APOE ε4 carrier status modifies plasma p-tau181 concentrations in cognitively healthy super-seniors.

INTRODUCTION: This study investigates the effect of apolipoprotein E (APOE) genotype on neurology plasma biomarkers in cognitively healthy Super-Seniors. METHODS: Three hundred seventy plasma specimens from Super-Senior participants ≥ 85 years old, who have never been diagnosed with dementia, cancer, diabetes, cardiovascular, or major pulmonary disease, were analyzed on the Quanterix Simoa HD-X analyzer using commercial Neurology 4-plex E and phosphorylated tau (p-tau)181 assays. RESULTS: Eighty (22%) participants were APOE ε4 carriers and 290 (73%) were non-carriers. No significant differences were found between APOE ε4 carriers and non-carriers regarding age, sex, or Mini-Mental State Examination scores. In APOE ε4 carriers, plasma amyloid beta 42/40 was lower and p-tau181 and glial fibrillary acidic protein were higher compared to non-APOE ε4 carriers. After adjusting for demographic variables, p-tau181 was the only biomarker to remain significantly associated with APOE ε4 carrier status. DISCUSSION: APOE ε4 genotype modifies plasma p-tau181 concentration in seniors resilient to age-related clinical disease, suggesting that some Super-Seniors may have Alzheimer's disease pathology without progressing to cognitive decline. HIGHLIGHTS: Healthy seniors enable identification of associations that may be masked by disease. Plasma phosphorylated tau (p-tau)181 concentrations associate with apolipoprotein E (APOE) ε4 carriership in healthy seniors. APOE should be accounted for when interpreting p-tau181, regardless of disease.

Gene and pathway based burden analyses in familial lymphoid cancer cases: Rare variants in immune pathway genes.

Genome-wide association studies have revealed common genetic variants with small effect sizes associated with diverse lymphoid cancers. Family studies have uncovered rare variants with high effect sizes. However, these variants explain only a portion of the heritability of these cancers. Some of the missing heritability may be attributable to rare variants with small effect sizes. We aim to identify rare germline variants associated with familial lymphoid cancers using exome sequencing. One case per family was selected from 39 lymphoid cancer families based on early onset of disease or rarity of subtype. Control data was from Non-Finnish Europeans in gnomAD exomes (N = 56,885) or ExAC (N = 33,370). Gene and pathway-based burden tests for rare variants were performed using TRAPD. Five putatively pathogenic germline variants were found in four genes: INTU, PEX7, EHHADH, and ASXL1. Pathway-based association tests identified the innate and adaptive immune systems, peroxisomal pathway and olfactory receptor pathway as associated with lymphoid cancers in familial cases. Our results suggest that rare inherited defects in the genes involved in immune system and peroxisomal pathway may predispose individuals to lymphoid cancers.

Costs and Effects of School-Based Licensed Practical Nurses on Elementary Student Attendance and Chronic Absenteeism.

Despite increasing reliance on licensed practical nurses (LPNs) to provide health services in schools, we do not know whether this is a cost-effective prevention strategy against student absenteeism. Therefore, we evaluated the costs and effectiveness of an LPN-based school nursing program for improving attendance and chronic absenteeism at a large, urban school district in the southeastern USA. We first identified a matched set of 46 elementary schools (23 nurse, 23 no-nurse) by using an optimal multilevel matching algorithm based on student- and school-level characteristics. We then conducted a cost-effectiveness analysis on the matched set, using the ingredients method to estimate societal costs and multilevel regression to estimate effects. The results indicated that despite substantial incremental costs of $68,228 per school, the presence of a full-time LPN was associated with at best negligible improvements, and at worst slight disimprovements, in attendance and chronic absenteeism. We recommend a careful review of the theory of change for LPN-based school nursing programs to clarify the specific inputs and activities that are expected to lead to improved student outcomes. Education agencies should develop explicit assignment, training, monitoring, and auditing plans to ensure LPNs are equitably distributed and that their activities are aligned with the theory of change. Education agencies should also explore whether expanded Medicaid billing can reduce their share of the nursing cost burden.

Material circumstances, health care access, and self-reported health: A latent class analysis.

