Rare variants in previously identified linkage regions associated with carotid plaque in Dominican Republic families

Carotid plaque is a subclinical measure of atherosclerosis. We have previously shown measures of carotid plaque to be heritable in a sample of 100 Dominican families and found evidence for linkage and association of common variants (CVs) on 7q36, 11p15, 14q32 and 15q23 with plaque presence. Our current study aimed to refine these regions further and identify rare variants (RVs) influencing plaque presence. Therefore, we performed targeted sequencing of the one LOD unit down region on 7q36, 11p15, 14q32 and 15q23 in 12 Dominican families with evidence for linkage to plaque presence. Gene-based RV analyses were performed using the Sequence Association Test for familial data (F-SKAT) under two filtering algorithms; 1. all exonic RVs and 2. non-synonymous RVs. Replication analyses were performed using a sample of 22 Dominican families and 556 unrelated Dominicans with Exome Array data. To identify additional non-synonymous RVs influencing plaque, we looked for co-segregation of RVs with plaque in each of the sequenced families. Our most strongly associated gene with evidence for replication was AMPD3 which showed suggestive association with plaque presence in the sequenced families (exonic RV p = 0.003, nonsynonymous RV p = 0.005) and replication families (exonic RV p = 0.04, nonsynonymous RV p = 0.02). Examination of the sequenced family pedigrees revealed two missense variants on chromosome 11 which co-segregated with plaque presence in one of our families; rs61751342 (located in DENND2B), and rs61760882 (located in RNF141). The rs61751342 missense variant is an eQTL for SCUBE2 in the atrial appendage. Notably, SCUBE2 encodes a protein which interacts with vascular endothelial growth factor (VEGF) receptor 2 to regulate VEGF-induced angiogenesis, thus providing biologic plausibility for this gene in atherosclerosis. In conclusion, using targeted sequencing of previously-identified linkage regions, we have identified suggestive evidence for the role of RVs in carotid plaque pathogenesis.

Artificial intelligence–assisted phenotype discovery of fragile X syndrome in a population-based sample

Purpose Fragile X syndrome (FXS), the most prevalent inherited cause of intellectual disability, remains underdiagnosed in the general population. Clinical studies have shown that individuals with FXS have a complex health profile leading to unique clinical needs. However, the full impact of this X-linked disorder on the health of affected individuals is unclear and the prevalence of co-occurring conditions is unknown. Methods We mined the longitudinal electronic health records from more than one million individuals to investigate the health characteristics of patients who have been clinically diagnosed with FXS. Additionally, using machine-learning approaches, we created predictive models to identify individuals with FXS in the general population. Results Our discovery-oriented approach identified the associations of FXS with a wide range of medical conditions including circulatory, endocrine, digestive, and genitourinary, in addition to mental and neurological disorders. We successfully created predictive models to identify cases five years prior to clinical diagnosis of FXS without relying on any genetic or familial data. Conclusion Although FXS is often thought of primarily as a neurological disorder, it is in fact a multisystem syndrome involving many co-occurring conditions, some primary and some secondary, and they are associated with a considerable burden on patients and their families.

Redefining the Bladder Cancer Phenotype using Patterns of Familial Risk

Relatives of bladder cancer (BCa) patients have been shown to be at increased risk for kidney, lung, thyroid, and cervical cancer after correcting for smoking related behaviors that may concentrate in some families. We demonstrate a new method to simultaneously assess risks for multiple cancers to identify distinct multi-cancer configurations (multiple different cancer types that cluster in relatives) surrounding BCa patients. We identified 6,416 individuals with urothelial carcinoma and familial information using the Utah Cancer Registry and Utah Population Database (UPDB). First-degree relatives, second-degree relatives, and first cousins were used to construct a familial enrichment matrix for cancer-types previously shown to be individually associated with BCa. K-medioids clustering were used to identify Familial Multi-Cancer Configurations (FMC). A case-control design and Cox regression with a 1:5 ratio of BCa cases to cancer-free controls was used to quantify the risk in specific relative-types and spouses in each FMC. Clustering analysis revealed 12 distinct FMCs, each exhibiting a different pattern of cancer co-aggregation. Of the 12 FMCs, four exhibited strong familial risk of bladder cancer along with specific patterns of increased risk of cancers in other sites (BCa FMCs), and were the focus of further investigation. Cancers at increased risk in these four BCa FMCs most commonly included melanoma, prostate and breast cancer and less commonly included leukemia, lung, pancreas and kidney cancer. A network-based approach can be used with familial data to discover new phenotype clusters for BCa, providing new directions for discovering patterns of cancer clustering.

