About

Douglas J. Epstein, Ph.D., is a Professor of Genetics and serves as Vice Chair of the Department of Genetics at the Perelman School of Medicine at the University of Pennsylvania. His research focuses on gene regulation during brain development and the genetic basis of inner ear morphogenesis, utilizing mouse models to study mechanisms underlying human congenital disorders such as brain malformations and hearing loss. His work investigates how Sonic hedgehog (Shh) expression is regulated during neurodevelopment, including the study of enhancer redundancy and 3D locus folding dynamics, as well as the genetic factors contributing to congenital and adult-onset hearing loss. Dr. Epstein's research aims to elucidate neural circuit development and identify genetic causes of sensory deficits, with ongoing projects involving the generation of mouse models and analysis of inner ear phenotypes to inform potential gene therapy approaches.

Research topics

• Genetics
• Biology
• Cell biology
• Internal medicine
• Audiology
• Medicine
• Neuroscience
• Endocrinology

Selected publications

• Genome-wide analysis implicates inner ear development in Ménière’s disease

  medRxiv · 2026-02-11

  articleOpen access

  Abstract Ménière’s disease (MD) is a chronic inner ear disorder characterized by recurrent vertigo, fluctuating sensorineural hearing loss, and tinnitus. Despite these distinctive symptoms, its etiology remains poorly understood. We performed a genome-wide meta-analysis of 8,969 cases and 1,962,542 controls across five large biobanks, identifying five independent genome-wide significant loci and estimating an observed-scale SNP heritability of 7% (SE 0.8%), consistent with a modest but significant genetic contribution to MD risk. Fine-mapping and integrative functional analyses implicate two convergent biological processes – developmental regulation of the inner ear, involving EYA4, EYA1 , and LMO4 – and retinoic acid metabolism, with loci near CYP26A1/C1 and ALDH1A2 suggesting disrupted RA signaling in sensory and fluid-pressure homeostasis. These developmental regulator genes are robustly expressed in fetal and adult human inner ear cell types, supporting a model in which altered developmental programs predispose to adult vestibular and auditory dysfunction. Phenome-wide and genetic correlation analyses further reveal shared genetic architecture between MD and related traits, including vertigo, tinnitus, hearing loss, migraine, and sleep apnea, situating MD within a broader spectrum of sensory and neurological disorders. Collectively, these findings establish a genetic framework for Ménière’s disease risk and implicate developmental regulators and retinoic acid signaling as key contributing pathways.

  PublisherOA PDFDOI

• Limited Utility of Existing Hearing Loss Panels in the Assessment of Early‐Onset, Bilateral Meniere's Disease

  OTO Open · 2025-10-01

  articleOpen access

  Abstract Objective While the etiology of Meniere's disease (MD) is likely multifactorial, genetics are thought to play a role. Several previous studies have yielded inconclusive results, potentially due to phenotypic uncertainty and variable diagnostic criteria. To explore potential genetic bases in a more rigorous context, we assessed the clinical predictors and diagnostic yield of current hearing loss panels in a highly curated cohort of patients with bilateral and/or early‐onset MD. Study Design Retrospective cohort study. Setting Multidisciplinary tertiary care hearing loss genetics clinic. Methods Data from clinical notes, audiograms, and genetic reports of adult patients diagnosed with bilateral and/or early‐onset (<40 years) MD from October 2019 to June 2025 were analyzed with logistic regression and summary statistics to determine predictive factors and diagnostic yields of existing genetic panels. Results Of the 37 patients analyzed (mean age 47.7 + 14.5 years, 54% male), 24 (64.8%) had early‐onset MD, 22 (59.5%) had bilateral MD, and 9 (24.3%) had both. Moderately severe to profound hearing loss prior to 65 was significantly associated with pathogenic or likely pathogenic variants (PLPV) (OR 8.98 [1.17, 101]; P = .046). No significant predictors were found for definitive diagnosis, plausible diagnosis, or negative panels. Eight (22%) patients had a PLPV detected on their hearing loss panel, with 0 definitive diagnoses, 3 (8.1%) plausible diagnoses ( MYO15A , SLC17A8 , P2RX2 ), and 6 (16%) completely negative panels. Conclusions Current hearing loss panels show limited diagnostic utility for MD. Future research should prioritize whole genome sequencing to identify novel MD‐associated loci and provide guidance to patients.