Latent class analysis was used to explore intersections of material circumstances and health care access among 308 adults, and associations between classes with health outcomes. Good fit was found for a four-class model: Resource Stable (Class 1, 62.43%), Unbalanced Meals with Health Care (Class 2, 16.91%), Resource Insecurity with Delayed Health Care (Class 3, 14.75%), and Resource Stability without Access to Health Care (Class 4, 5.91%). Class 1 reported greater well-being and self-rated health than Class 2 and 3. Class 1 reported lower BMI than Class 2. Findings document intersections among economic marginalization indicators with varying health outcomes among classes.

Restorative Practices: Using local evidence on costs and student outcomes to inform school district decisions about behavioral interventions.

School disciplinary practices affect student academic and life outcomes. Many schools have recently shifted towards the prevention of behavioral disorders rather than the punishment of such disorders, but disciplinary actions are still disproportionately meted out to Black students. We took advantage of a natural experiment in a large school district to investigate the costs and effects of a school-wide intervention based on the principles of restorative justice on suspensions, referrals, and three school climate constructs. The study involved 14 elementary and middle schools, each of which was already implementing Positive Behavioral Interventions and Supports (PBIS). Six of the schools integrated Restorative Practices into their PBIS framework during the first year of the study, whereas the other eight served as comparison schools and implemented the program the following year. We tested a difference-in-difference regression model for each of our five outcomes of interest after 1 year of implementation using Quasi-Poisson models for referrals and suspensions. We found no statistically significant effects on four of the outcomes, either for the overall sample or by racial subgroup. We found negative effects on student-reported personal safety. An additional analysis 1 year later showed that Black students in schools implementing Restorative Practices for 2 years experienced a greater reduction in suspensions than Black students in schools implementing the program for only 1 year. We used the ingredients method to estimate start-up costs and ongoing costs for the first full year of implementation. Our reference case analysis results using a societal perspective, national average prices, and a 3% discount rate were $57,450 per school and $139 per student for the first year of Restorative Practices implementation. These estimates included training costs from the prior year and were incremental to the costs of PBIS, which served as the business-as-usual condition. We compared these costs to those of a number of other behavioral interventions and concluded that Restorative Practices are relatively low cost but may need to be implemented for several years with greater fidelity in order to produce the desired improvements in behavior events and school climate.

Mindfulness, self-reported health, and cortisol: A latent profile analysis.

This study utilized a latent profile analysis approach to examine the relationship between mindfulness profiles and self-reported mental and physical health, as well as salivary cortisol levels in a sample of 85 undergraduate students. Consistent with theory, the Judgmentally Observing (high monitoring, low acceptance) reported poorer mental health and exhibited flatter diurnal cortisol slopes than the Unobservant Accepting (low monitoring, high acceptance) and Average Mindfulness profiles. No differences in self-reported physical health, cortisol response to awakening, or diurnal mean cortisol were observed among the profiles. Future directions are discussed.

Allele-Specific Transcript Abundance: A Pilot Study in Healthy Centenarians.

The genetic basis of healthy aging and longevity remains largely unexplained. One hypothesis as to why long-lived individuals do not appear to have a lower number of common-complex disease variants, is that despite carrying risk variants, they express disease-linked alleles at a lower level than the wild-type alleles. Allele-specific abundance (ASA) is the different transcript abundance of the two haplotypes of a diploid individual. We sequenced the transcriptomes of four healthy centenarians and four mid-life controls. CIBERSORT was used to estimate blood cell fractions: neutrophils were the most abundant source of RNA, followed by CD8+ T cells, resting NK cells, and monocytes. ASA variants were more common in noncoding than coding regions. Centenarians and controls had a comparable distribution of ASA variants by predicted effect, and we did not observe an overall bias in expression toward major or minor alleles. Immune pathways were most highly represented among the gene set that showed ASA. Although we found evidence of ASA in disease-associated genes and transcription factors, we did not observe any differences in the pattern of expression between centenarians and controls in this small pilot study.

Families and Schools Together (FAST) for improving outcomes for children and their families.

