OBJECTIVE: To investigate linkage and association between the leptin receptor (LEPR) gene and body composition variables in the Que  bec Family Study (QFS). DESIGN: Single-point linkage analysis using families, and covariance and chi-square analyses using normal weight and obese unrelated subjects from QFS. SUBJECTS: 169 nuclear families were used for linkage study. 308 unrelated subjects (146 males; 162 females) from these families were used for chi-square testing of genotype and allele distributions between subjects with body mass index (BMI)`27 kgam 2 (n 167) and those with BMI ! 27 kgam 2 (n 141), and for a series of covariance analyses using age, plus height for fat mass (FM) and fat free mass (FFM), as covariates. A corrected P value (P*) for multiple tests has been calculated according to P* 1-(1-P) number of phenotypes . MEASUREMENTS: Variables were BMI (in kgam 2 ), sum of six skinfolds (SF6 in mm), FM (in kg), percent body fat (%FAT) and FFM (in kg). Polymerase chain react restricted fragment length polymorphisms PCR-RFLP) was used to identi®ed a K109R substitution in exon 4, a Q223R in exon 6, a K656N in exon 14 and an automatic DNA sequencer for a CA microsatellite repeat in intron 3, and heteroduplex pattern on non-denaturing gel for a CTTT repeat in intron 16. RESULTS: Good evidence of linkage was observed for Q223R with FM (P 0.005; P* 0.02), and for the CTTT repeat with FFM (P 0.007; P* 0.03). Weaker linkages (0.02 P 0.05) were also observed between Q223R and BMI, SF6 and FFM, between the CA repeat and BMI, SF6 and FM, and between the CTTT repeat and FM. Moreover, FFM values were found to be different among genotypes for the CTTT repeat polymorphism with heavier females, carriers of the 123* allele at the CTTT repeat, showing 4 kg less of FFM (43.6 AE 1.0, n 21 vs 47.7 AE 0.8, n 30; P 0.005; P* 0.02) than non-carriers. Also, at the Q223R polymorphism, in lower BMI males, carriers of the Q223 allele were 4 kg lighter in FFM (53.4 AE 0.6, n 47 vs 56.6 AE 0.9, n 18; P 0.005; P* 0.02) than non-carriers. No signi®cant differences were observed between lower and higher BMI subjects in genotype and allele frequency distributions for any of the polymorphisms. CONCLUSIONS: These results indicate that the LEPR gene is involved in the regulation of the body composition in human particularly of FFM in the QFS.

Objective: To test for association of the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) K121Q polymorphism with body mass index (BMI) and diabetes in a large sample of Caucasians and African-Americans by selectively genotyping individuals at the extremes of the phenotypic distribution. Subjects: Subsets comprising the extremes of the BMI distribution (10th-20th and above the 90th BMI percentile for Caucasians and between the 10th-30th and above the 80th percentile for African-Americans) from a group of 10 260 Caucasian and 2268 African-American adults participating in New York Cancer Project were studied. Methods: Subjects were genotyped for the ENPP1 K121Q polymorphism by pyrosequencing and tested for association with BMI and diabetes by regression analysis. Results: Regression analysis with BMI as the dependent variable demonstrated a significant association (P ¼ 0.02) of genotype at K121Q with BMI, with no significant race-by-genotype interaction (P ¼ 0.30). Compared with Q/Q or Q/K individuals, the K/K individuals had a BMI approximately 1.3 kg/m 2 higher, without effects of age, gender or race. By logistic regression analysis, the K121Q alleles had no significant effect on diabetes status (P ¼ 0.37) in obese subjects. Conclusion: In both Caucasians and African-Americans, the K121 polymorphism in ENPP1 was associated with increased BMI, but not with diabetes.

Suggestive linkages between markers on human lp32-p22 and body fat and insulin levels in the Quebec family study. Obes Res. 1997;5:115-121. A single-gene rodent mutation (diabetes) and a quantitative trait locus (dietary obese I) mapped to the mid portion of mouse chromosome 4 have been related to obesity and/or insulin levels. Synteny relationships place their putative human homologs on lp31 and 1~3 5~3 1 , respectively. In 137 sibships of adult brothers and sisters from the Quebec Family Study, genetic linkages between seven microsatellite markers from lp32-p22 and various obesity-and diabetes-related quantitative phenotypes were examined using single locus sibpair linkage analysis. Suggestive linkages were observed between markers DlS476 and body mass index (p=0.05), fat mass (p=0.02), the sum of six skinfolds (p=0.02), the insulin area after an oral glucose tolerance test (p=0.02), and between the neighboring marker DlS200 and body mass index (p=0.03), and fat mass (p=0.009). Suggestive linkages were also observed between the more telomeric markers DlS193 and body mass index (p=0.03), and between the neighboring marker DlS197 and fasting insulin level extremity skinfolds ratio. These linkages suggest that human homologs of the mouse diabetes or dietary obese I and/or other genes in this interval on chromosome 1 play a role in the regulation of body mass, body composition, and insulin levels, but not of subcutaneous fat distribution.

