Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.
Adolescent
Child
Child, Preschool
DNA Copy Number Variations
/ genetics
Eczema
/ diagnosis
Exome
/ genetics
Facies
Female
Genetic Predisposition to Disease
Genome, Human
/ genetics
Genomics
/ methods
Growth Disorders
/ diagnosis
Histone Deacetylases
/ genetics
Humans
Infant
Intellectual Disability
/ diagnosis
Male
Microcephaly
/ diagnosis
Phenotype
Repressor Proteins
/ genetics
Exome Sequencing
Dubowitz syndrome
exome sequencing
genetic heterogeneity
genome sequencing
microarray
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
01
05
2020
revised:
09
08
2020
accepted:
19
09
2020
pubmed:
25
10
2020
medline:
30
6
2021
entrez:
24
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33098347
doi: 10.1002/ajmg.a.61926
pmc: PMC8197629
mid: NIHMS1706494
doi:
Substances chimiques
Repressor Proteins
0
HDAC8 protein, human
EC 3.5.1.98
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
119-133Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006504
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD052896
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : NHGRI NIH HHS
ID : U24 HG008956
Pays : United States
Organisme : NHGRI NIH HHS
ID : K08 HG008986
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006493
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090255
Pays : United States
Organisme : CIHR
Pays : Canada
Informations de copyright
© 2020 Wiley Periodicals LLC.
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