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

Am J Med Genet A. 2021 Jan;185(1):119-133. doi: 10.1002/ajmg.a.61926. Epub 2020 Oct 24.

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.

Keywords: Dubowitz syndrome; exome sequencing; genetic heterogeneity; genome sequencing; microarray.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • DNA Copy Number Variations / genetics
  • Eczema / diagnosis*
  • Eczema / genetics*
  • Eczema / pathology
  • Exome / genetics
  • Facies
  • Female
  • Genetic Predisposition to Disease*
  • Genome, Human / genetics
  • Genomics / methods
  • Growth Disorders / diagnosis*
  • Growth Disorders / genetics*
  • Growth Disorders / pathology
  • Histone Deacetylases / genetics*
  • Humans
  • Infant
  • Intellectual Disability / diagnosis*
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Male
  • Microcephaly / diagnosis*
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Phenotype
  • Repressor Proteins / genetics*
  • Whole Exome Sequencing

Substances

  • Repressor Proteins
  • HDAC8 protein, human
  • Histone Deacetylases

Supplementary concepts

  • Dubowitz syndrome