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Background Three genes clustered together on chromosome 12 comprise a group of hydroxycarboxylic acid receptors (HCARs): HCAR1, HCAR2, and HCAR3. These paralogous genes encode different G-protein coupled receptors responsible for detecting glycolytic metabolites and controlling fatty acid oxidation. Though better known for regulating lipid metabolism in adipocytes, more recently, HCARs have been functionally associated with breast cancer proliferation/survival; HCAR2 has been described as a tumor suppressor and HCAR1 and HCAR3 as oncogenes. Thus, we sought to identify germline variants in HCAR1, HCAR2, and HCAR3 that could potentially be associated with breast cancer risk. Methods Two different cohorts of breast cancer cases were investigated, the Alabama Hereditary Cancer Cohort and The Cancer Genome Atlas, which were analyzed through nested PCRs/Sanger sequencing and whole-exome sequencing, respectively. All datasets were screened for rare, non-synonymous coding variants. Results Variants were identified in both breast cancer cohorts, some of which appeared to be associated with breast cancer BC risk, including HCAR1 c.58C > G (p.P20A), HCAR2 c.424C > T (p.R142W), HCAR2 c.517_518delinsAC (p.G173T), HCAR2 c.1036A > G (p.M346V), HCAR2 c.1086_1090del (p.P363Nfs*26), HCAR3 c.560G > A (p.R187Q), and HCAR3 c.1117delC (p.Q373Kfs*82). Additionally, HCAR2 c.515C > T (p.S172L), a previously identified loss-of-function variant, was identified. Conclusions Due to the important role of HCARs in breast cancer, it is vital to understand how these genetic variants play a role in breast cancer risk and proliferation and their consequences on treatment strategies. Additional studies will be needed to validate these findings. Nevertheless, the identification of these potentially pathogenic variants supports the need to investigate their functional consequences.

Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent–offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case–parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry. Electronic supplementary material The online version of this article (10.1007/s00439-019-02099-1) contains supplementary material, which is available to authorized users.

There is a need to investigate and better understand the inherited risk of cancer to ensure that clinical applications provide more accurate assessments and management strategies. Developing research-based next-generation sequencing gene panels that not only target (present-day) clinically actionable susceptibility genes but also genes that currently lack sufficient evidence for risk as well as candidate genes, such as those in DNA repair pathways, can help aid this effort. Therefore, gene panel B.O.P. (Breast, Ovarian, and Prostate) was developed to evaluate the genetic risk of breast, ovarian and/or prostate cancer, and this manuscript serves as an introduction to B.O.P. and highlights its initial analytical validity assessment. B.O.P targets 87 genes that have been suggested, predicted, or clinically proven to be associated with breast, ovarian, and/or prostate cancer risk using Agilent Technologies Haloplex probes. The probes were designed for 100 base pair reads on an Illumina platform and target both coding and non-coding exons as well as 10 intronic base pairs flanking the intron-exon boundaries. The initial B.O.P screening involved 43 individuals from the Alabama Hereditary Cancer Cohort, and an average sequencing depth of 809X was obtained. Upon variant filtering and validation, true positives had an average sequencing depth of 659X and allele balance of 0.51. The average false positive sequencing depth was 34X and allele balance was 0.33. Although low sequencing depth was not always indicative of a false positive, high sequencing depths (>100X) signified a true positive. Furthermore, sensitivity and specificity of BRCA1/2 were calculated to be 100% and 92.3%, respectively. Overall, this screening enabled the establishment of criteria to alleviate future validation efforts and strongly supports the use of B.O.P. to further elucidate hereditary cancer susceptibility. Ultimately, continued B.O.P. screening will provide insights toward the genetic risk of and overlap between breast, ovarian, and/or prostate cancer.