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Clinical Exome Sequencing – Results from 2819 Samples Reflecting 1000 Families

Daniel Trujillano, PhD Aida M. Bertoli-Avella, MD Krishna Kumar Kandaswamy, PhD Maximilian E. R. Weiss Julia Köster Omid Paknia, PhD Rolf Schröder Jose Maria Garcia-Aznar Martin Werber Oliver Brandau, MD Maria Calvo del Castillo, PhD Caterina Baldi, PhD Karen Wessel, PhD Shivendra Kishore, PhD Nahid Nahavandi Wafaa Eyaid Muhammad Talal Alrifai Ahmed Al-Rumayyan, MD Waleed Al-Twaijri Ali Al Othaim Amal Al Hashem Nouriya Al-Sannaa Mohammed Al-Balwi Majid Alfadhel, MD Prof. Arndt Rolfs, MD Rami Abou Jamra, MD
November 16, 2016

European Journal of Human Genetics advance; doi:10.1038/ejhg.2016.146


We report our results of 1000 diagnostic WES cases based on 2819 sequenced samples from 54 countries with a wide phenotypic spectrum. Clinical information given by the requesting physicians was translated to HPO terms. WES processes were performed according to standardized settings. We identified the underlying pathogenic or likely pathogenic variants in 307 families (30.7%). In further 253 families (25.3%) a variant of unknown significance, possibly explaining the clinical symptoms of the index patient was identified. WES enabled timely diagnosing of genetic diseases, validation of causality of specific genetic disorders of PTPN23, KCTD3, SCN3A, PPOX, FRMPD4, and SCN1B, and setting dual diagnoses by detecting two causative variants in distinct genes in the same patient. We observed a better diagnostic yield in consanguineous families, in severe and in syndromic phenotypes. Our results suggest that WES has a better yield in patients that present with several symptoms, rather than an isolated abnormality. We also validate the clinical benefit of WES as an effective diagnostic tool, particularly in nonspecific or heterogeneous phenotypes. We recommend WES as a first-line diagnostic in all cases without a clear differential diagnosis, to facilitate personal medical care.