Speech and language delay in a patient with WDR4 mutations
Introduction
Primordial dwarfism (PD) is a group of clinically and genetically heterogenous diseases, mainly consisting of five subtypes: Seckel syndrome, Majewski/Microcephalic osteodysplastic primordial dwarfism type I/III and type II (MOPD I/II/III), Meier-Gorlin syndrome and Sliver-Russell syndrome (Khetarpal et al., 2016). MOPD III is considered as the variant of MOPD I with similar features (Alkuraya, 2015). Many PD patients have a molecular diagnosis based on a large number of diseases genes identified (Alkuraya, 2015). Most of them inherited in an autosomal recessive manner. Chromosomal abnormality and copy number variations (CNV) involving the known PD-causing genes have also been reported (Khetarpal et al., 2016). Several genetic disorders also have overlapped features with PD. So genetic testing is necessary to confirm the diagnoses of patients with PD-like features.
WDR4 is a newly discovered disease-causing gene of PD with autosomal recessive inherit manner in 2015. It was first reported in two unrelated consanguineous families. Patients present primordial dwarfism, distinct facial deformity, brain malformation, severe encephalopathy and seizures. Brain malformation includes microcephaly, agenesis of corpus callosum and simplified gyration (Shaheen et al., 2015). The Arg170Gln is detected in two sisters with similar phenotypes in a family (Trimouille et al., 2017). WDR4 locates at chromosome 21q22.3 and spans 37 kb of human genome. It has 12 exons including 11 coding exons and one 3′-UTR exon (Michaud et al., 2000). WDR4 belongs to WDR repeat family characterized as highly conserved repeating units. Transcript of 1.5 kb is mainly expressed in fetal tissue and transcript of 2.1 kb weakly expressed in virtually all tissues (Michaud et al., 2000). WDR4 and METTL1 are human orthologous protein of trm82 and trm8 respectively in yeast. METTL1 forms a heterodimer with WDR4 as a complex participating in catalyzing the tRNA m7G46 modification (Alexandrov et al., 2002, 2005; Leulliot et al., 2008). Modification of tRNA m7G has a key role in protein synthesis and cellular function in temperature-sensitive storage in yeast (Alexandrov et al., 2005). Lacking m7G46 leads to degradation of tRNA by rapid tRNA pathway (Phizicky and Hopper, 2010). Reduction of m7G46 methylation of specific tRNA participates in the potential pathogenic mechanism of primordial dwarfism (Shaheen et al., 2015). In this study, we reported a child with motor and speech delay as well as intellectual disability. WES detected two novel mutations in WDR4, inherited from father and mother respectively.
Section snippets
Clinical reports
A term baby was born to a non-consanguineous couple by cesarean section (Table 1). His birth weight was 2650 g and has no condition of intrauterine growth retardation. Head circumference is not recorded but mentioned to be smaller than normal range. He did not meet the age-appropriate developmental milestones. He was able to walk at 2-year-old without spasticity or abnormal gait. He presents persistent speech development delay evident by speaking only single simple words at 3-year-old and
Discussion
In this study, we revealed two novel WDR4 mutations from one patient diagnosed as PD. The main phenotype is motor, speech and language development delay as well as intellectual disability. All five subtypes of PD have features of mental retardation and/or intellectual disability (Willems et al., 2010; Loeys et al., 1999; Pierce and Morse, 2012; Coutton et al., 2012). Motor delay is only reported in Seckel syndrome and MOPD II patients (Verloes et al., 1993; Perry et al., 2013). Speech and
Financial disclosure
The authors have indicated they have no financial relationships relevant to this article to disclose.
Conflicts of interest
The authors declare no competing interests.
Contributors' statement page
Chen X, Gao Y and Wang H prepare this manuscript. Wu B, Yang L and Zhou W are in charge of the clinical genetic diagnosis. Lu Y, Dong X and Liu B fulfill data analysis.
Acknowledgements
We are very grateful to the patient family and thanks for their trust for our lab. This work was funded by the National Key Research and Development Program (2016YFC1000500, 2016YFC0905102), National Natural Science Foundation of China (81471483, 81471484).
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These authors contributed equally to this work.