BACKGROUND: Parents and carers have a major influence on children's learning and development from birth, through the school years, and into adulthood. Parental contributions to education include providing a secure environment in which to learn, providing intellectual stimulation, transmitting social norms and values, shaping the child's resilience through fostering literacy and problem-solving, and encouraging personal and social aspiration. Increasingly, providers of formalised education are recognising the primary role of parents, carers, and the wider family, as well as peers and the environment, in shaping children's education, health, and life experiences. OBJECTIVES: To assess the effectiveness of the Families and Schools Together (FAST) programme in improving outcomes among children and their families. SEARCH METHODS: Between October 2018 and December 2018, we searched CENTRAL, MEDLINE, Embase, PsycINFO, 11 additional databases, and three trial registers. We handsearched the reference lists of included studies and relevant reports and reviews, contacted the programme developer and independent researchers, and searched relevant websites to identify other eligible studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs examining the effects of FAST, relative to waiting list, usual or alternative services, or no intervention, on outcomes for children (aged from birth to completion of compulsory education) and their families. DATA COLLECTION AND ANALYSIS: At least two review authors independently evaluated the records retrieved from the search for relevance. One review author (JV) extracted data from eligible studies with a second independent review author (AF, DK, or SL). Review authors consulted with one another to resolve disagreements. We used a fixed-effect model for meta-analysis. We presented results as standardised mean differences (SMDs) because all outcomes were continuously scaled, and we accompanied these with 95% confidence intervals (CIs). We used the GRADE approach to assess the certainty of evidence for each outcome. MAIN RESULTS: We identified 10 completed RCTs, most of which were relatively recent (2007 or later) and were conducted with at least some involvement from the intervention developer or the FAST organisation. Nine of the 10 trials were from the USA; the other was from the UK. Children were young (five to nine years old; mean age approximately six years), and therefore, whilst not so named in the reports, evaluations consisted of what is sometimes referred to as 'Kids FAST' and sometimes 'Elementary Level FAST'). Among the USA-based studies, at least 62% of participants were members of a racial/ethnic minority group (most commonly, African American or Latino). FAST was usually delivered in schools after the school day. Trials lasted about eight weeks and usually examined the effects of FAST relative to no additional intervention. Most studies were funded by agencies in the US federal government. We judged the certainty of evidence in the included studies to be moderate or low for the main review outcomes. Failure to include all families in outcome analyses (attrition) and possible bias in recruitment of families into the trials were the main limitations in the evidence.We included over 9000 children and their families in at least one meta-analysis. The follow results relate to meta-analyses of data at long-term follow-up.Primary outcomesFour studies (approximately 6276 children) assessed child school performance at long-term follow-up. The effect size was very small, and the CI did not include effects that, if real, suggest possibly important positive or negative effects if viewed from an individual perspective (SMD -0.02, 95% CI -0.11 to 0.08). We assessed the certainty of evidence for this outcome as moderate. No studies assessed child adverse events, parental substance use, or parental stress.Secondary outcomesParent reports of child internalising behaviour (SMD -0.03, 95% CI -0.11 to 0.17; 4 RCTs, approximately 908 children; low-certainty evidence) and family relationships (SMD 0.08, 95% CI -0.03 to 0.19; 4 RCTs, approximately 2569 children; moderate-certainty evidence) also yielded CIs that did not include effects that, if real, suggest possibly important positive or negative effects.The CI for parent reports of child externalising behaviour, however, did include effects that, if real, were possibly large enough to be important (SMD -0.19, 95% CI -0.32 to -0.05; 4 RCTs, approximately 754 children; low-certainty evidence). AUTHORS' CONCLUSIONS: Given these results, it is hard to support the assertion that assignment to FAST is associated with important positive outcomes for children and their parents.

Structure and Reactivity of Al-O(H)-Al Moieties in Siloxide Frameworks: Solution and Gas-Phase Model Studies.

Even though aluminas and aluminosilicates have found widespread application, a consistent molecular understanding of their surface heterogeneity and the behavior of defects resulting from hydroxylation/dehydroxylation remains unclear. Here, we study the well-defined molecular model compound, [Al3 (µ2 -OH)3 (THF)3 (PhSi(OSiPh2 O)3 )2 ], 1, to gain insight into the acid-base reactivity of cyclic trinuclear Al3 (µ2 -OH)3 moieties at the atomic level. We find that, like zeolites, they are sufficiently acidic to catalyze the isomerization of olefins. DFT and gas phase vibrational spectroscopy on solvent-free and deprotonated 1 show that the six-membered ring structure of its Al3 (µ2 -OH)3 core is unstable with respect to deprotonation of one of its hydroxy groups and rearranges into two edge-sharing four-membered rings. This renders AlIV -O(H)-AlIV units strong acid sites, and all results together suggest that their acidity is similar to that of zeolitic SiIV -O(H)-AlIV groups.

The Super-Seniors Study: Phenotypic characterization of a healthy 85+ population.

