test (TDT), and DFAM to combine the parent-offspring trio data and unrelated case/control data in a single analysis were carried out using PLINK.ResultsFor the case-control analyses that included all the clefts and for the CLP subtype, none of the SNPs were statistically significant. Statistically increased risk for the following SNPs rs34775372 (p = 0.02; OR = 1.54, CI:1.07–2.22), rs55658222 (p = 0.009; OR = 2.64, CI:1.28–5.45) and rs72728755 (p = 0.02; OR=2.27, CI:1.17–4.45) was observed with the CL only sub-group. None of these were significant after Bonferoni correction. In the TDT analyses, a significantly reduced risk with rs10941679 (p = 0.003; OR = 0.43, CI:0.24–0.75) was observed and this was significant after Bonferroni correction. The rs10941679 was also significant (p = 0.003) in the DFAM analyses as well even after Bonferroni correction.ConclusionThe results from this study represent an important starting point for understanding the concurrent presentation of some cancers in orofacial clefts, and cancer risks in cleft patients. The associations observed warrant further investigation in a larger cohort and will set the stage for a more mechanistic approach toward understanding the risk for cancers in families with clefts.