Clinical and genetic heterogeneity in Dubowitz syndrome: Implications for diagnosis, management and further research

Abstract

Dubowitz syndrome was described in 1965 as a recognizable syndrome characterized by microcephaly, short stature, eczema, mild developmental delays, and an increased risk of malignancy. Since its original description, there have been over 200 reported cases though no single gene has been identified to explain a significant proportion of affected individuals. Since the last definitive review of Dubowitz syndrome in 1996, there have been 63 individuals with a clinical, or suspected, diagnosis of Dubowitz syndrome reported in 51 publications. These individuals show a markedly wide spectrum with respect to growth, facial gestalt, psychomotor development, and risk of malignancy; genetic causes were identified in 33% (21/63). Seven individuals had deleterious copy number variants, in particular deletions at 14q32 and 17q24 were reported and showed overlap with the Dubowitz phenotype. Several cases were shown to have single gene disorders that included de novo or biallelic pathogenic variants in several genes including NSUN2 and LIG4 frequently identified by next‐generation sequencing methods. It appears that the inability to identify a single gene responsible for Dubowitz syndrome reflects its extreme clinical and genetic heterogeneity. However, detailed phenotyping combined with careful grouping of subsets of unsolved cases and in conjunction with data‐sharing will identify novel disease genes responsible for additional cases. In the interim, for those clinically diagnosed with a Dubowitz phenotype, we recommend assessment by a Medical Geneticist, a microarray and, if available, clinical or research based genome‐wide sequencing. Management suggestions, including decisions regarding malignancy screening in select patients will be discussed.

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

“…The combined set of 7 novel candidate genes (Supplemental Table S2), 16 genes offering an alternative diagnosis (Table 2), and 8 DubS genes from the literature (Innes et al, 2018) exhibited significant PPI enrichment: 29 observed edges, 12 expected, PPI enrichment p ‐value = 4.5e‐05. The network, shown in Figure 2, captures four clusters: the two smallest clusters connecting our novel candidate genes to genes previously implicated in DubS under a recessive model: CDK11B to PCNT and VPS13B to UBE3B (Dieks et al, 2014; Innes et al, 2018); a second cluster driven by the genes within the chromosome X deletion observed in one case (note HDHD1 is another name for PUDP ); and a large cluster capturing many genes underlying syndromes similar to DubS and one of our novel candidate genes, TOP2A . This set of 27 genes is significantly enriched in 37 GO:Biological Processes (Supplemental Table S3).…”

“…We hypothesized that the genes implicated by our analyses share biological pathways with each other and the genes underlying single gene disorders previously implicated in individuals diagnosed with DubS). The novel candidate genes, the genes driving alternative diagnoses among our cases and the genes implicated in the literature for individuals clinically diagnosed with DubS (Innes et al, 2018) were provided to STRING‐db (v11.0) (Szklarczyk et al, 2019) to assess for common pathways or interactions (Figure 1). This was performed by using human reference data, only the queried proteins, protein–protein interaction (PPI) data from known interactions (curated databases, experimentally determined), predicted interactions based on gene fusions and gene co‐occurrence, co‐expression, protein homology, and text mining; medium confidence (0.400) was the minimum required for interaction scores.…”

“…A recognizable pattern of facial dysmorphology includes a sloping forehead, ptosis, telecanthus, blepharophimosis, facial asymmetry, and micrognathia (Dubowitz, 1965; Grosse et al, 1971). Since its original description, a significant degree of phenotypic variability has been recognized to be part of DubS (Innes, McInnes, & Dyment, 2018; Stewart et al, 2014; Tsukahara & Opitz, 1996). In the absence of a laboratory diagnostic biomarker or pathognomonic feature, the phenotypic expansion associated with the syndrome has led to discussion regarding its existence as a single unifying diagnosis (Dyment et al, 2018; O'Donnell‐Luria et al, 2018).…”

“…The observation of affected siblings in some families has suggested a potential autosomal recessive disease trait; however, no single gene, group of related genes, or common pathway has been identified to explain DubS (Innes et al, 2018). Biallelic variants in LIG4 have been identified in two families with a clinical diagnosis of DubS (Gruhn et al, 2007; Stewart et al, 2014).…”

Unsolved recognizable patterns of human malformation: Challenges and opportunities

“…This issue of Seminars leads off with Dubowitz syndrome (MIM 223370), a condition first reported in 1965 and now reported more than 200 times (Dubowitz, ). In their research article, Innes, McInnes, and Dyment review the literature and provide evidence that both clinical and molecular/causal heterogeneity is likely the primary explanation why a major gene has yet to be identified for this disorder (Innes, McInnes, & Dyment, ). The same phenomenon is likely underlying the complexity of other recognizable conditions not included in this issue, including Toriello‐Carey syndrome (Toriello, Colley, & Bamshad, ), Fryns syndrome (Bone et al, ; Thompson & Cole, ), PEHO syndrome (Chitre et al, ), and 3C syndrome (Elliott et al, ; Kolanczyk et al, ).…”