BACKGROUND: To understand why some people live to advanced age in good health and others do not, it is important to study not only disease, but also long-term good health. The Super-Seniors Study aims to identify factors associated with healthy aging. METHODS: 480 healthy oldest-old 'Super-Seniors' aged 85 to 105 years and never diagnosed with cancer, cardiovascular disease, diabetes, dementia, or major pulmonary disease, were compared to 545 mid-life controls aged 41-54, who represent a group that is unselected for survival from late-life diseases. Health and lifestyle information, personal and family medical history, and blood samples were collected from all participants. Super-Seniors also underwent four geriatric tests. RESULTS: Super-Seniors showed high cognitive (Mini-Mental State Exam mean = 28.3) and functional capacity (Instrumental Activities of Daily Living Scale mean = 21.4), as well as high physical function (Timed Up and Go mean = 12.3 seconds) and low levels of depression (Geriatric Depression Scale mean = 1.5). Super-Seniors were less likely to be current smokers than controls, but the frequency of drinking alcohol was the same in both groups. Super-Seniors were more likely to have 4 or more offspring; controls were more likely to have no children. Female Super-Seniors had a mean age of last fertility 1.9 years older than controls, and were 2.3 times more likely to have had a child at ≥ 40 years. The parents of Super-Seniors had mean ages of deaths of 79.3 years for mothers, and 74.5 years for fathers, each exceeding the life expectancy for their era by a decade. CONCLUSIONS: Super-Seniors are cognitively and physically high functioning individuals who have evaded major age-related chronic diseases into old age, representing the approximately top 1% for healthspan. The familiality of long lifespan of the parents of Super-Seniors supports the hypothesis that heritable factors contribute to this desirable phenotype.

Precipitating polyelectrolyte-surfactant systems by admixing a nonionic surfactant - a case of cononsurfactancy.

The formation of water insoluble polyelectrolyte/surfactant complexes (PESCs) upon mixing two homogeneous polycation/anionic surfactant and polycation/nonionic surfactant solutions is reported here. This phase separation is unexpected and differs markedly from the commonly observed enhanced solubility of colloidal systems in mixed surfactant systems. The study was performed on mixtures of the cationic biopolysaccharide chitosan (poly d-glucosamine) and mixed micelles composed of an ethoxylated fatty alcohol and its carboxylic acid terminated equivalent. The thermodynamics of mixing was probed via isothermal titration calorimetry (ITC), while the structural characterisation was conducted by means of light and neutron scattering (SANS). The results show that the substitution of a weakly anionic surfactant with its nonionic equivalent has profound effects on the interactions at very different length scales. The dilution of the ionic headgroups allows for a more efficient interaction between micelles and polymer chains, and results in an elongation of the mixed micelles which reduces the bending cost of the semi-rigid chitosan and introduces an additional attractive potential of entropic origin. In this work, as a result of a comprehensive thermodynamic and structural analysis, we demonstrate how the subtle interplay of different forces leads to such an unexpected behaviour, where the addition of a nonionic surfactant causes the phase separation of electrostatic complexes.

Lipid and Alzheimer's disease genes associated with healthy aging and longevity in healthy oldest-old.

Several studies have found that long-lived individuals do not appear to carry lower numbers of common disease-associated variants than ordinary people; it has been hypothesized that they may instead carry protective variants. An intriguing type of protective variant is buffering variants that protect against variants that have deleterious effects. We genotyped 18 variants in 15 genes related to longevity or healthy aging that had been previously reported as having a gene-gene interaction or buffering effect. We compared a group of 446 healthy oldest-old 'Super-Seniors' (individuals 85 or older who have never been diagnosed with cancer, cardiovascular disease, dementia, diabetes or major pulmonary disease) to 421 random population-based midlife controls. Cases and controls were of European ancestry. Association tests of individual SNPs showed that Super-Seniors were less likely than controls to carry an APOEε4 allele or a haptoglobin HP2 allele. Interactions between APOE/FOXO3, APOE/CRYL1, and LPA/CRYL1 did not remain significant after multiple testing correction. In a network analysis of the candidate genes, lipid and cholesterol metabolism was a common theme. APOE, HP, and CRYL1 have all been associated with Alzheimer's Disease, the pathology of which involves lipid and cholesterol pathways. Age-related changes in lipid and cholesterol maintenance, particularly in the brain, may be central to healthy aging and longevity.

Burden of Common Complex Disease Variants in the Exomes of Two Healthy Centenarian Brothers.

