TY - JOUR
T1 - Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome
AU - Care4Rare Consortium
AU - Centers for Mendelian Genomics
AU - Dyment, David A.
AU - O'Donnell-Luria, Anne
AU - Agrawal, Pankaj B.
AU - Coban Akdemir, Zeynep
AU - Aleck, Kyrieckos A.
AU - Antaki, Danny
AU - Al Sharhan, Hind
AU - Au, Ping Yee B.
AU - Aydin, Hatip
AU - Beggs, Alan H.
AU - Bilguvar, Kaya
AU - Boerwinkle, Eric
AU - Brand, Harrison
AU - Brownstein, Catherine A.
AU - Buyske, Steve
AU - Chodirker, Bernard
AU - Choi, Jungmin
AU - Chudley, Albert E.
AU - Clericuzio, Carol L.
AU - Cox, Gerald F.
AU - Curry, Cynthia
AU - de Boer, Elke
AU - de Vries, Bert B.A.
AU - Dunn, Kathryn
AU - Dutmer, Cullen M.
AU - England, Eleina M.
AU - Fahrner, Jill A.
AU - Geckinli, Bilgen B.
AU - Genetti, Casie A.
AU - Gezdirici, Alper
AU - Gibson, William T.
AU - Gleeson, Joseph G.
AU - Greenberg, Cheryl R.
AU - Hall, April
AU - Hamosh, Ada
AU - Hartley, Taila
AU - Jhangiani, Shalini N.
AU - Karaca, Ender
AU - Kernohan, Kristin
AU - Lauzon, Julie L.
AU - Lewis, M. E.Suzanne
AU - Lowry, R. Brian
AU - López-Giráldez, Francesc
AU - Matise, Tara C.
AU - McEvoy-Venneri, Jennifer
AU - McInnes, Brenda
AU - Mhanni, Aziz
AU - Garcia Minaur, Sixto
AU - Moilanen, Jukka
AU - Nguyen, An
N1 - Publisher Copyright:
© 2020 Wiley Periodicals LLC
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Dubowitz syndrome
KW - exome sequencing
KW - genetic heterogeneity
KW - genome sequencing
KW - microarray
UR - http://www.scopus.com/inward/record.url?scp=85097746888&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.61926
DO - 10.1002/ajmg.a.61926
M3 - Article
AN - SCOPUS:85097746888
SN - 1552-4825
VL - 185
SP - 119
EP - 133
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 1
ER -