Genetics of multiplex familial vitiligo as cases and controls: a preliminary report

<p class="abstract"><strong>Background:</strong> Studies on etiology of generalized vitiligo have established that it is a genetically determined, autoimmune, auto inflammatory diathesis. Polymorphism in myriad genes is associated with vitiligo and newer ones are being identified with advancement in research methods. This study enabled inheritance pattern recognition in multiplex familial cases of vitiligo and subject members to whole exome sequencing (WES) to find out the etiological gene defect in a particular family.</p><p class="abstract"><strong>Methods:</strong> 7 multiplex families with at least two cases and two healthy counterparts, spread across generations were enrolled. Demographic data, clinical history and familial data were collected for pedigree analysis and blood samples were collected for extraction of genomic DNA.<strong></strong></p><p class="abstract"><strong>Results:</strong> Multiple possible modes of Mendelian inheritance could be contemplated to cause disease expression in probands. Autosomal recessive pattern was observed to be the most likely amongst various possible modes, followed closely by autosomal dominant, with X-linked recessive, and X- linked dominant occurring less frequently. WES for one of the multiplex families is desirable and planned at an apex institute of genetic studies which will reveal the etiologic gene defect on conclusion of analysis.</p><p><strong>Conclusions:</strong> In this study we have used to our advantage the familial occurrence of the disease to seek for genes which occurred with a greater frequency in affected members of a family than their healthy counterparts, assuming that the same mutated gene should be universally present in all affected members across generations in the same family, enabling a better understanding of genetic predisposition in familial vitiligo. </p>

A pragmatic analysis of L2 Spanish requests: Acquisition in three situational contexts during short-term study abroad

This study examines pragmatic acquisition of requests for English-speaking learners of Spanish. This research expands upon previous work by investigating the acquisition of second language requests during a short-term immersion program (6 weeks) in Madrid, Spain and in three situational contexts: food and drink, general merchandise, and familial. Data were collected using an experimental computerized oral discourse completion task. Requests made by learners (501 requests) and native speakers (224 requests) were compared considering personal deictic orientation and directness of the requests. For learners, shifts from speaker-oriented to hearer-oriented requests indicated greater pragmatic development in food and drink and familial contexts. Results are discussed considering pragmatic developmental stages and differential results in the three contexts.

Fabry disease, a complex pathology not easy to diagnose

Fabry disease is a multisystemic lysosomal storage disorder, inherited in an X-linked manner. It is a defect of metabolism of the glycosphingolipids, due to the reduction or absence of the activity of lysosomal enzyme α-galactosidase A. This reduction of activity causes the storage of globotriaosylceramide and derivatives in the lysosomes, triggering a cascade of cellular events, mainly in vascular endothelium. These events are the responsible for the systemic clinical manifestations and the renal, cardiac and cerebrovascular complications, or a combination of them. The symptomatology can lead to the premature death of patient between the fourth or fifth decade of life. The first symptoms can occur at different ages, generally in childhood, with different severity and course. Fabry disease is suspected on the basis of clinical and anamnestic-familial data, and it is confirmed by enzymatic and genetic assays. However, Fabry disease could be a pathology more complex than previously considered, and the diagnostic tests that are currently in use could be not always sufficient to confirm the clinical diagnosis. Probably, other factors could be also involved in the onset of symptomatology. In the last years, the knowledge of the disease is considerably increased but other studies are necessary to make a prompt and reliable diagnosis. An early diagnosis of Fabry disease is essential for the beginning of the enzyme replacement therapy, which can contribute to arrest its progression and improve the quality of life of patients.