title: Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
abstract: 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.
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Trujillano
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Aida M
authors.initials: AM
authors.lastname: Bertoli-Avella
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Krishna
authors.initials: K
authors.lastname: Kumar Kandaswamy
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Maximilian Er
authors.initials: ME
authors.lastname: Weiss
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Köster
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Marais
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Omid
authors.initials: O
authors.lastname: Paknia
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Schröder
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Garcia-Aznar
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Werber
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Brandau
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Calvo Del Castillo
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Caterina
authors.initials: C
authors.lastname: Baldi
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Wessel
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Shivendra
authors.initials: S
authors.lastname: Kishore
authors.affiliation: Centogene AG, Rostock, Germany.
authors.forename: Nahid
authors.initials: N
authors.lastname: Nahavandi
authors.affiliation: Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.|College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors.forename: Wafaa
authors.initials: W
authors.lastname: Eyaid
authors.affiliation: College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.|Division of Neurology, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Muhammad Talal
authors.initials: MT
authors.lastname: Al Rifai
authors.affiliation: College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.|Division of Neurology, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al-Rumayyan
authors.affiliation: College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.|Division of Neurology, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Twaijri
authors.affiliation: College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.|Department of pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Ali
authors.initials: A
authors.lastname: Alothaim
authors.affiliation: Division of Metabolic and Genetics, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
authors.forename: Amal
authors.initials: A
authors.lastname: Alhashem
authors.affiliation: Division of Pediatrics, Johns Hopkins Aramco hospital, Dhahran Health Center, Saudi Aramco, Dhahran, Saudi Arabia.
authors.forename: Nouriya
authors.initials: N
authors.lastname: Al-Sannaa
authors.affiliation: College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.|Division of Neurology, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Balwi
authors.affiliation: Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.|College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors.forename: Majid
authors.initials: M
authors.lastname: Alfadhel
authors.affiliation: Centogene AG, Rostock, Germany.|Albrecht-Kossel-Institute for Neuroregeneration, Medical University Rostock, Rostock, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.affiliation: Centogene AG, Rostock, Germany.|Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
authors.forename: Rami
authors.identifier: 0000-0002-1542-1399
authors.initials: R
authors.lastname: Abou Jamra
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D005420:Flavoproteins / Q000235:genetics; D005820:Genetic Testing / Q000379:methods* / Q000592:standards; D060005:Genotyping Techniques / Q000379:methods* / Q000592:standards; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000235:genetics; D009679:Nuclear Family; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D050768:Protoporphyrinogen Oxidase / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods* / Q000592:standards; D015222:Sodium Channels / Q000235:genetics; D062547:Voltage-Gated Sodium Channel beta-1 Subunit / Q000235:genetics
chemical_list: C539678:FRMPD4 protein, human; D005420:Flavoproteins; D047908:Intracellular Signaling Peptides and Proteins; C581029:KCTD3 protein, human; D024101:Mitochondrial Proteins; D062552:NAV1.3 Voltage-Gated Sodium Channel; D015221:Potassium Channels; C470379:SCN1B protein, human; C424715:SCN3A protein, human; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; C493978:PPOX protein, human; D050768:Protoporphyrinogen Oxidase; C114102:PTPN23 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor