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

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.

SUBMITTER: Dyment DA

PROVIDER: S-EPMC8197629 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Dyment David A DA O'Donnell-Luria Anne A Agrawal Pankaj B PB Coban Akdemir Zeynep Z Aleck Kyrieckos A KA Antaki Danny D Al Sharhan Hind H Au Ping-Yee B PB Aydin Hatip H Beggs Alan H AH Bilguvar Kaya K Boerwinkle Eric E Brand Harrison H Brownstein Catherine A CA Buyske Steve S Chodirker Bernard B Choi Jungmin J Chudley Albert E AE Clericuzio Carol L CL Cox Gerald F GF Curry Cynthia C de Boer Elke E de Vries Bert B A BBA Dunn Kathryn K Dutmer Cullen M CM England Eleina M EM Fahrner Jill A JA Geckinli Bilgen B BB Genetti Casie A CA Gezdirici Alper A Gibson William T WT Gleeson Joseph G JG Greenberg Cheryl R CR Hall April A Hamosh Ada A Hartley Taila T Jhangiani Shalini N SN Karaca Ender E Kernohan Kristin K Lauzon Julie L JL Lewis M E Suzanne MES Lowry R Brian RB López-Giráldez Francesc F Matise Tara C TC McEvoy-Venneri Jennifer J McInnes Brenda B Mhanni Aziz A Garcia Minaur Sixto S Moilanen Jukka J Nguyen An A Nowaczyk Malgorzata J M MJM Posey Jennifer E JE Õunap Katrin K Pehlivan Davut D Pajusalu Sander S Penney Lynette S LS Poterba Timothy T Prontera Paolo P Doriqui Maria Juliana Rodovalho MJR Sawyer Sarah L SL Sobreira Nara N Stanley Valentina V Torun Deniz D Wargowski David D Witmer P Dane PD Wong Isaac I Xing Jinchuan J Zaki Maha S MS Zhang Yeting Y Boycott Kym M KM Bamshad Michael J MJ Nickerson Deborah A DA Blue Elizabeth E EE Innes A Micheil AM

American journal of medical genetics. Part A 20201024 1

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 M ...[more]

PMID: 33098347

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Project description:Dubowitz syndrome is a rare disorder characterized by multiple congenital anomalies, cognitive delay, growth failure, an immune defect, and an increased risk of blood dyscrasia and malignancy. There is considerable phenotypic variability, suggesting genetic heterogeneity. We clinically characterized and performed exome sequencing and high-density array SNP genotyping on three individuals with Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister) and an unpublished patient (Patient 3). Given the siblings' history of bone marrow abnormalities, we also evaluated telomere length and performed radiosensitivity assays. In the siblings, exome sequencing identified compound heterozygosity for a known rare nonsense substitution in the nuclear ligase gene LIG4 (rs104894419, NM_002312.3:c.2440C>T) that predicts p.Arg814X (MAF:0.0002) and an NM_002312.3:c.613delT variant that predicts a p.Ser205Leufs*29 frameshift. The frameshift mutation has not been reported in 1000 Genomes, ESP, or ClinSeq. These LIG4 mutations were previously reported in the sibling sister; her brother had not been previously tested. Western blotting showed an absence of a ligase IV band in both siblings. In the third patient, array SNP genotyping revealed a de novo ∼ 3.89 Mb interstitial deletion at chromosome 17q24.2 (chr 17:62,068,463-65,963,102, hg18), which spanned the known Carney complex gene PRKAR1A. In all three patients, a median lymphocyte telomere length of ≤ 1st centile was observed and radiosensitivity assays showed increased sensitivity to ionizing radiation. Our work suggests that, in addition to dyskeratosis congenita, LIG4 and 17q24.2 syndromes also feature shortened telomeres; to confirm this, telomere length testing should be considered in both disorders. Taken together, our work and other reports on Dubowitz syndrome, as currently recognized, suggest that it is not a unitary entity but instead a collection of phenotypically similar disorders. As a clinical entity, Dubowitz syndrome will need continual re-evaluation and re-definition as its constituent phenotypes are determined.

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

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

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