Degree Relatives Research Articles

Trends and Symptoms Among Increasing Proportion of African Americans with Early-Onset Colorectal Cancer over a 60-Year Period.

The proportion of early onset colorectal cancer (EOCRC) is alarming in adults, including in African Americans (AA). To investigate differences between EOCRC compared to late-onset colorectal cancer (LOCRC) among AA patients. This retrospective study reviewed demographic, clinical presentations, colonoscopy, and pathology reports of patients at Howard University Hospital from 1959 to 2023. The study included 176 EOCRC cases (< 45years) and 2034 LOCRC cases (> 45years). Both EOCRC and LOCRC groups were predominantly AA (> 80%) with slightly more females (53%) than males. The mean age was 38years for EOCRC and 66years for LOCRC cases. EOCRC cases increased as a proportion of total detected CRC cases since 2010 (over 13%) after several decades of just above 6%. Family history of CRC in first degree relatives was higher among EOCRC (15.5% vs.3.4% in LOCRC patients, p < 0.01). Symptoms at presentation were prevalent in both EOCRC (93.8%) and LOCRC (92.6%). EOCRC patients exhibited higher incidence of abdominal pain (23.3% vs. 17.2%, p = 0.05) and changes in bowel habits (24.4% vs. 14%, p < 0.01) compared to LOCRC patients. Other symptoms such as melena, hematochezia, and weight loss were less prevalent in EOCRC patients. Comorbidities like hypertension (HTN), diabetes mellitus (DM), and inflammatory bowel disease (IBD) were less frequent among EOCRC patients. EOCRC was primarily observed in the sigmoid and rectosigmoid regions (p = 0.02). Metastasis at index colonoscopy was more prevalent with EOCRC compared to LOCRC (p = 0.04), with a higher proportion of patients at stage 3 cancer (p < 0.05). Significant differences were noted in the timeline for undergoing surgery after the diagnosis of colorectal cancer, with EOCRC patients taking longer than LOCRC patients (p = 0.03). Presentation of EOCRC over LOCRC increased proportionally in our cohort since 2010 and is associated with family history, and symptoms such as abdominal pain and change in bowel habits. Likely because of age at presentation, there are less comorbidities among EOCRC patients who predominantly present in the outpatient setting, and more likely diagnosed with advanced stage lesions that are predominantly sigmoid or rectosigmoid. These findings are similar to observations seen in the general population with EOCRC, albeit African American patients have commonly had earlier age presentation of CRC than White American patients.

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

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

Barriers to opioid use in the Arab world.

The Arab world consists of 22 countries, representing 5.5% of the world's population. Morphine consumption accounts for less than 1% of the world's consumption. This is the first study to identify barriers to opioid use in the Arab world. This study aimed to investigate the barriers to opioid use in pain management in the Arab world. Online survey was developed to investigate barriers to governance, prescribing, distributing, dispensing and administering, as well as educational barriers in the Arab world. The questionnaire was sent via email and a mobile app to one expert physician in pain management and one licensed pharmacist from each Arab country. With the exception of Tunisia, Djibouti and Comoros, 34(77%) participants from 19 Arab countries answered the survey. Most countries lack local opioid production, necessitate special licenses for physicians, and restrict opioid prescribing to medical specialists. Special prescription forms are mandated, and pharmacists lack the authority to correct prescription errors or accept refill or verbal orders on opioids. Storage requirements for empty ampoules and prescriptions are enforced. Nurses are not allowed to carry opioids during home visits, and only first degree relatives can collect opioids for patients. Furthermore, the integration of palliative care and pain management curricula into pharmacies and medical schools is lacking. There is a wide range of regulatory and other barriers to opioid use in the Arab world. There is a substantial need for regulatory review and reform, as well as for educational initiatives, in most Arab countries.

Diagnosing Monogenic Stroke at Younger Age.

