Enriched phenotypes in rare variant carriers suggest pathogenic mechanisms in rare disease patients
Authors: Fitzsimmons Lane ,   Undiagnosed Diseases Network, Acosta Maria T. , Adams David R. , Afzali Ben , Al-Beshri Ali , Allenspach Eric , Allworth Aimee , Alvarez Raquel L. , Alvey Justin , Andrews Ashley , Ashley Euan A. , Bacino Carlos A. , Bademci Guney , Balasubramanyam Ashok , Baldridge Dustin , Baldwin Erin , Bale Jim , Bamshad Michael , Barbouth Deborah , Bayrak-Toydemir Pinar , Beck Anita , Beggs Alan H. , Behrens Edward , Bejerano Gill , Bellen Hugo J. , Bennett Jimmy , Bernstein Jonathan A. , Berry Gerard T. , Bican Anna , Bivona Stephanie , Blue Elizabeth , Bohnsack John , Bonner Devon , Borja Nicholas , Botto Lorenzo , Briere Lauren C. , Burke Elizabeth A. , Burrage Lindsay C. , Butte Manish J. , Byers Peter , Byrd William E. , Callaway Kaitlin , Carey John , Carvalho George , Cassini Thomas , Chanprasert Sirisak , Chao Hsiao-Tuan , Chinn Ivan , Clark Gary D. , Coakley Terra R. , Cobban Laurel A. , Cogan Joy D. , Coggins Matthew , Cole F. Sessions , Corner Brian , Corona Rosario I. , Craigen William J. , Crouse Andrew B. , Cuddapah Vishnu , D’Souza Precilla , Dai Hongzheng , Darr Kahlen , Dasari Surendra , Davis Joie , Delgado Margaret , Dell’Angelica Esteban C. , Dipple Katrina , Doherty Daniel , Dorrani Naghmeh , Douglas Jessica , Douine Emilie D. , Earl Dawn , Emrick Lisa T. , Eng Christine M. , Esteves Cecilia , Ezell Kimberly , Fieg Elizabeth L. , Fisher Paul G. , Fogel Brent L. , Fu Jiayu , Gahl William A. , Ganetzky Rebecca , Glanton Emily , Glass Ian , Goddard Page C. , Gonzalez Joanna M. , Gropman Andrea , Halley Meghan C. , Hamid Rizwan , Hanchard Neal , Hassey Kelly , Hayes Nichole , High Frances , Hing Anne , Hisama Fuki M. , Holm Ingrid A. , Hom Jason , Horike-Pyne Martha , Huang Alden , Huang Yan , Hurst Anna , Introne Wendy , Jarvik Gail P. , Jayadev Suman , Jean-Marie Orpa , Jobanputra Vaidehi , Kanca Oguz , Karasozen Yigit , Ketkar Shamika , Kiley Dana , Kilich Gonench , Klee Eric , Kobren Shilpa N. , Kohane Isaac S. , Kohler Jennefer N. , Korf Bruce , Korrick Susan , Krakow Deborah , Kravets Elijah , Lalani Seema R. , Lam Christina , Lanpher Brendan C. , Lanza Ian R. , Latchman Kumarie , LeBlanc Kimberly , Lee Brendan H. , Leppig Kathleen A. , Lewis Richard A. , Liu Pengfei , Longo Nicola , Loscalzo Joseph , Maas Richard L. , Macnamara Ellen F. , MacRae Calum A. , Maduro Valerie V. , Maghiro AudreyStephannie , Mahoney Rachel , Malicdan May Christine V. , Mao Rong , Marom Ronit , Marth Gabor , Martin Beth A. , Martin Martin G. , Martínez-Agosto Julian A. , Marwaha Shruti , McConkie-Rosell Allyn , McMinn Ashley , Might Matthew , Mikati Mohamad , Miller Danny , Mirzaa Ghayda , Mitchell Breanna , Moretti Paolo , Morimoto Marie , Mulvihill John J. , Mulvihill Lindsay , Nakano-Okuno Mariko , Nelson Stanley F. , Neumann Serena , Nitsuh Dargie , Novacic Donna , Oglesbee Devin , Orengo James P. , Pace Laura , Pak Stephen , Pallais J. Carl , Parker Neil H. , Peart LéShon , Petcharet Leoyklang , Phillips John A. , Vairo Filippo Pinto e , Posey Jennifer E. , Potocki Lorraine , Swerdzewski Barbara N. Pusey , Quinlan Aaron , Rader Daniel J. , Rajagopalan Ramakrishnan , Rao Deepak A. , Raper Anna , Raskind Wendy , Rebelo Adriana , Reuter Chloe M. , Rives Lynette , Rodan Lance H. , Rodriguez Martin , Rosenfeld Jill A. , Rosenthal Elizabeth , Rossignol Francis , Ruzhnikov Maura , Sabaii Marla , Sampson Jacinda B. , Schedl Timothy , Schimmenti Lisa , Schoch Kelly , Scott Daryl A. , Seto Elaine , Shashi Vandana , Shelkowitz Emily , Sheppeard Sam , Shin Jimann , Silverman Edwin K. , Sirugo Giorgio , Sisco Kathy , Skelton Tammi , Skraban Cara , Smith Carson A. , Smith Kevin S. , Solnica-Krezel Lilianna , Solomon Ben , Spillmann Rebecca C. , Stergachis Andrew , Stoler Joan M. , Sullivan Kathleen , Sunyaev Shamil R. , Sutton Shirley , Sweetser David A. , Sybert Virginia , Tabor Holly K. , Tan Queenie , Tarakad Arjun , Taylor Herman , Tekin Mustafa , Thorson Willa , Tifft Cynthia J. , Toro Camilo , Tran Alyssa A. , Ungar Rachel A. , Vanderver Adeline , Velinder Matt , Viskochil Dave , Vogel Tiphanie P. , Wahl Colleen E. , Walker Melissa , Walley Nicole M. , Wambach Jennifer , Wangler Michael F. , Ward Patricia A. , Wegner Daniel , Hubshman Monika Weisz , Wener Mark , Wenger Tara , Westerfield Monte , Wheeler Matthew T. , Whitlock Jordan , Wolfe Lynne A. , Wood Heidi , Worley Kim , Yamamoto Shinya , Zhang Zhe , Zuchner Stephan , Beaulieu-Jones Brett , Kobren Shilpa Nadimpalli 
Published: January 2025

