Proband only exome sequencing in 403 Indian children with neurodevelopmental disorders: Diagnostic yield,utility and challenges in a resource-limited setting |
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| Affiliation: | 1. Neuberg Centre for Genomic Medicine, Ahmedabad, 380059, Gujarat, India;2. Kids Neuro Clinic and Child Rehabilitation Center, Nagpur, Maharashtra, India;3. Kpond Children Super Specialty Hospital, Aurangabad, Maharashtra, India;4. Apollo Hospitals, Ahmedabad, India;5. Integrated Centre for Child Neurodevelopment, Aurangabad, Maharashtra, India;6. Nizam''s Institute of Medical Sciences, Hyderabad, India;7. MGM Medical College and Hospitals, Aurangabad, India;8. Christian Medical College and Hospital, Vellore, India;9. Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India;10. SMS Medical College, Jaipur, India;1. Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Germany;2. Department of Human Genetics, Hannover Medical School, Hannover, Germany;3. Institute of Pathology, University Hospital Bonn, 53127, Bonn, Germany;4. Department of Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;5. Technical University of Munich, School of Medicine, Department of Pediatrics and Children''s Cancer Research Center, Kinderklinik München Schwabing, Munich, Germany;6. Gerhard Domagk Institute of Pathology, University Hospital Muenster, Muenster, Germany;7. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany;1. Department of Pediatric Genetics, Department of Pediatrics, Hacettepe University, Faculty of Medicine, Ankara, Turkey;2. Department of Pediatric Dentistry, Hacettepe University, Faculty of Dentistry, Ankara, Turkey;3. Department of Oral and Maxillofacial Radiology, Hacettepe University, Faculty of Dentistry, Ankara, Turkey;4. Department of Pediatric Genetics, Department of Pediatrics, Ac?badem University, Faculty of Medicine, Istanbul, Turkey;1. School of Naval Architecture, Ocean and Civil Engineering (State Key Laboratory of Ocean Engineering), Shanghai Jiao Tong University, Shanghai, 200240, China;2. School of Aerospace Engineering and Applied Mechanics, Tongji University, Shanghai, 200092, China;3. Department of Engineering Mechanics, Tsinghua University, Beijing, 100084, China;1. The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children''s Hospital, Columbus, OH, USA;2. Departments of Pathology, Departments of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA;3. Division of Pediatric Neurology, Renown Children''s Hospital, Reno, NV, USA;4. University of Nevada, Reno School of Medicine, Reno, NV, USA;5. MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK;6. Division of Hospital Medicine, Nationwide Children''s Hospital, Columbus, OH, USA;7. Department of Radiology, Nationwide Children''s Hospital, Columbus, OH, USA;8. The Ohio State University College of Medicine, Columbus, OH, 43210, USA;9. Division of Pediatric Neurology, Nationwide Children''s Hospital, Columbus, OH, USA;10. Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Université de Paris, Paris, France;11. Division of Genetic and Genomic Medicine, Nationwide Children''s Hospital, Columbus, OH, USA;1. Research Centre for Anthropology and Health (CIAS), Department of Life Sciences, University of Coimbra, Portugal;2. Department of Clinical Hematology, Centro Hospitalar e Universitário de Coimbra, Portugal;3. Miguel Torga Superior Institute, Coimbra, Portugal;4. Center for Research in Neuropsychology and Cognitive and Behavioral Intervention (CINEICC), Faculty of Psychology and Educational Sciences, University of Coimbra, Portugal |
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| Abstract: | Whole exome sequencing is recommended as the first tier test for neurodevelopmental disorders (NDDs) with trio being an ideal option for the detection of de novo variants. Cost constraints have led to adoption of sequential testing i.e. proband-only whole exome followed by targeted testing of parents. The reported diagnostic yield for proband exome approach ranges between 31 and 53%. Typically, these study designs have aptly incorporated targeted parental segregation before concluding a genetic diagnosis to be confirmed. The reported estimates however do not accurately reflect the yield of proband only standalone whole -exome, a question commonly posed to the referring clinician in self pay medical systems like India. To assess the utility of standalone proband exome (without follow up targeted parental testing), we retrospectively evaluated 403 cases of neurodevelopmental disorders referred for proband-only whole exome sequencing at Neuberg Centre for Genomic Medicine (NCGM), Ahmedabad during the period of January 2019 and December 2021. A diagnosis was considered confirmed only upon the detection of Pathogenic/Likely Pathogenic variants in concordance with patient's phenotype as well as established inheritance pattern. Targeted parental/familial segregation analysis was recommended as a follow up test where applicable. The diagnostic yield of the proband-only standalone whole exome was 31.5%. Only 20 families submitted samples for follow up targeted testing, and a genetic diagnosis was confirmed in twelve cases increasing the yield to 34.5%. To understand factors leading to poor uptake of sequential parental testing, we focused on cases where an ultra-rare variant was detected in hitherto described de novo dominant neurodevelopmental disorder. A total of 40 novel variants in genes associated with de novo autosomal dominant disorders could not be reclassified as parental segregation was denied. Semi-structured telephonic interviews were conducted upon informed consent to comprehend reasons for denial. Major factors influencing decision making included lack of definitive cure in the detected disorders; especially when couples not planning further conception and financial constraints to fund further targeted testing. Our study thus depicts the utility and challenges of proband-only exome approach and highlights the need for larger studies to understand factors influencing decision making in sequential testing. |
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| Keywords: | Neurodevelopmental disorders Next generation sequencing Exome sequencing Copy number variations |
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