An increasing number of monogenic conditions underlying stroke are being identified. We explored the possibilities of increasing the diagnostic yield of monogenic stroke in a population under 56 years of age. Fifty probands ≤55 years at their first stroke episode were characterized clinically and investigated by whole genome sequencing. Probands had one or more of: (1) one or more first to second degree relatives with stroke under 60 years or same stroke-causing condition/disease; (2) no hypertension, hypercholesterolemia, diabetes, heart disease, or smoking; or (3) either multiple stroke episodes or multiple arterial dissections. Variants with minor allele frequency under 0.01, identified by using our stroke gene panels, were assessed. The stroke subtypes, including large artery atherosclerotic, large artery nonatherosclerotic (tortuosity, dolichoectasia, aneurysm, nonatherosclerotic dissection, or occlusion), cerebral small vessel disease, cardioembolic (arrhythmia, heart defect, or cardiomyopathy), coagulation dysfunctions (venous thrombosis, arterial thrombosis, or bleeding tendency), intracerebral hemorrhage, vascular malformations (cavernoma or arteriovenous malformations), metabolic disorders, or cryptogenic embolic, were used for genotype-phenotype correlation. In a final step, we combined genetic and clinical information to determine if the genetic variant likely was the cause of stroke in the patients. Whole genome sequencing of younger patients with stroke identified 17 clinically matching genetic variants in 15 of 50 (30%) patients, while a stronger clinical correlation with stroke was established in only 6 (12%) of them. Stroke-related genetic variants were identified in 4 of 5 (80%) patients with cardioembolic stroke subtype, 3 of 4 (75%) with intracerebral hemorrhage, 7 of 18 (39%) with cryptogenic embolic stroke, 1 of 6 (17%) with small vessel disease, and 3 of 15 (20%) of patients with nonatherosclerotic large artery stroke, including 1 of 11 (9%) with cervical dissection stroke. Careful clinical interpretation of whole genome data using stroke gene panels can detect monogenic causes of early stroke, allowing individualized follow-up and opening new possibilities for potential treatment.

Case report: A finding of PVOD and PAH in first degree relatives suggests shared heritable risk and overlapping features of both pulmonary vascular diseases.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary vascular disease that is difficult to distinguish clinically from pulmonary arterial hypertension (PAH). Multiple genes have been implicated in disease pathogenesis in PAH and PVOD and the diseases are thought to be genetically distinct. In this report we present a case of first-degree relatives with pathological evidence of PVOD and PAH. The index patient was diagnosed with PAH at age 42, was treated with escalating pulmonary vasodilator therapy, but eventually succumbed to her disease. On autopsy, her pathology was consistent with PAH. Her son was diagnosed with PAH at age 16, did well on pulmonary vasodilator therapy for over 10 years, but ultimately developed refractory right ventricular failure and received a heart and lung transplantation. Pathology of his explanted lung was consistent with PVOD, and genetic testing was negative for recognized variants that cause PAH or PVOD.

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

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

Who should be prioritized for screening for adult onset dilated cardiomyopathy among first degree relatives?

Abstract Introduction Familial genetic and cardiovascular screening is highly recommended to detect dilated cardiomyopathy (DCM) in first-degree relatives (FDRs). Consequently, questions arise regarding the prioritization of screening among FDRs especially in Asian populations. Purpose To investigate prevalence and proportion of FDRs of DCM patients presenting with DCM. Methods Patients with DCM and their FDRs who underwent genetic counseling between April 2017 and March 2023 at a single tertiary center were retrospectively enrolled. The study collected baseline demographics and conducted sequential echocardiograms, along with genetic cascade sequencing for 36 genes clinically relevant to DCM. A positive DCM phenotype in FDRs was determined based on the presence of a decreased left ventricular ejection fraction (LVEF) with left ventricular enlargement, with a full phenotype containing both criteria and a partial phenotype containing either of them. Results A total of 122 probands (median age 59 years) and 241 FDRs (median age 43 years) participated in the study. Out of 72 FDRs (29.9%) with P/LP proband variants, only 18.6% of FDRs showed a positive DCM-phenotype. Overall, 29 individuals (15.5%) exhibited a positive DCM-phenotype, with 2.7% displaying a full DCM-phenotype and 12.8% displaying a partial DCM-phenotype. Among them, 69% exhibited heart failure (HF) with preserved EF, 20.7% had HF with mildly reduced EF, and 10.3% had HF with reduced EF. Siblings tended to be older compared to offspring (52.1 years vs. 35.5 years), aligning with the tendency shown in the more fulminant manifestation of the positive phenotype. Accordingly, a higher prevalence was observed among siblings (n=4, 80%) with a full phenotype and in those with a partial phenotype. Conclusion This study demonstrated higher prevalence of phenotype-positive DCM among siblings of probands. Given disease’s manifestation in adulthood, it is essential to prioritize the screening of all FDRs with emphasis on the siblings.