BACKGROUND: It is not understood whether long-term good health is promoted by the absence of disease risk variants, the presence of protective variants, or both. We characterized the exomes of two exceptionally healthy centenarian brothers aged 106 and 109 years who had never been diagnosed with cancer, cardiovascular disease, diabetes, Alzheimer's disease, or major pulmonary disease. OBJECTIVE: The aim of this study was to gain insight into whether exceptional health and longevity are a result of carrying fewer disease-associated variants than typical individuals. METHODS: We compared the number of disease-associated alleles, and the proportion of alleles predicted to be functionally damaging, between the centenarian brothers and published population data. Mitochondrial sequence reads were extracted from the exome data in order to analyze mitochondrial variants. RESULTS: The brothers carry a similar number of common disease-associated variants and predicted damaging variants compared to reference groups. They did not carry any high-penetrance clinically actionable variants. They carry mitochondrial haplogroup T, and one brother has a single heteroplasmic variant. CONCLUSION: Although our small sample size does not allow for definitive conclusions, a healthy aging and longevity phenotype is not necessarily due to a decreased burden of common disease-associated variants. Instead, it may be rare 'positive' variants that play a role in this desirable phenotype.

Rare and common variants in the Apolipoprotein E gene in healthy oldest old.

Apolipoprotein E (APOE) alleles are associated with longevity in genome-wide scans, with ε4 correlated with shorter life, and ε2 with longer life, than ε3. We hypothesized that rare APOE variants with large individual effects might also contribute to long-term good health. The APOE exons and promoter were resequenced in DNA samples from 376 healthy oldest old aged ≥ 85 yrs with no self-reported history of cancer, cardiovascular disease, diabetes, major pulmonary disease or Alzheimer disease ("Super-Seniors") and 376 population-based controls aged 41-54. Forty variants were observed: 32 were rare (minor allele frequency <2%); 9 were nonsynonymous. Controls were more likely to have an ε4 allele (Pearson χ(2) = 6.61, p = 0.04). Among the Super-Seniors, APOE allele status was not associated with body mass index or Mini Mental State Examination score. There was no excess of rare APOE variants in healthy oldest old compared with midlife controls, or vice-versa; however, this does not rule out an effect of some variants on ApoE function. Our findings were consistent with ε4 being a risk factor for early mortality.

Functional characterization of genetic polymorphisms in the H2AFX distal promoter.

Due to the critical role of the H2AX histone variant in double-strand break repair, genetic variants in the H2AX gene, H2AFX, may influence cancer susceptibility. Genetic association studies have correlated H2AFX upstream variants with cancer risk; however it is unclear if any are causal. H2AFX has at least two alternate transcripts that encode the same reading frame; a short 0.6kb transcript that lacks an intron or poly-A tail and is predicted to be highly expressed during the replication stage of the cell cycle, and a long 1.6kb poly-A tailed transcript that is expressed in a replication-independent manner. To examine the functional impact of the rs643788, rs8551, rs7759, and rs2509049 upstream variants, we characterized their influence on gene expression, cell survival after DNA assault, and transcription factor binding. Analysis of allelic imbalance using quantitative sequencing of cDNA from lymphoblast cell lines did not reveal any difference in expression of the 1.6kb polyadenylated transcript between the common H2AFX upstream haplotypes. We did, however, identify a previously unreported 197 base pair intron in the H2AFX 3'untranslated region that appears to be present regardless of haplotype. Assessment of cell survival after irradiation treatment did not show any difference in survival between cell lines of different haplotypes. Gel shift assays revealed that the rs643788 C allele disrupts YY1 transcription factor binding and the rs2509049 C allele binds more strongly to a protein complex than does the rs2509049 T allele. Though we did not identify any differences in expression or survival between haplotypes, differential protein binding at two of the polymorphisms suggests further functional analyses may reveal a role for these variants in influencing gene expression at specific points of the cell cycle or in specific tissues.

Non-Hodgkin lymphoma risk and variants in genes controlling lymphocyte development.