  PublisherOA PDFDOI

• Multiple allelic configurations govern long-range Shh enhancer-promoter communication in the embryonic forebrain

  Molecular Cell · 2024-11-22 · 5 citations

  articleOpen access
  PublisherOA PDFDOI

• Impaired pain in mice lacking first-order posterior medial thalamic neurons

  Pain · 2024-08-23 · 1 citations

  articleOpen accessSenior author

  ABSTRACT: The thalamus plays an important role in sensory and motor information processing by mediating communication between the periphery and the cerebral cortex. Alterations in thalamic development have profound consequences on sensory and motor function. In this study, we investigated a mouse model in which thalamic nuclei formation is disrupted because of the absence of Sonic hedgehog ( Shh ) expression from 2 key signaling centers that are required for embryonic forebrain development. The resulting defects observed in distinct thalamic sensory nuclei in Shh mutant embryos persisted into adulthood prompting us to examine their effect on behavioral responses to somatosensory stimulation. Our findings reveal a role for first-order posterior medial thalamic neurons and their projections to layer 4 of the secondary somatosensory cortex in the transmission of nociceptive information. Together, these results establish a connection between a neurodevelopmental lesion in the thalamus and a modality-specific disruption in pain perception.

  PublisherOA PDFDOI

• Gene burden analysis identifies genes associated with increased risk and severity of adult-onset hearing loss in a diverse hospital-based cohort

  PLoS Genetics · 2023-01-19 · 10 citations

  articleOpen accessCorresponding

  Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are often studied separately, there is increasing evidence that their genetic basis is at least partially overlapping. In particular, both common and rare variants in genes associated with monogenic forms of hearing loss also contribute to the more polygenic basis of age-related hearing loss. Here, we directly test this model in the Penn Medicine BioBank-a healthcare system cohort of around 40,000 individuals with linked genetic and electronic health record data. We show that increased burden of predicted deleterious variants in Mendelian hearing loss genes is associated with increased risk and severity of adult-onset hearing loss. As a specific example, we identify one gene-TCOF1, responsible for a syndromic form of congenital hearing loss-in which deleterious variants are also associated with adult-onset hearing loss. We also identify four additional novel candidate genes (COL5A1, HMMR, RAPGEF3, and NNT) in which rare variant burden may be associated with hearing loss. Our results confirm that rare variants in Mendelian hearing loss genes contribute to polygenic risk of hearing loss, and emphasize the utility of healthcare system cohorts to study common complex traits and diseases.

  PublisherOA PDFDOI

• Developmental trajectories of thalamic progenitors revealed by single-cell transcriptome profiling and Shh perturbation

  Cell Reports · 2022-12-01 · 30 citations

  articleOpen accessCorresponding

  The thalamus is the principal information hub of the vertebrate brain, with essential roles in sensory and motor information processing, attention, and memory. The complex array of thalamic nuclei develops from a restricted pool of neural progenitors. We apply longitudinal single-cell RNA sequencing and regional abrogation of Sonic hedgehog (Shh) to map the developmental trajectories of thalamic progenitors, intermediate progenitors, and post-mitotic neurons as they coalesce into distinct thalamic nuclei. These data reveal that the complex architecture of the thalamus is established early during embryonic brain development through the coordinated action of four cell differentiation lineages derived from Shh-dependent and -independent progenitors. We systematically characterize the gene expression programs that define these thalamic lineages across time and demonstrate how their disruption upon Shh depletion causes pronounced locomotor impairment resembling infantile Parkinson's disease. These results reveal key principles of thalamic development and provide mechanistic insights into neurodevelopmental disorders resulting from thalamic dysfunction.