Nexilin-related cardiomyopathy (NEXN-CMP) - an island's perspective

Abstract Introduction The phenotypic features of Nexilin related cardiomyopathies (NEXN-CMP) are poorly understood and under-reported. A better understanding of the genotype-phenotype association is paramount. Objectives The main objective of this study was to investigate the causative role and phenotypic expression of the NEXN gene in the Maltese Islands. Methodology Probands and relatives referred for a cardiac gene panel were evaluated. Subjects harbouring NEXN variants were identified. Those finally classified as having NEXN-CMP were evaluated for the purpose of this study. Results Out of 444 probands (confirmed or suspected cardiomyopathy), 12 probands were labelled with NEXN-CMP. This equates to a prevalence of 2.7% in the local cardiomyopathy pool, substantially higher to what has been previously reported. Genetic testing identified 19 individuals (probands [n=15] and relatives [n=4]) all harbouring the same novel frameshift variant: NEXN c.1589_1590del p.(Arg530LysfsTer3), classified as likely pathogenic according to ACMG criteria. Three (15.8%) harboured a second pathogenic variant (n=2 MYH7, n=1 TTN). Another 3 were not clinically affected (n=1 FH of SCD, n=2 first degree relatives of NEXN-CMP probands). These individuals were excluded from further analysis. The NEXN-CMP cohort (n=13) consisted of a dominant male (68.8%) population (54±22 years at presentation, 7.7% athletes, 12 families). Most were probands (n=12/13). DCM was the dominant phenotype (n=8, 61.5%) followed by HNDLVC (n=3, 23.1%) and HCM (n=2, 15.4%). One infantile DCM was homozygous for the NEXN variant. Symptoms were the most frequent method of presentation (n=6, 46.2%), followed by a FH of SCD and/or cardiomyopathy (n=3, 23.1%), abnormal echocardiogram (n=2 15.4%), OHCA (n=1, 7.7%) and inutero diagnosis (n=1, 7.7%). A FH of SCD was present in a third (n=4/12, 33.3%). The ECG was abnormal in the majority (n=10/11, 90.9%). Most patients had a LBBB (6/11, 54.5%) followed by inferolateral TWI (n=3, 27.3%), ventricular arrhythmias/high-grade AVB (n=1, 9.1% each). NEXN-CMP appears to be a left dominant cardiomyopathy. LV dilation and reduced LVEF were present in 84.6%. Non-ischaemic scar was present in 3/8 cases (37.5%), 2 had a ring-like pattern. RV morphology and function was normal in all cases. Tachyarrhythmias were frequently observed (n=4/6, 66.7%) during holter monitoring or exercise testing (n=2 NSVTs, n=1 VEs, n=1 SVEs). A fourth (n=3/11, 27.3%) were implanted with an electrophysiological device. No significant predictors for device implantation were identified at univariate analysis. One patient is on the transplant list (infantile DCM). Conclusion The prevalence of NEXN-CMP in Malta appears higher than previously reported (2.7%), possibly because of a founder mutation. DCM and HCM are the dominant presenting phenotypes, frequently associated with symptoms, an abnormal ECG, a FH of SCD and LV dilatation/dysfunction.

Using polarization sensitive SMLM to infer the interaction strength of dye-plasmonic nanosphere systems

Single-molecule microscopy is an effective tool for the characterization of fluorophore–plasmonic structure interaction. However, sophisticated evaluation is required as specific information is hidden in the emission. Here, we theoretically and experimentally investigated the emission polarization of rotationally mobile fluorophores near plasmonic Au–Ag alloy nanospheres. We developed an elaborate calculation based on the Mie theory, which considers the rotational mobility of dyes near spherical plasmonic nanoparticles of any size. Furthermore, we have created a simplified model that describes the emission’s degree of polarization within 10% accuracy in the case of small nanoparticles, when dipole approximation is valid. Our results indicate the close relation of the polarization degree of the emission, which can reach up to be ∼0.8 in the resonant case, to fluorescence scattering. DNA-PAINT single-molecule localization microscopy experiments conducted using AF488 and Atto647N dyes revealed that the measured polarization degree distribution followed the tendency predicted by calculations.

Familial risk of myocardial infarction with non-obstructive and obstructive coronary arteries -A nation-wide cohort study.

The familial risk among patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) is unknown. Previous studies of family history in myocardial infarction (MI), have not made a distinction between MINOCA and MI due to coronary artery disease (MI-CAD), based on angiographic findings. We therefore sought to investigate familial risk of MI without and with obstructive coronary arteries. Register-based cohort study with a total of 15,462 MINOCA cases, 204,424 MI-CAD cases, 38,220 control subjects without MI and with non-obstructive coronary arteries. First-degree relatives were identified 1995-2020. Cox proportional hazard regression models were used to compare familial risk in MINOCA and MI-CAD with control subjects. During a mean follow-up of 8.1 ± 4.2 years, MINOCA occurred in 1.0% of first-degree relatives with MINOCA whereas MI-CAD occurred in 9.7% of first-degree relatives of MINOCA. The age- and sex-adjusted hazard ratio (HR) for a MINOCA-relative experiencing MINOCA and MI-CAD, compared to control subjects, was 0.99 (95% confidence interval [CI] 0.80-1.23) and 1.10 (95% CI 1.03-1.18), respectively. During a mean follow-up of 8.5 ±4.8 years, MI-CAD occurred in 12.2% of first- degree relatives with MI-CAD with age- and sex-adjusted HR 1.43 (95% CI 1.37-1.49). No increased familial risk of MINOCA was observed for MINOCA-patients whereas there was an increased familial risk for MI-CAD when compared to control subjects. These results may indicate that genetic factors and shared environmental factors within a family leading to CAD are important also for MINOCA, thus MI-CAD and MINOCA could share underlying mechanisms.

12505 Prevalence Of Mody Diabetes Polymorphism Of Thai Urban Families By Targeted Next Generation Sequencing Of Diabetes Polymorphism

Abstract Disclosure: S. Niramitmahapanya: None. Prevalence of MODY diabetes polymorphism of Thai Urban families by targeted next-generation sequencing in diabetes polymorphismObjective: To study the prevalence between single nucleotide polymorphism of urban diabetes (UD) and non-diabetes (noD) in Thai population. Method: Cross-sectional study was collected 240 participant samples; 60 from UD, 60 from RnoD, 60 from non-relative, non-diabetes (noRnoD) and 60 diabetes, non-relatives (noRD). And generated diabetes variant frequency in Thai population by targeted next-generation sequencing. Result; Among group of UD and RnoD found that age, fasting blood glucose (FBG), HbA1c and LDL level were statistic significant all parameter by p&amp;lt;0.001. Age in UD was 64.15±10.74 vs. 43.43±12.46 in RnoD, FBs in UD was 129.39±44.91 vs. 99.74±39.75 in RnoD, A1c in UD was 8.26±4.76 vs. 6.17±1.35 in RnoD and LDL level in UD was 98.28±38.52 vs. 129.35±39.75 in RnoD.In subgroup analysis of diabetes variant, we designed Ion AmpliSeq On-Demand Panels (25 genes related diabetes) for targeted sequencing. We didn’t found statistic significant between UD and RnoD group by p-value =0.998 (23 genes; ABCC8, FGA, SELE, PAX4, HNF1A, BLK, LOC10028732, NEUROD1, KCNJ11, MMP2, APPL1, LPL, CAT, CEL, HNF1A, HNF1B, ICAM1, INSR, SOD, GCK, INS and UCP3). We identified 12 mutations of MODY in UD, the most polymorphism was HNF1a and ABCC8 that found 16.4%, PAX4 found 13.1%, APPL1 found 11.5%, KCNJ11 and NEUROD1 found 8.2%, BLK 6.6% and other less polymorphism that found &amp;lt;5% (HNF1B, HNF4a, CEL, GCK, INS). Conclusion; From the study, we analyzed genetic data from 12 genes that involved pathogenesis for diabetes polymorphism between UD and noD groups. We focus on diabetes variant frequency. We found that 5 pathogenic polymorphism such as HNF1a, GCK, CEL, INS and APPL1. Further study needs to evaluate correlation diabetes polymorphism and their treatment protocols. Keywords; Thai urban diabetes, first degree relatives and MODY diabetes polymorphism Presentation: 6/1/2024

Papillary microcarcinoma in three generations of the first degree relatives

Family papillary microcarcinoma of the thyroid gland is observed in 3–10 % of patients with cancer from follicular epithelial cells. Diagnosis and treatment are controversial. Three patients from the same family of the first degree of kinship were operated for family papillary microcarcinoma of the thyroid gland in Voronezh Regional Clinical Hospital No. 1. Only the first patient complained of the neck deformity, her son and granddaughter had an asymptomatic course of the disease. Metastases to the lymph nodes of the neck and bilateral localization of the tumor were not revealed. In the third generation, multifocal tumor growth was diagnosed at the age of 19. All patients underwent thyroidectomy. In the first patient, the period of relapse–free follow-up after surgery was 18 years, in the second and third – 5 years. In the family form of papillary thyroid carcinoma, we consider active screening of relatives justified since the disease in the new generation may develop at a younger age and with the risk of multifocal thyroid damage even in microcarcinomas.

Musculoskeletal Ultrasound Findings in First Degree Relatives of Rheumatoid Arthritis Patients

Abstract Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that primarily targets synovial joints. Retrospective analysis of individuals who ultimately developed RA have shown RA autoantibodies such as rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) develop months to years prior to the onset of clinically evident synovitis. So there has been increasing interest in identifying individuals at risk for future development of RA, with the hope of intervening to prevent the onset of disease. Aim of the Work To detect the presence of early synovitis (preclinical stage of RA) among healthy first degree relatives of RA patients by MSUS and its correlation to serological markers. Patients and Methods This was a cross sectional study which was conducted on 60 subjects with high risk of developing arthritis; healthy first degree relatives (FDR) of RA patients classified according to ACR/EULAR 2010 criteria. It was carried out at Ain Shams University Hospital. All patients were recruited from Rheumatology outpatient clinic and the inpatient department of Ain Shams University Hospital. Results The study included subjects aged 16 to 55 years, predominantly female, with a mean BMI of 26.44 kg/m². Rheumatoid arthritis (RA) duration ranged from 1 month to 30 years, averaging 6.96 years. Among familial disease relatives (FDRs), 78.3% were nonsmokers. Arthralgia was common (58.3%), with varied joint involvement. Laboratory findings showed elevated ESR and CRP levels. Wrist and MTP-II joints were most frequently affected on ultrasound. A 7-joint ultrasound score (US7) was developed for efficient rheumatological evaluation. Conclusion This cross-sectional study aimed to assess preclinical synovitis by musculoskeletal ultrasound (MSUS) in first-degree relatives (FDRs) of rheumatoid arthritis (RA) patients and its correlation with laboratory findings. We found a prevalence of 51.6% for MSUS positive findings, primarily synovitis. ESR was significantly higher in FDRs with positive MSUS findings. RF showed the highest positive predictive value (75%) for MSUS positivity. Clinical arthralgia exhibited the highest sensitivity (58%). Our study underscores the potential of combining RF, Anti-CCP, and clinical arthralgia in predicting preclinical synovitis in at-risk populations, facilitating early intervention strategies.

Germline p.R181H variant in TP53 in a family exemplifying the genotype-phenotype correlations in Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline pathogenic/likely pathogenic variants in TP53. Genotype-phenotype correlations are progressively being characterized in LFS with certain TP53 variants associated with attenuated penetrance and phenotypes. We report on a family harboring a TP53 p.R181H variant presenting with a restricted cancer phenotype in adulthood. The proband was a female with breast cancer at the age of 71 years who had three first degree relatives also diagnosed with breast cancer after the age of 40 years (mother, two sisters). Of the nine individuals harboring the variant (6 genetically confirmed, 3 obligate heterozygous), six have not developed malignancies at this time (age range: 36-42). No childhood-onset cancers were reported in this family. A concomitant literature review identified 51 additional individuals harboring the p.R181H variant in TP53, presenting a tumor phenotype dominated by breast cancer. Rare occurrences of other adult-onset cancers (prostate, colorectal and thyroid) and only few childhood onset cancer were documented. These observations are consistent with functional analysis showing that p.R181H retains partial p53 function and suggesting possible reduced cancer penetrance, particularly in the pediatric setting.

Anxiety and disease awareness in individuals with heredity for abdominal aortic aneurysm.

