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 Publication2021
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
Volume185
Issue1
Pagination119-133
Date Published2021 01
ISSN1552-4833
KeywordsAdolescent, Child, Child, Preschool, DNA Copy Number Variations, Eczema, Exome, Facies, Female, Genetic Predisposition to Disease, Genome, Human, Genomics, Growth Disorders, Histone Deacetylases, Humans, Infant, Intellectual Disability, Male, Microcephaly, Phenotype, Repressor Proteins, Whole Exome Sequencing
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
PubMed Central IDPMC8197629
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
K12 HD052896 / HD / NICHD NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
R01 HG009141 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
/ / CIHR / Canada