  PublisherDOI

• Combined single-cell RNA-seq profiling and enhancer editing reveals critical spatiotemporal controls over thalamic nuclei formation in the murine embryo

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-02-20 · 3 citations

  preprintOpen accessCorresponding

  Abstract The thalamus is the principal information hub of the vertebrate brain, with essential roles in sensory and motor information processing, attention, and memory. The molecular mechanisms regulating the formation of thalamic nuclei are unclear. We apply longitudinal single-cell RNA-sequencing, regional abrogation of Sonic-hedgehog (Shh), and spatial profiling of gene expression to map the developmental trajectories of thalamic progenitors, intermediate progenitors, and post-mitotic neurons as they coalesce into distinct thalamic nuclei. These data reveal that the complex architecture of the thalamus is established early during embryonic brain development through the coordinated action of four cell differentiation lineages derived from Shh-dependent and independent progenitors. We systematically characterize the gene expression programs that define these lineages across time and demonstrate how their disruption upon Shh depletion causes pronounced locomotor impairment resembling infantile Parkinson’s disease. These results reveal key principles of thalamic development and provide mechanistic insights into neurodevelopmental disorders resulting from thalamic dysfunction.

  PublisherOA PDFDOI

• Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing

  Developmental Cell · 2021 · 52 citations

  Senior authorCorresponding
  • Biology
  • Cell biology
  • Audiology
  PublisherOA PDFDOI

• Genome-first approach to rare EYA4 variants and cardio-auditory phenotypes in adults

  Human Genetics · 2021-03-21 · 19 citations

  article
  PublisherDOI

• A Genome‐First Approach to Rare Variants in Dominant Postlingual Hearing Loss Genes in a Large Adult Population

  Otolaryngology · 2021-07-20 · 5 citations

  article

  Objective To investigate the importance of rare variants in adult‐onset hearing loss. Study Design Genomic association study. Setting Large biobank from tertiary care center. Methods We investigated rare variants (minor allele frequency <5%) in 42 autosomal dominant (DFNA) postlingual hearing loss (HL) genes in 16,657 unselected individuals in the Penn Medicine Biobank. We determined the prevalence of known pathogenic and predicted deleterious variants in subjects with audiometric‐proven sensorineural hearing loss. We scanned across known postlingual DFNA HL genes to determine those most significantly contributing to the phenotype. We replicated findings in an independent cohort (UK Biobank). Results While rare individually, when considering the accumulation of variants in all postlingual DFNA genes, more than 90% of participants carried at least 1 rare variant. Rare variants predicted to be deleterious were enriched in adults with audiometric‐proven hearing loss (pure‐tone average >25 dB; P =. 015). Patients with a rare predicted deleterious variant had an odds ratio of 1.27 for HL compared with genotypic controls ( P =. 029). Gene burden in DIABLO, PTPRQ, TJP2 , and POU4F3 were independently associated with sensorineural hearing loss. Conclusion Although prior reports have focused on common variants, we find that rare predicted deleterious variants in DFNA postlingual HL genes are enriched in patients with adult‐onset HL in a large health care system population. We show the value of investigating rare variants to uncover hearing loss phenotypes related to implicated genes.

  PublisherDOI

Recent grants

• Transcriptional control of Sonic hedgehog signaling

  NIH · $8.5M · 2000–2025

• Role of Gas2 in cytoskeletal architecture, support cell stiffness, and cochlear function

  NIH · $7.6M · 2003–2024

• Center for Molecular Studies in Digestive and Liver Diseases

  NIH · $12.2M · 1997–2027

• Predoctoral Training Program in Genetics

  NIH · $10.5M · 1987–2024

Frequent coauthors

• Andrew P. McMahon

  20 shared

• Martin M. Riccomagno

  University of California, Riverside

  17 shared

• Christine E. Seidman

  Harvard University

  16 shared

• Tatjana Levi

  Cooper Medical School of Rowan University

  16 shared

• Drucilla J. Roberts

  Massachusetts General Hospital

  16 shared

• Cliff Tabin

  Harvard University

  16 shared

• Julie M. Gastier

  16 shared

• Valeria Marigo

  University of Modena and Reggio Emilia

  16 shared

Labs

• Epstein labPI