Yoo-Mi Kim1, Yun-Jin Lee1, Jae Hong Park1, Hyoung-Doo Lee1, Chong Kun Cheon1, Su-Young Kim1, Jae-Yeon Hwang2, Ja-Hyun Jang3, Han-Wook Yoo4. 1. Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea. 2. Department of Radiology, Pusan National University College of Medicine, Pusan National University Children's Hospital, Yangsan, Korea. 3. Laboratory Medicine, Green Cross Genome, Yongin, Korea. 4. Medical Genetics Center, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.
Abstract
BACKGROUND: As syndromic short stature and overgrowth are heterogeneous and the list of causative genes is rapidly expanding, there is an unmet need for identifying genetic causes based on conventional gene testing or karyotyping. Early diagnosis leads to the proper management of the patient and providing genetic counseling for family members at risk in a timely manner. MATERIALS AND METHODS: We conducted targeted exome sequencing to identify the genetic causes of undiagnosed syndromic short stature or overgrowth in 15 pediatric patients from 13 families in Korea. We applied targeted exome sequencing using the Next Seq platform and a TruSight One panel. RESULTS: Among the 13 families, 6 different disorders in 8 patients with short stature or overgrowth were identified, and the diagnostic yield was 46.2%. One boy with overgrowth had a TGFB3 gene mutation. In the short stature group, Coffin-Lowry syndrome (CLS), trichorhinophalangeal syndrome, DYRK1A haploinsufficiency syndrome, short stature with optic atrophy and Pelger-Huët anomaly syndrome with recurrent hepatitis, and type 4 Meier-Gorlin syndrome were identified. One CLS patient had a co-existing monogenic disease, congenital glaucoma, caused by the compound heterozygote mutations of the CYP1B1 gene. CONCLUSION: Targeted exome sequencing is a powerful method for diagnosing syndromic growth disorders. It enables us to understand molecular pathophysiology and investigate new treatments for growth disorders.
BACKGROUND: As syndromic short stature and overgrowth are heterogeneous and the list of causative genes is rapidly expanding, there is an unmet need for identifying genetic causes based on conventional gene testing or karyotyping. Early diagnosis leads to the proper management of the patient and providing genetic counseling for family members at risk in a timely manner. MATERIALS AND METHODS: We conducted targeted exome sequencing to identify the genetic causes of undiagnosed syndromic short stature or overgrowth in 15 pediatric patients from 13 families in Korea. We applied targeted exome sequencing using the Next Seq platform and a TruSight One panel. RESULTS: Among the 13 families, 6 different disorders in 8 patients with short stature or overgrowth were identified, and the diagnostic yield was 46.2%. One boy with overgrowth had a TGFB3 gene mutation. In the short stature group, Coffin-Lowry syndrome (CLS), trichorhinophalangeal syndrome, DYRK1Ahaploinsufficiency syndrome, short stature with optic atrophy and Pelger-Huët anomaly syndrome with recurrent hepatitis, and type 4 Meier-Gorlin syndrome were identified. One CLSpatient had a co-existing monogenic disease, congenital glaucoma, caused by the compound heterozygote mutations of the CYP1B1 gene. CONCLUSION: Targeted exome sequencing is a powerful method for diagnosing syndromic growth disorders. It enables us to understand molecular pathophysiology and investigate new treatments for growth disorders.
Authors: Christian Staufner; Bianca Peters; Matias Wagner; Seham Alameer; Ivo Barić; Pierre Broué; Derya Bulut; Joseph A Church; Ellen Crushell; Buket Dalgıç; Anibh M Das; Anke Dick; Nicola Dikow; Carlo Dionisi-Vici; Felix Distelmaier; Neslihan Ekşi Bozbulut; François Feillet; Emmanuel Gonzales; Nedim Hadzic; Fabian Hauck; Robert Hegarty; Maja Hempel; Theresia Herget; Christoph Klein; Vassiliki Konstantopoulou; Robert Kopajtich; Alice Kuster; Martin W Laass; Elke Lainka; Catherine Larson-Nath; Alexander Leibner; Eberhard Lurz; Johannes A Mayr; Patrick McKiernan; Karine Mention; Ute Moog; Neslihan Onenli Mungan; Korbinian M Riedhammer; René Santer; Irene Valenzuela Palafoll; Jerry Vockley; Dominik S Westphal; Arnaud Wiedemann; Saskia B Wortmann; Gaurav D Diwan; Robert B Russell; Holger Prokisch; Sven F Garbade; Stefan Kölker; Georg F Hoffmann; Dominic Lenz Journal: Genet Med Date: 2019-11-25 Impact factor: 8.822