Speech and language delay in a patient with WDR4 mutations

Abstract

Primordial dwarfism (PD) is mainly characterized by growth deficiency with heterogeneous phenotypes. A group of genes are known to be associated with PD or PD-related syndrome. WD repeat domain 4 (WDR4) is recently reported to be responsible for PD. Here we report a 6-year-old boy from a non-consanguineous couple with motor and speech delay as well as intellectual disability. Whole exome sequencing (WES) identified a missense mutation (NM_033661.4:c.491A > C; p.(Asp164Ala)) and a small insertion (NM_033661.4:c.940dupC; p.(Leu314Profs*16)) of WDR4 in this patient. Two novel mutations confirmed by Sanger sequencing are from father and mother respectively according to a recessive inheritance pattern. Asp164Ala located in functional region is predicted to be deleterious by two kinds of algorithm. The small insertion causing a frameshift mutation leads to truncated protein. In this study, we present two novel WDR4 mutations responsible for PD in a 6-year-old patient, expanding the molecular and phenotype spectrum of WDR4-related PD.

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 m^7G 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.