Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.
Document Type
Article
Publication Date
1-1-2021
Abstract
Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.
Publication Title
American journal of medical genetics. Part A
ISSN
1552-4833
Volume
185
Issue
1
First Page
119
Last Page
133
DOI
0.1002/ajmg.a.61926
Recommended Citation
Dyment, David A; Anne O'Donnell-Luria; Pankaj B Agrawal; Zeynep Coban Akdemir; Kyrieckos A Aleck; Danny Antaki; Hind Al Sharhan; Ping-Yee B Au; Hatip Aydin; Alan H Beggs; Kaya Bilguvar; Eric Boerwinkle; Harrison Brand; Catherine A Brownstein; Steve Buyske; Bernard Chodirker; Jungmin Choi; Albert E Chudley; Carol L Clericuzio; Gerald F Cox; Cynthia Curry; Elke de Boer; Bert B A de Vries; Kathryn Dunn; Cullen M Dutmer; Eleina M England; Jill A Fahrner; Bilgen B Geckinli; Casie A Genetti; Alper Gezdirici; William T Gibson; Joseph G Gleeson; Cheryl R Greenberg; April Hall; Ada Hamosh; Taila Hartley; Shalini N Jhangiani; Ender Karaca; Kristin Kernohan; Julie L Lauzon; M E Suzanne Lewis; R Brian Lowry; Francesc López-Giráldez; Tara C Matise; Jennifer McEvoy-Venneri; Brenda McInnes; Aziz Mhanni; Sixto Garcia Minaur; Jukka Moilanen; An Nguyen; Malgorzata J M Nowaczyk; Jennifer E Posey; Katrin Õunap; Davut Pehlivan; Sander Pajusalu; Lynette S Penney; Timothy Poterba; Paolo Prontera; Maria Juliana Rodovalho Doriqui; Sarah L Sawyer; Nara Sobreira; Valentina Stanley; Deniz Torun; David Wargowski; P Dane Witmer; Isaac Wong; Jinchuan Xing; Maha S Zaki; Yeting Zhang; Care4Rare Consortium; Centers for Mendelian Genomics; Kym M Boycott; Michael J Bamshad; Deborah A Nickerson; Elizabeth E Blue; and A Micheil Innes.
"Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.."
American journal of medical genetics. Part A