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of solid tumours of lymphoid cell origin. Three important aspects of lymphocyte development include immunity and inflammation, DNA repair, and programmed cell death. We have used a previously established case-control study of NHL to ask whether genetic variation in genes involved in these three important processes influences risk of this cancer. 118 genes in these three categories were tagged with single nucleotide polymorphisms (SNPs), which were tested for association with NHL and its subtypes. The main analysis used logistic regression (additive model) to estimate odds ratios in European-ancestry cases and controls. 599 SNPs and 1116 samples (569 cases and 547 controls) passed quality control measures and were included in analyses. Following multiple-testing correction, one SNP in MSH3, a mismatch repair gene, showed an association with diffuse large B-cell lymphoma (OR: 1.91; 95% CI: 1.41-2.59; uncorrected p = 0.00003; corrected p = 0.010). This association was not replicated in an independent European-ancestry sample set of 251 diffuse large B-cell lymphoma cases and 737 controls, indicating this result was likely a false positive. It is likely that moderate sample size, inter-subtype and other genetic heterogeneity, and small true effect sizes account for the lack of replicable findings.

Shift work, circadian gene variants and risk of breast cancer.

Circadian (clock) genes have been linked with several functions relevant to cancer, and epidemiologic research has suggested relationships with breast cancer risk for variants in NPAS2, CLOCK, CRY2 and TIMELESS. Increased breast cancer risk has also been observed among shift workers, suggesting potential interactions in relationships of circadian genes with breast cancer. Relationships with breast cancer of 100 SNPs in 14 clock-related genes, as well as potential interactions with shift work history, were investigated in a case-control study (1042 cases, 1051 controls). Odds ratios in an additive genetic model for European-ancestry participants (645 cases, 806 controls) were calculated, using a two-step correction for multiple testing: within each gene through permutation testing (10,000 permutations), and correcting for the false discovery rate across genes. Interactions of genotypes with ethnicity and shift work (<2 years vs ≥2 years) were evaluated individually. Following permutation analysis, two SNPs (rs3816360 in ARNTL and rs11113179 in CRY1) displayed significant associations with breast cancer and one SNP (rs3027188 in PER1) was marginally significant; however, none were significant following adjustment for the false discovery rate. No significant interaction with shift work history was detected. If shift work causes circadian disruption, this was not reflected in associations between clock gene variants and breast cancer risk in this study. Larger studies are needed to assess interactions with longer durations (>30 years) of shift work that have been associated with breast cancer.

Genetic polymorphisms at TIMP3 are associated with survival of adenocarcinoma of the gastroesophageal junction.

The poor survival of adenocarcinomas of the gastroesophageal junction (GEJ) makes them clinically important. Discovery of host genetic factors that affect outcome may guide more individualized treatment. This study tests whether constitutional genetic variants in matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) genes are associated with outcome of GEJ adenocarcinoma. Single nucleotide polymorphisms (SNPs) at four TIMP (TIMP1-4) and three MMP genes (MMP2, MMP7 and MMP9) were genotyped in DNA samples from a prospective cohort of patients with primary adenocarcinoma of the GEJ admitted to the British Columbia Cancer Agency. Cox proportional hazards regression, with adjustment for patient, disease and treatment variables, was used to estimate the association of SNPs with survival. Genotypes for 85 samples and 48 SNPs were analyzed. Four SNPs across TIMP3, (rs130274, rs715572, rs1962223 and rs5754312) were associated with survival. Interaction analyses revealed that the survival associations with rs715572 and rs5754312 are specific and significant for 5FU+cisplatin treated patients. Sanger sequencing of the TIMP3 coding and promoter regions revealed an additional SNP, rs9862, also associated with survival. TIMP3 genetic variants are associated with survival and may be potentially useful in optimizing treatment strategies for individual patients.

Catenin family genes are not commonly mutated in hereditary diffuse gastric cancer.

BACKGROUND: Approximately one third of the hereditary diffuse gastric cancer (HDGC) families carry germline mutations in the E-cadherin gene (CDH1). Risk prediction in members of families with this rare but deadly cancer could be improved by the identification of additional HDGC genes in non-CDH1 families. METHODS: Affected individuals from 22 CDH1 mutation-negative families were screened for germline mutations in four catenin genes: CTNNA1, CTNNB1, JUP, and CTNND1. Catenins interact closely with E-cadherin molecules in cells, and are therefore logical candidate genes for mutation screening in HDGC families. RESULTS: No nonsynonymous variants were seen in CTNNA1, CTNNB1, or CTNND1; only JUP contained nonsynonymous variants, of which only two rare variants were predicted to be deleterious. CONCLUSION: Catenin genes are not commonly mutated in non-CDH1 HDGC families. IMPACT: Germline mutations in CTNNA1, CTNNB1, JUP, or CTNND1 are unlikely to play a major role in HDGC.