Медицинская библиотека · American journal of medical genetics. Part A · 2020

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

Dyment David A, O'Donnell-Luria Anne, Agrawal Pankaj B, Coban Akdemir Zeynep, Aleck Kyrieckos A, Antaki Danny, Al Sharhan Hind, Au Ping-Yee B, Aydin Hatip, Beggs Alan H, Bilguvar Kaya, Boerwinkle Eric, Brand Harrison, Brownstein Catherine A, Buyske Steve, Chodirker Bernard, Choi Jungmin, Chudley Albert E, Clericuzio Carol L, Cox Gerald F, Curry Cynthia, de Boer Elke, de Vries Bert B A, Dunn Kathryn, Dutmer Cullen M, England Eleina M, Fahrner Jill A, Geckinli Bilgen B, Genetti Casie A, Gezdirici Alper, Gibson William T, Gleeson Joseph G, Greenberg Cheryl R, Hall April, Hamosh Ada, Hartley Taila, Jhangiani Shalini N, Karaca Ender, Kernohan Kristin, Lauzon Julie L, Lewis M E Suzanne, Lowry R Brian, López-Giráldez Francesc, Matise Tara C, McEvoy-Venneri Jennifer, McInnes Brenda, Mhanni Aziz, Garcia Minaur Sixto, Moilanen Jukka, Nguyen An, Nowaczyk Malgorzata J M, Posey Jennifer E, Õunap Katrin, Pehlivan Davut, Pajusalu Sander, Penney Lynette S, Poterba Timothy, Prontera Paolo, Doriqui Maria Juliana Rodovalho, Sawyer Sarah L, Sobreira Nara, Stanley Valentina, Torun Deniz, Wargowski David, Witmer P Dane, Wong Isaac, Xing Jinchuan, Zaki Maha S, Zhang Yeting, Care4Rare Consortium, Centers for Mendelian Genomics, Boycott Kym M, Bamshad Michael J, Nickerson Deborah A, Blue Elizabeth E, Innes A Micheil

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Аннотация

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.

Для цитирования: Dyment David A, O'Donnell-Luria Anne, Agrawal Pankaj B, Coban Akdemir Zeynep, Aleck Kyrieckos A, Antaki Danny, Al Sharhan Hind, Au Ping-Yee B, Aydin Hatip, Beggs Alan H, Bilguvar Kaya, Boerwinkle Eric, Brand Harrison, Brownstein Catherine A, Buyske Steve, Chodirker Bernard, Choi Jungmin, Chudley Albert E, Clericuzio Carol L, Cox Gerald F, Curry Cynthia, de Boer Elke, de Vries Bert B A, Dunn Kathryn, Dutmer Cullen M, England Eleina M, Fahrner Jill A, Geckinli Bilgen B, Genetti Casie A, Gezdirici Alper, Gibson William T, Gleeson Joseph G, Greenberg Cheryl R, Hall April, Hamosh Ada, Hartley Taila, Jhangiani Shalini N, Karaca Ender, Kernohan Kristin, Lauzon Julie L, Lewis M E Suzanne, Lowry R Brian, López-Giráldez Francesc, Matise Tara C, McEvoy-Venneri Jennifer, McInnes Brenda, Mhanni Aziz, Garcia Minaur Sixto, Moilanen Jukka, Nguyen An, Nowaczyk Malgorzata J M, Posey Jennifer E, Õunap Katrin, Pehlivan Davut, Pajusalu Sander, Penney Lynette S, Poterba Timothy, Prontera Paolo, Doriqui Maria Juliana Rodovalho, Sawyer Sarah L, Sobreira Nara, Stanley Valentina, Torun Deniz, Wargowski David, Witmer P Dane, Wong Isaac, Xing Jinchuan, Zaki Maha S, Zhang Yeting, Care4Rare Consortium, Centers for Mendelian Genomics, Boycott Kym M, Bamshad Michael J, Nickerson Deborah A, Blue Elizabeth E, Innes A Micheil. Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.. American journal of medical genetics. Part A. 2020. DOI: 10.1002/ajmg.a.61926.

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