Abstract

Background
The mechanistic pathways that give rise to the extreme symptoms exhibited by rare disease patients are complex, heterogeneous, and difficult to discern. Understanding these mechanisms is critical for developing treatments that address the underlying causes of diseases rather than merely the presenting symptoms. Moreover, the same dysfunctional series of interrelated symptoms implicated in rare recessive diseases may also lead to milder and potentially preventable symptoms in carriers in the general population. Seizures are a common and extreme phenotype that can result from diverse and often elusive pathways in patients with ultrarare or undiagnosed disorders.

Methods
In this pilot study, we present an approach to understand the underlying pathways leading to seizures in patients from the Undiagnosed Diseases Network (UDN) by analyzing aggregated genotype and phenotype data from the UK Biobank (UKB). Specifically, we look for enriched phenotypes across UKB participants who harbor rare variants in the same gene known or suspected to be causally implicated in a UDN patient’s recessively manifesting disorder. Analyzing these milder but related associated phenotypes in UKB participants can provide insight into the disease-causing mechanisms at play in rare disease UDN patients.

Results
We present six vignettes of undiagnosed patients experiencing seizures as part of their recessive genetic condition. For each patient, we analyze a gene of interest: MPO, P2RX7, SQSTM1, COL27A1, PIGQ, or CACNA2D2, and find relevant symptoms associated with UKB participants. We discuss the potential mechanisms by which the digestive, skeletal, circulatory, and immune system abnormalities found in the UKB patients may contribute to the severe presentations exhibited by UDN patients. We find that in our set of rare disease patients, seizures may result from diverse, multi-step pathways that involve multiple body systems.

Conclusions
Analyses of large-scale population cohorts such as the UKB can be a critical tool to further our understanding of rare diseases in general. Continued research in this area could lead to more precise diagnostics and personalized treatment strategies for patients with rare and undiagnosed conditions.