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

Yi Gu,Xiang Chen,Lina Zhu,Xiuwei Ma,Tao Cai,Bingwu Xiang

doi:10.1186/s12881-020-01042-w

Abstract

BackgroundTo 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.MethodsConsidering 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.ResultsThree 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.ConclusionsWe 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.

Highlights

To date, at least 746 genes have been identified to cause intellectual disability (ID)
Potential inherited mutations and de novo mutation (DNM) related to neurodevelopmental disorders were screened using a recently developed program mirTrios [15]
Mutation description A nonsense [NC_000023.10: g.153296777G > A, NM_ 004992.3: c.502C > T, p.(Arg168*)] and two missense mutations [NC_000023.10: g.153296363G > A, NM_ 004992.3: c.916C > T, p.(Arg306Cys); NC_000023.10: g.153296400G > C, NM_004992.3: c.879C > G, p.(Ile293Met)] in exon 4 of Methyl CpG binding protein 2 (MECP2) were identified in case 1, case 2 and case 3 respectively

Summary

Introduction

At least 746 genes have been identified to cause intellectual disability (ID). Mutations in the Methyl CpG binding protein 2 (MECP2) gene are the leading cause of Rett syndrome and associated ID. 85% of patients with ID could be classified as mild ID. Environmental factors, such as malnutrition during pregnancy, perinatal asphyxia, and neurotoxic compounds exposure, are believed to play an important role in the mild ID [4]. Genetic causes are more frequently observed in affected individuals with severe ID [4]. Chromosomal abnormalities, like Down syndrome (trisomy 21) and DiGeorge syndrome (22q11.2 deletion), are the common causes of genetic ID [4]. At least 746 genes that influence intelligence have been identified [5]. 141 of them are located on X-chromosome [6], such as FMR1

Methods

Results

Discussion

Conclusion