Advancing Diagnostic Precision in Rare Genetic Disorders: Insights from the University of Wisconsin Undiagnosed Disease Program
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
The University of Wisconsin Undiagnosed Disease Program (UW-UDP), recognized as an Undiagnosed Disease Network (UDN) Diagnostic Center of Excellence, was established in 2020 to provide diagnostic clarity for patients with suspected rare genetic disorders who have remained undiagnosed despite extensive clinical testing, including exome sequencing (ES). Our program originated as a partnership between the UW Center for Human Genomics and Precision Medicine (CHGPM) and the Division of Genetics & Metabolism and leverages expertise in neurodevelopmental disorders through its integration with the Waisman Center, a designated NIH-funded Intellectual & Developmental Disabilities Research Center (IDDRC). Our nationally recognized multidisciplinary programs include pulmonary genetics, pediatric bone and mineral metabolism, craniofacial, hereditary hematology, ocular genetics, pediatric dermatology, and skeletal dysplasias, among others. We aim to advance health equity through targeted outreach to under-represented, rural, and underinsured communities in Wisconsin and Florida, and to advance understanding of the social, emotional, and practical aspects of living with an undiagnosed disease through partnership with UW’s Qualitative and Health Experiences Research Lab.
Methods:
The UW-UDP enrolls patients and families into our UW IRB-approved genetics research study. Patients undergo comprehensive genetic analyses, starting with short-read and/or long-read genome sequencing (GS). For some patients, advanced technologies such as RNA sequencing (RNA-seq), optical genome mapping, and functional validation studies are employed to enhance diagnostic precision.
Results:
To date, the UW-UDP has received over 250 referrals, enrolling 120 families comprising 138 affected individuals and 210 unaffected relatives. Of these families, 9% reside in rural areas, and 24% live in highly disadvantaged areas, with a national Area Deprivation Index (ADI) score above 70. Among the probands, 91.6% had previously undergone clinical ES without diagnosis. We identified putative disease-causing variants in 36.7% of analyzed cases. Key findings include: 1) Identification of variants in newly recognized disease genes via exome reanalysis; 2) Detection of intronic variants through GS; 3) Elucidation of structural rearrangements using long-read GS and/or optical genome mapping; and 4) Functional insights gained from RNA-seq. Collaborative efforts through platforms like GeneMatcher have facilitated the further characterization of specific variants of interest. Notably, the UW-UDP has identified multiple ultra-rare disorders associated with pathogenic variants in genes including AGO1, CAPZA2, EMC1, SMARCA2, SPTAN1, and VPS50 as well as patients who have two or three unrelated rare genetic conditions.
Conclusion:
Through a comprehensive, research-driven approach that uses advanced sequencing and molecular analyses, the UW-UDP has been able to diagnose over a third of patients suspected of a genetic disorder who have had negative clinical ES. Employing emerging technologies like long-read GS, RNA-seq, and optical genome mapping has allowed us to improve diagnostic precision and foster meaningful clinical insights. This approach not only increases diagnostic rates but also improves patient care by enabling precise genetic counseling with disease-specific prognostic information and by enabling timely, targeted interventions. Looking forward, the UW-UDP aims to expand its reach and impact by integrating new technologies, exploring the impact of social determinants like ADI on outcomes, and deepening collaboration to set new standards for diagnosing and managing rare diseases in underserved populations.
The University of Wisconsin Undiagnosed Disease Program (UW-UDP), recognized as an Undiagnosed Disease Network (UDN) Diagnostic Center of Excellence, was established in 2020 to provide diagnostic clarity for patients with suspected rare genetic disorders who have remained undiagnosed despite extensive clinical testing, including exome sequencing (ES). Our program originated as a partnership between the UW Center for Human Genomics and Precision Medicine (CHGPM) and the Division of Genetics & Metabolism and leverages expertise in neurodevelopmental disorders through its integration with the Waisman Center, a designated NIH-funded Intellectual & Developmental Disabilities Research Center (IDDRC). Our nationally recognized multidisciplinary programs include pulmonary genetics, pediatric bone and mineral metabolism, craniofacial, hereditary hematology, ocular genetics, pediatric dermatology, and skeletal dysplasias, among others. We aim to advance health equity through targeted outreach to under-represented, rural, and underinsured communities in Wisconsin and Florida, and to advance understanding of the social, emotional, and practical aspects of living with an undiagnosed disease through partnership with UW’s Qualitative and Health Experiences Research Lab.
Methods:
The UW-UDP enrolls patients and families into our UW IRB-approved genetics research study. Patients undergo comprehensive genetic analyses, starting with short-read and/or long-read genome sequencing (GS). For some patients, advanced technologies such as RNA sequencing (RNA-seq), optical genome mapping, and functional validation studies are employed to enhance diagnostic precision.
Results:
To date, the UW-UDP has received over 250 referrals, enrolling 120 families comprising 138 affected individuals and 210 unaffected relatives. Of these families, 9% reside in rural areas, and 24% live in highly disadvantaged areas, with a national Area Deprivation Index (ADI) score above 70. Among the probands, 91.6% had previously undergone clinical ES without diagnosis. We identified putative disease-causing variants in 36.7% of analyzed cases. Key findings include: 1) Identification of variants in newly recognized disease genes via exome reanalysis; 2) Detection of intronic variants through GS; 3) Elucidation of structural rearrangements using long-read GS and/or optical genome mapping; and 4) Functional insights gained from RNA-seq. Collaborative efforts through platforms like GeneMatcher have facilitated the further characterization of specific variants of interest. Notably, the UW-UDP has identified multiple ultra-rare disorders associated with pathogenic variants in genes including AGO1, CAPZA2, EMC1, SMARCA2, SPTAN1, and VPS50 as well as patients who have two or three unrelated rare genetic conditions.
Conclusion:
Through a comprehensive, research-driven approach that uses advanced sequencing and molecular analyses, the UW-UDP has been able to diagnose over a third of patients suspected of a genetic disorder who have had negative clinical ES. Employing emerging technologies like long-read GS, RNA-seq, and optical genome mapping has allowed us to improve diagnostic precision and foster meaningful clinical insights. This approach not only increases diagnostic rates but also improves patient care by enabling precise genetic counseling with disease-specific prognostic information and by enabling timely, targeted interventions. Looking forward, the UW-UDP aims to expand its reach and impact by integrating new technologies, exploring the impact of social determinants like ADI on outcomes, and deepening collaboration to set new standards for diagnosing and managing rare diseases in underserved populations.