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

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.

Centers for Mendelian Genomics: A decade of facilitating gene discovery

“…Diagnoses were made for a number of recently molecularly defined and phenotypically similar conditions with growth restriction, microcephaly and developmental delay, with a molecular diagnosis made in 13/27 families (48%) or strong candidate variants in known and candidate disease genes identified in an additional 7/27 families (26%). 41 Only one gene , HDAC8, was linked to the phenotype in multiple families (2 families). This experience highlights the need to continue to work across national and international rare disease programs to build larger cohorts for rare conditions.…”

Case Report: Novel Compound-Heterozygous Variants of SKIV2L Gene that Cause Trichohepatoenteric Syndrome 2

“…The patient was diagnosed with Dubowitz syndrome in Dyment et al, 2021 [45]. Monies et al, 2015;Lee et al, 2016;Zheng et al, 2016;Bick et al, 2017;Hiejima et al, 2017;Bourgeois et al, 2018;Vardi et al, 2018;Rudilla et al, 2019;Fung et al, 2020;Taher et al, 2020;Dyment et al, 2021;Klee et al, 2021), the incidence of this disease is not significantly different between genders (M:F 17:20) (Table 1). Patients have their onset mostly in the neonatal period, ranging from birth to 0.8 years of age (mean, 29.5 days; median, 17 days).…”

Correlations between phenotype and gene region-specific episignatures in Rubinstein-Taybi syndrome and Menke-Hennekam syndrome

“…To comprehensively evaluate phenotype similarities and differences, we further collected clinical information from our patients and literatures published previously (3,(7)(8)(9)(10)(11)(12)(13)(14)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). In total, 37 MKHK and 151 RSTS patients (including 115 classical RSTS and 36 patients with non-NMD variants) were enrolled (Table 2).…”