Genetic testing for hereditary breast and ovarian cancer (HBOC) is recommended for breast cancer patients diagnosed at age ≤ 50 years. Our objective was to examine racial/ethnic differences in genetic testing frequency and results among diverse breast cancer patients. A retrospective cohort study among women diagnosed with breast cancer at age ≤ 50 years from January 2007 to December 2017 at Columbia University in New York, NY. Among 1503 diverse young breast cancer patients, nearly half (46.2%) completed HBOC genetic testing. Genetic testing completion was associated with younger age, family history of breast cancer, and earlier stage, but not race/ethnicity or health insurance status. Blacks had the highest frequency of pathogenic/likely pathogenic (P/LP) variants (18.6%), and Hispanics and Asians had the most variants of uncertain significance (VUS), 19.0% and 21.9%, respectively. The percentage of women undergoing genetic testing increased over time from 15.3% in 2007 to a peak of 72.8% in 2015. Over the same time period, there was a significant increase in P/LP and VUS results. Due to uncertainty about the clinical implications of P/LP variants in moderate penetrance genes and VUSs, our findings underscore the need for targeted genetic counseling education, particularly among young minority breast cancer patients. Keywords BRCA1/2 genetic testing. Multigene panel testing. Young breast cancer patients. Racial/ethnic minorities

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities (HPPs) of being causal.Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the 178 highest confidence target genes.

Background: The prevalence of BRCA1/2 mutations among Ashkenazi Jews is 1 in 40. Compared to family history-based BRCA testing, population-based testing has been shown to detect more mutation carriers in this population. Orthodox Jews (OJ) are the largest and fastest-growing Jewish population in NY and represent a spectrum of observance including Modern Orthodox, Yeshivish, and Chassidic. This understudied population has unique social, cultural, and religious factors that may influence BRCA genetic testing. We examined factors influencing BRCA genetic testing decision-making and uptake among OJ women. Methods: Using a mixed-methods approach, we conducted a cross-sectional online survey and 4 focus groups among OJ women in 5 communities in the NY/NJ area. The online survey included items on demographics, breast cancer risk factors, and validated measures of genetic testing intention/knowledge, breast cancer worry/risk perception, stigma, and religious/cultural factors affecting medical decision-making. Descriptive statistics and bivariate and multivariable logistic regression models were conducted. We conducted 4 focus groups with purposive sampling of women who responded to the survey. The qualitative analysis of the semi-structured focus group discussions further explored factors affecting BRCA genetic testing uptake. Results: Among 321 evaluable survey participants, median age was 47 years (range, 25-82); 55.8% were Modern Orthodox, 30.5% Yeshivish, and 2.8% Chassidic; 84% were married; 6.2% and 0.6% had a history of breast and ovarian cancer, respectively. Although 57.6% had a masters or doctoral degree, only 37.7% had adequate genetic testing knowledge. Nearly 20% of the surveyed women had undergone BRCA genetic testing. After adjusting for known confounders, women who met family history criteria for BRCA genetic testing were nearly 10 times more likely to undergo genetic testing. Modern Orthodox compared to non-Modern Orthodox women and married compared to unmarried women were more likely to undergo genetic testing (odds ratio [OR]=2.31, 95% confidence interval [CI]=1.03-5.17; OR=3.49, 95% CI=1.03-11.80, respectively). Compared to Modern Orthodox women, non-Modern Orthodox women were more likely to consult with a rabbi or religious figure when considering genetic testing and other medical decisions. The focus group participants (N=31) confirmed the importance of rabbinic consultation in medical decision-making. Although stigma was not associated with genetic testing uptake in our survey data, it emerged as a prominent factor in decision-making among focus group participants due to its potential impact on marriageability and family. Conclusions: We found that non-Modern Orthodox and unmarried women are less likely to seek BRCA genetic testing. Among non-Modern Orthodox women, rabbinic consultation was an important factor in genetic testing decision-making. By understanding the religious and cultural issues regarding genetic testing in the OJ community and by engaging faith-based leaders, we can develop culturally sensitive interventions designed to enhance knowledge and informed choice about BRCA genetic testing, which may facilitate the implementation of population-based genetic screening among Ashkenazi Jews. Citation Format: Trivedi MS, Colbeth H, Yi H, Vanegas A, Starck R, Chung WK, Appelbaum PS, Kukafka R, Schechter I, Crew KD. Understanding factors associated with uptake of BRCA genetic testing among Orthodox Jewish women using a mixed-methods approach [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-19.