The psychological consequences of being aware of an increased risk of developing abdominal aortic aneurysm as a first-degree relative of a person with abdominal aortic aneurysm are hitherto unexplored. This study investigates the awareness of heritability and anxiety in male and female adult offspring of abdominal aortic aneurysm patients compared to controls. Health-related quality of life among participants with aortic pathology was compared to participants with normal aortic diameters. This was a cross-sectional point prevalence study based on the participants examined in the Detecting Abdominal Aortic Aneurysm in First Degree Relatives Trial (DAAAD; 752 adult offspring, 756 matched controls), 2020-2022. Questionnaires about health-related quality of life and study-specific questions regarding awareness of heritability were collected prior to the aortic ultrasound. Attendance rate was higher among individuals with heredity compared to controls (67% vs. 52%, p < 0.001). Of 1508 adult offspring examined, 65% reported having a close relative with abdominal aortic aneurysm (6% in controls). Female adult offspring reported higher awareness of heritability than controls (38% vs. 12%, p < 0.001), as did males (32% vs. 8%, p < 0.001). A slight majority of participants with awareness reported anxiety (54% of female offspring; 51% of male). There were no measured differences in health-related quality of life between the groups when standard health-related quality of life instruments were used. The higher-than-expected proportion of adult offspring with awareness of heritability and anxiety about such risk indicates that we fail to communicate risk to this group appropriately via the current channels of information within the healthcare system. This calls for the development of dedicated strategies for improved communication of abdominal aortic aneurysm risk to patients and their next of kin.

GENETIC AND ENVIRONMENTAL COMPONENTS IN THE PATHOGENESIS OF DYSMETABOLIC NEPHROPATHY WITH OXALATE-CALCIUM CRYSTALLURIA

Introduction. In recent years, the prevalence of dysmetabolic nephropathies (DN) in children has been increasing, constituting a significant portion of the overall structure of kidney diseases in this age group. Aim. To elucidate the role of genetic and epigenetic components in the pathogenesis of dysmetabolic nephropathy with oxalate-calcium crystalluria in children using the methods of G. Edwards and D. Falconer. Materials and methods. A genealogical history was collected for 108 children aged 6 to 18 years with dysmetabolic nephropathy and 65 healthy children from the Ivano-Frankivsk region. Data were collected on 1076 relatives of affected children of I-II-III degrees of relatedness and 676 relatives of healthy children. Calculation of the contribution of genetic and environmental factors to the occurrence of multifactorial diseases in children was carried out using the model proposed by G. Edwards and G. Smith, and the heritability coefficient for susceptibility to these diseases was calculated using D. Falconer's model. Results and discussion. In the pathogenesis of dysmetabolic nephropathy in children, the genetic component plays a significant role, being 2-3 times greater than in the general population. The heritability coefficient for susceptibility to dysmetabolic nephropathy is very high: for first-degree relatives of affected children – 24%, for second-degree relatives – 20.9%, and for third-degree relatives, it does not differ from the population average – 3.6%. Conclusions. 1. If a family has a child with dysmetabolic nephropathy or a relative with metabolic pathology, the risk of dysmetabolic nephropathy in the second child is higher according to the G. Edward's and G. Smith's models is very high – 36.76% and 48.81%. 2. For relatives of sick children of the first degree of consanguinity, the inheritance rate of predisposition to dysmetabolic nephropathy is very high – 24% and 22%, respectively, in the observation groups and does not depend on the variant of the course of dysmetabolic nephropathy, nor on who is sick – parents or siblings. 3. The risk of having dysmetabolic nephropathy for relatives of the second degree of consanguinity of children with dysmetabolic nephropathy is also quite high – 20.9%. For relatives of the third degree – 3.6%.

It’s all relative: A multi-generational study using ForenSeq™ Kintelligence

The successful application of Forensic Investigative Genetic Genealogy (FIGG) to the identification of unidentified human remains and perpetrators of serious crime has led to a growing interest in its use internationally, including Australia. Routinely, FIGG has relied on the generation of high-density single nucleotide polymorphism (SNP) profiles from forensic samples using whole genome array (WGA) (∼650,000 or more SNPs) or whole genome sequencing (WGS) (millions of SNPs) for DNA segment-based comparisons in commercially available genealogy databases. To date, this approach has required DNA of a quality and quantity that is often not compatible with forensic samples. Furthermore, it requires the management of large data sets that include SNPs of medical relevance. The ForenSeq™ Kintelligence kit, comprising of 10,230 SNPs including 9867 for kinship association, was designed to overcome these challenges using a targeted amplicon sequencing-based method developed for low DNA inputs, inhibited and/or degraded forensic samples. To assess the ability of the ForenSeq™ Kintelligence workflow to correctly predict biological relationships, a comparative study comprising of 12 individuals from a family (with varying degrees of relatedness from 1st to 6th degree relatives) was undertaken using ForenSeq™ Kintelligence and a WGA approach using the Illumina Global Screening Array-24 version 3.0 Beadchip. All expected 1st, 2nd, 3rd, 4th and 5th degree relationships were correctly predicted using ForenSeq™ Kintelligence, while the expected 6th degree relationships were not detected. Given the (often) limited availability of forensic samples, findings from this study will assist Australian Law enforcement and other agencies considering the use of FIGG, to determine if the ForenSeq™ Kintelligence is suitable for existing workflows and casework sample types considered for FIGG.

