Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.
Am J Med Genet A
; 185(1): 119-133, 2021 01.
Article
em En
| MEDLINE
| ID: mdl-33098347
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Predisposição Genética para Doença
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Eczema
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Transtornos do Crescimento
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Histona Desacetilases
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Deficiência Intelectual
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Microcefalia
Tipo de estudo:
Diagnostic_studies
Limite:
Adolescent
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article