Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.

TitleAlternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.
Publication TypeJournal Article
Year of Publication2020
AuthorsDyment, DA, O'Donnell-Luria, A, Agrawal, PB, Akdemir, ZCoban, Aleck, KA, Antaki, D, Sharhan, HAl, Au, P-YB, Aydin, H, Beggs, AH, Bilguvar, K, Boerwinkle, E, Brand, H, Brownstein, CA, Buyske, S, Chodirker, B, Choi, J, Chudley, AE, Clericuzio, CL, Cox, GF, Curry, C, de Boer, E, de Vries, BBA, Dunn, K, Dutmer, CM, England, EM, Fahrner, JA, Geckinli, BB, Genetti, CA, Gezdirici, A, Gibson, WT, Gleeson, JG, Greenberg, CR, Hall, A, Hamosh, A, Hartley, T, Jhangiani, SN, Karaca, E, Kernohan, K, Lauzon, JL, Lewis, MESuzanne, R Lowry, B, López-Giráldez, F, Matise, TC, McEvoy-Venneri, J, McInnes, B, Mhanni, A, Minaur, SGarcia, Moilanen, J, Nguyen, A, Nowaczyk, MJM, Posey, JE, Õunap, K, Pehlivan, D, Pajusalu, S, Penney, LS, Poterba, T, Prontera, P, Doriqui, MJuliana Ro, Sawyer, SL, Sobreira, N, Stanley, V, Torun, D, Wargowski, D, P Witmer, D, Wong, I, Xing, J, Zaki, MS, Zhang, Y, Boycott, KM, Bamshad, MJ, Nickerson, DA, Blue, EE, A Innes, M
Corporate AuthorsCare4Rare Consortium, Centers for Mendelian Genomics
JournalAm J Med Genet A
Date Published2020 Oct 24
ISSN1552-4833
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.

DOI10.1002/ajmg.a.61926
Alternate JournalAm J Med Genet A
PubMed ID33098347
Grant List / / Boston Children's Hospital OFD Career Development Award /
/ CAPMC / CIHR / Canada
/ / Children's Hospital of Eastern Ontario Foundation /
912-12-109 / / Dutch Organization for Health Research and Development Grant /
917-86-319 / / Dutch Organization for Health Research and Development Grant /
PRG471 / / Estonian Research Council /
PUTJD827 / / Estonian Research Council /
/ / Genome Alberta, British Columbia and Quebec /
OGI-147 / / Genome Canada and the Ontario Genomics Institute /
/ / National Heart, Lung, and Blood Institute (NHLBI) /
UM1 HG006493 / HG / NHGRI NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States
R01 HG009141 / HG / NHGRI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States
K12 HD052896 / HD / NICHD NIH HHS / United States
/ / National Organization of Rare Disorders (NORD) /
/ / Ontario Research Fund /