Three intellectual disability-associated de novo mutations in MECP2 identified by trio-WES analysis

Abstract

Background: To date, at least 746 genes have been identified to cause intellectual disability (ID). Among them, mutations in the Methyl CpG binding protein 2 (MECP2) gene are the leading cause of Rett syndrome and associated ID.

Methods: Considering the large number of ID-associated genes, we applied trio-based whole-exome sequencing (trio-WES) and in silico analysis for genetic diagnosis of 294 children with ID.

Results: Three de novo heterozygous mutations [NM_004992.3: c.502C > T, p.(Arg168*), c.916C > T, p.(Arg306Cys), and c.879C > G, p.(Ile293Met)] in MECP2 were identified in three unrelated girls. The first two mutations were detected in two patients who were diagnosed as typical Rett syndrome, X-linked ID and psychomotor retardation. The third mutation (c.879C > G), a previously unreported, was found in a 6-year-old girl with ID, microcephaly, severe underweight and psychomotor retardation. Particularly, this extremely rare de novo mutation (DNM) is located in the transcriptional repression domain (TRD) of MECP2, where at least 62 different causal mutations are identified.

Conclusions: We identified three DNMs in MECP2 in a cohort of 294 individuals with ID. The novel c.879C > G mutation, as a likely pathogenic allele, may become a risk factor associated with X-linked ID, microcephaly and psychomotor retardation.

Keywords: Intellectual disability (ID); MECP2; Rett syndrome; Whole-exome sequencing (WES); de novo mutation (DNM).

Fig. 1

Family 1 and verification of a de novo nonsense mutation c.502C > T, p.(Arg168*) of MECP2. a The mutation is detected in the proband, but not in the parents, is confirmed by Sanger sequencing. b Pedigree of the family and facial photograph of the proband at 3 years old

Fig. 2

Sanger sequencing of the mutation c.916C > T, p.(Arg360Cys) of MECP2 in case 2. a The mutation is present in the proband, but not in the parents, is confirmed by Sanger sequencing. b Pedigree of the family and facial photograph of the proband at 8 years old

Fig. 3

Three de novo mutations in MECP2 identified in this study are located in MBD and TRD domain of MeCP2 protein. Location of the novel DNM p.(Ile293Met) (I293M) in TRD domain is labeled in red. Multiple vertical lines beneath the blue box represent 62 different mutations in TRD domain (HGMD), which appears to be evenly distributed within the domain composed of 104 amino acids. Both p.(Arg168*) (R168X) and p.(Arg306Cys) (R306C) mutations in the first two patients are hot alleles. MeCP2 domains are predicted by SMART analysis (http://smart.embl-heidelberg.de/). AT-hook is a DNA-binding motif. Pink boxes represent low compositional complexity regions