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Vilain Lab

Our Research

Precision Medicine

The laboratory identifies genomics, epigenomics and microbiomic variants associated with susceptibility and resilience to disease. 

The lab is identifying associations of microbiome with disease severity due to bitter cassava in the Democratic Republic of the Congo (DRC). The lab is also identifying epigenetic markers of fetal stress in collaboration with the Developing Brain Institute and is also designing novel variant analysis pipelines to identify genetic risk factors. Finally, the team is building reference genomes from diverse ethnolinguistic groups in sub-Saharan Africa.

Project members:

  • Emmanuèle Délot, Ph.D.
  • Hayk Barseghyan, Ph.D.
  • Surajit Bhattacharya, Ph.D.
  • Yulong Fu, Ph.D.
  • Kristen Kocher, M.S.
  • Jon LoTempio
  • Neerja Vashist
  • Tina Li
  • Miguel Almalvez

Etiology of Differences of Sex Development

Differences of Sex Development (DSD) are a spectrum of developmental conditions with complex, overlapping phenotypes placing affected individuals at risk for life-threatening hormonal crises, infertility, cancer, sexual dysfunction, gender dysphoria and psychosocial distress. While at least 75 genes are known to cause these conditions in humans, each explains a small number of cases and a majority of patients remain undiagnosed. The team has used animal and cellular models, through candidate gene or genome-wide approaches, to identify new genes and validate novel pathogenic variants for several DSD conditions. The team identified 15 novel candidate genes and demonstrated that they are expressed in a sex-specific manner in the developing gonad, many under the control of the well-known, sex-determining gene Sox9 (Barseghyan et al. 2018). To further validate these candidate genes, the team has now undertaken to clone variants of unknown clinical significance found in the genomes of patients with DSD into expression vectors to assay their effects on function of the proteins in vitro. The team is also developing a model of testicular (Sertoli) cells in culture using transdifferentiation to test gene function and variants directly in patient-derived cells.

Project members:

  • Emmanuèle Délot, Ph.D.
  • Hayk Barseghyan, Ph.D.
  • Abhinav Parivesh, Ph.D.

Neural Stem Cells and Brain Sex Differences

The laboratory is interested in exploring the biological bases for sex differences in health and disease, in particular, what leads to sex differences in brain and behavior. While hormonal influences are well established, genetic diversity and modulation of epigenetic signatures in glia are emerging as mechanisms supporting the establishment of differences between males and females. The laboratory had demonstrated that sexually dimorphic expression of a set of genes in the brains of mouse embryos precedes the making of any sex hormones by the embryonic gonad. The lab has developed a model of mouse neural stem cells to test how these sex differences may be established during development. Using RNA-Seq, the lab has identified ~100 genes that are differentially expressed in XX and XY neural stem cells. The team further showed that neural stem cells respond to androgens in a sex-dependent fashion. For example, when XX cells are treated with testosterone, about 40% of the differentially expressed genes acquire a male pattern of expression. Furthermore, testosterone exposure causes a global reduction in DNA methylation, which persists even after testosterone is removed, indicating a possible new reprogramming role for androgens within the developing central nervous system. The team continues exploring these mechanisms as a basis for understanding behavioral and cognitive sex differences in humans, including patients with DSD.

Project members:

  • Matthew Bramble, Ph.D.
  • Neerja Vashist

DSD-Translational Research Network

To address the lack of available evidence and the controversies in DSD management, in 2011, the lab founded the first (and only) North American network with four sites and a group of patient advocates, Accord Alliance. The alliance has now expanded to 12 sites, including Children’s National Hospital, and created a unique infrastructure consisting of a registry and a biobank (both of which are now hosted at Children’s National). The team organizes network-wide clinical case conferences to discuss challenging cases. The team created an entire set of clinical forms tailored for DSD patients in all specialties concerned in this interdisciplinary model of care (endocrine, genetics, psychosocial, urology, gynecology, etc.). The registry longitudinally collects the standardized deep phenotyping (including psychosocial), genotyping, as well as parameters of clinical care, allowing for outcomes research. The scientists recently published the principles governing the network and the first analysis of genetic registry data (Délot et al. 2017), as well as a detailed survey of the state of DSD clinical practice across the U.S. (Rolston et al. 2017).

The goals of the DSD-TRN are to:

  • Determine links between intervention and health outcomes
  • Establish best practice guidelines based on this evidence
  • Educate both providers and patients to these new standards of care
  • Pilot integration of those standardized clinical forms into Electronic Medical Records to streamline the clinical workflow and generalize the best practices the team benchmarks in this disease-specific precision medicine effort

Members of this research program include:

  • Emmanuèle Délot, Ph.D.
  • Eric Vilain, M.D., Ph.D.

Precision Medicine in Low-to-Middle-Income Countries

The public health burden of birth defects/congenital anomalies is on the rise in low-to-middle-income countries (LMICs). Birth defects disproportionately affect children in LMICs due to limited access to poor quality health care services. The World Health Organization (WHO) estimates that approximately 3.2 million birth defects-related disabilities kill 300,000 newborns every year. The rate of birth defects in the Democratic Republic of the Congo (DRC) is estimated at 71 per 1,000 children, making the DRC the highest regionally and one of the highest in the world. Congenital anomalies affect individuals, their families and societies. Early and accurate identification and characterization of these conditions are fundamental for optimal management. While many birth defects in LMICs are a result of environmental factors/nutrition, others have genetic influences; however, access to genetic resources is extraordinarily limited, as is the case in the DRC. This high prevalence and lack of specialized health care make DRC an impactful model for developing services for screening of syndromic birth defects in LMICs. The team is developing tools for newborn screening using genetic approaches as well as facial recognition methods in collaboration with Marius George Linguraru, D.Phil., M.A., M.Sc. (Sheikh Zayed Institute for Pediatric Surgical Innovation). The team is also identifying environmental factors such as the microbiome as modulator of disease severity.

Project members: 

  • Eric Vilain, M.D., Ph.D.
  • Matthew Bramble, Ph.D.
  • D’Andre Spencer, M.P.H.
  • Neerja Vashist