Screening for familial disease presence in first-degree relatives of Behçet's disease patients: Is measurement of common femoral vein wall thickness valuable for the diagnosis?

We aimed to assess first degree relatives (FDRs) of BD patients for the presence of clinical symptoms and signs of BD and evaluate common femoral vein (CFV) wall thickness measurement for the diagnosis. Patients with BD(n=129) and FDRs(n=230) of these patients were included. FDRs were questioned in terms of BD symptoms by phone. Pathergy test and CFV wall thickness measurement were performed among 111 FDRs who accepted the clinical assessment. Clinical assessment group were classified according to the criteria sets for BD. FDRs who did not meet the criteria sets and had at least one clinical finding in addition to oral aphthae(OA) were categorized as the "suspected BD". :We observed increased frequency of isolated BD manifestations in FDRs. Ten FDRs were diagnosed with BD during clinical evaluation. Significantly increased CFV wall thickness was observed in FDRs of BD patients fulfilling diagnostic BD criteria (p<0.001 for both sides) and also in those with suspected BD group (p<0.05 for both sides). Presence of OA, genital ulcer, folliculitis or erythema nodosum were associated with increased CFV wall thickness (p<0.05). . Our results suggest that CFV wall thickness measurement can be used in diagnosis of familial BD.

How Academicians Fell for Ramsey’s Canard that Keynes did not Give a Definition of Probability

It was F P Ramsey who first claimed that Keynes had stated that probability was indefinable in his 1922 review of Keynes’s A Treatise on Probability in the January issue of Cambridge Magazine: “Mr Keynes takes probabilities or probability relations as indefinable, and says that if q has to p the probability relation of degree a, then knowledge of p justifies rational belief of degree a.” (Ramsey,1922, p.3). Ramsey made an intellectual mess that made it impossible for a reader to understand what Keynes’s formal relational, propositional logic was. This mess can be fixed to some degree by rewriting it in the following manner-Mr. Keynes takes probability as being indefinable if a single definition is required to be given. Let p and q be related propositions, where p contains the premise(s) and q is a conclusion(s) of an argument form based on p. Then knowledge of p justifies a rational degree of partial belief of a in q.

Perspectives of relatives of patients with end-stage kidney disease on kidney sources, commercial kidney donation, and barriers to living kidney donation in Nigeria: a qualitative study.

Kidney transplantation is the best mode of kidney replacement therapy. However, the shortage of organ donations has been a major challenge globally. Relatives of patients with end-stage kidney disease (ESKD) are potential kidney donors. We explored their perspectives about kidney donation, kidney commercialisation, and barriers to kidney donation. In-depth interviews were conducted among 28 relatives of ESKD patients across the six geopolitical zones and Federal Capital Territory of Nigeria. The interview focused on potential sources of kidney donors, kidney commercialisation and barriers to kidney donation. ATLAS.ti version 9.0.22.0 was used for data analysis. Mean age of the study participants was 41.57 ± 14.55years; 54% were females, 60.7% were married, 93% had tertiary education and 75% were first degree relatives of ESKD patients. There were 7 themes and 28 subthemes generated in this study. The potential sources of kidney donors identified by the study participants included commercial, hospital, family and non-family member donors. While some opined that a family member is the best choice as a kidney donor, others preferred a commercial donor. The majority of those interviewed do not believe that it is wrong to purchase a kidney, and would be willing to do so. Identified factors that promote kidney commercialisation were unwillingness of a family member to donate, having the financial capacity to purchase a kidney, non-fitness of family members to donate. Identified barriers to kidney donation were age, poor health status, polygamy, perceived poor expertise of the medical team, perceived risk of the procedure, parental influence and religious beliefs. The majority of participants lacked correct information about kidney donation. Implementation of educational programpolicies and laws regulating and reinforcing ethical principles of kidney donation and transplantation should be ensured.