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

Care4Rare Consortium, Centers for Mendelian Genomics

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)119-133
Number of pages15
JournalAmerican Journal of Medical Genetics, Part A
Volume185
Issue number1
DOIs
Publication statusPublished - 2021 Jan

Keywords

  • Dubowitz syndrome
  • exome sequencing
  • genetic heterogeneity
  • genome sequencing
  • microarray

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint

Dive into the research topics of 'Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome'. Together they form a unique fingerprint.

Cite this