76From a GeneMatcher-enabled international collaboration, we identified ten individuals with 77 intellectual disability, speech delay, ataxia and facial dysmorphism and a mutation in EBF3, 78 encoding a transcription factor required for neuronal differentiation. Structural assessments, 79 transactivation assays, in situ fractionation, RNA-seq and ChIP-seq experiments collectively 80 show that the mutations are deleterious and impair EBF3 transcriptional regulation. These 81 findings demonstrate that EBF3-mediated dysregulation of gene expression has profound 82 effects on neuronal development in humans. 83 84 85 ⏐ 4Intellectual disability (ID) is a common phenotype with extreme clinical and genetic 86 heterogeneity. Widespread application of whole-genome and whole-exome sequencing 87 (WES) has tremendously increased the elucidation of the genetic causes of non-syndromic 88 and syndromic forms of ID 1,2 . WES together with the freely accessible tool GeneMatcher 89 (http://genematcher.org) which brings together clinicians and researchers with an interest in 90 the same gene, significantly aid in identifying new disease genes 3 . 91 We investigated a family with three healthy and two affected children, who both 92 presented with global developmental delay, febrile seizures, and gait instability with frequent 93 falls. WES was performed in both probands and one healthy sibling. We initially 94 hypothesized a Mendelian recessive trait; however, we did not identify any rare, potentially 95 pathogenic biallelic variants in the affected siblings (data not shown). WES data were 96 analyzed for heterozygous variants absent in dbSNP138, 1000 Genomes Project, Exome 97 Variant Server, and ExAC Browser, shared by both affected subjects and absent in the healthy 98 sibling. This analysis identified 16 variants (Supplementary Table 1). We used objective 99 metrics from ExAC to prioritize genes intolerant to functional variation (pLI ≥0.9 and high 100 values for Z score) ( Supplementary Table 1) 101 (http://biorxiv.org/content/early/2015/10/30/030338); five genes were identified with strong 102 selection against various classes of variants for segregation analysis in the family 103 (Supplementary Table 1). Four variants were inherited from a healthy parent and/or were 104 present in two healthy siblings (Supplementary Table 2). The missense variant c.625C>T 105[p.(Arg209Trp)] in EBF3 was confirmed in both affected siblings and was absent in the father 106 and all healthy siblings ( Supplementary Fig. 1a and Supplementary Table 2). In leukocyte-107 derived DNA from the mother, the Sanger sequence profile showed a very low signal for the 108 mutated base (thymine) superimposed on the wild-type sequence (cytosine) suggesting that 109 she had somatic mosaicism for the EBF3 variant (Supplementary Fig. 1a) 4 . By cloning the 110 mutation-bearing EBF3 amplicon followed by sequencing of colony PCR products, we 111 ⏐ 5 confirmed the mother to be a mosaic carrier (18% and 4% of leukocytes and buccal cells, 112 respectively, wer...

Accurate prediction of damaging missense variants is critically important for interpretating genome sequence. While many methods have been developed, their performance has been limited. Recent progress in machine learning and availability of large-scale population genomic sequencing data provide new opportunities to significantly improve computational predictions. Here we describe gMVP, a new method based on graph attention neural networks. Its main component is a graph with nodes capturing predictive features of amino acids and edges weighted by coevolution strength, which enables effective pooling of information from local protein sequence context and functionally correlated distal positions. Evaluated by deep mutational scan data, gMVP outperforms published methods in identifying damaging variants in TP53, PTEN, BRCA1, and MSH2. Additionally, it achieves the best separation of de novo missense variants in neurodevelopmental disorder cases from the ones in controls. Finally, the model supports transfer learning to optimize gain- and loss-of-function predictions in sodium and calcium channels. In summary, we demonstrate that gMVP can improve interpretation of missense variants in clinical testing and genetic studies.