Abstract
ObjectiveGlobal developmental delay has markedly high phenotypic and genetic heterogeneity, and is a great challenge for clinical diagnosis. Hypotonia, ataxia, and delayed development syndrome (HADDS), first reported in 2017, is one type of global development delay. The aim of the present study was to investigate the genetic etiology of a Chinese boy with global developmental delay.MethodsWe combined clinical and imaging phenotyping with trio whole-exome sequencing and Sanger sequencing to the patient and his clinically unaffected parents. A luciferase reporter and immunofluorescence were performed to detect the effect of mutation on transcriptional activity and subcellular localization.ResultsThe patient presented with several previously unreported symptoms in the patients with HADDS, including hemangiomas, mild hearing abnormalities and tracheomalacia. A novel EBF3 c.589A > G missense mutation (p.Asn197Asp, p.N197D) was identified in the patient but not in his parents. By constructing the plasmid and transfecting HEK293T cells, EBF3-N197D mutant showed impaired activation of luciferase reporter expression of the p21 promoter, and the mutant affected its entry into the nucleus.ConclusionTo the best of our knowledge, this is the first report of EBF3 pathogenic mutation which associated with HADDS in the Chinese population. Our results expand the phenotypes and pathogenic mutation spectrum of HADDS, thus potentially facilitating the clinical diagnosis and genetic counseling of HADDS patients.
Highlights
Global developmental delay refers to a significant retardation of a child’s growth and development relative to its peers (Shevell et al, 2003)
The proband, a Chinese boy, was referred to the genetic counseling clinic of our hospital owing to global developmental delay
We found a novel heterozygous EBF3 mutation with TrioWES in a Chinese boy with HADDS
Summary
Global developmental delay refers to a significant retardation of a child’s growth and development relative to its peers (Shevell et al, 2003). It affects cognitive or thinking skills, motor skills, social and emotional, language, and vision.. The etiology of global developmental delay includes exogenous and genetic (non-metabolic or metabolic) factors (Papavasiliou et al, 2000; Michelson et al, 2011). EBF3 Novel Mutation With HADDS the diagnosis of children with global developmental delay (Srour and Shevell, 2014). Whole-exome sequencing (WES), wholegenome sequencing (WGS), and genome-wide microarrays have facilitated the identification of several candidate genes associated with developmental delays
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