Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2

Abstract

Purpose: Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by de novo mutations in MECP2 and sometimes in CDKL5 and FOXG1. However, some RTT patients lack mutations in these genes.

Methods: Twenty-two RTT patients without apparent MECP2, CDKL5, and FOXG1 mutations were subjected to both whole-exome sequencing and single-nucleotide polymorphism array-based copy-number variant (CNV) analyses.

Results: Three patients had MECP2 mutations initially missed by clinical testing. Of the remaining 19, 17 (89.5%) had 29 other likely pathogenic intragenic mutations and/or CNVs (10 patients had 2 or more). Interestingly, 13 patients had mutations in a gene/region previously reported in other neurodevelopmental disorders (NDDs), thereby providing a potential diagnostic yield of 68.4%. These mutations were significantly enriched in chromatin regulators (corrected P = 0.0068) and moderately enriched in postsynaptic cell membrane molecules (corrected P = 0.076), implicating glutamate receptor signaling.

Conclusion: The genetic etiology of RTT without MECP2, CDKL5, and FOXG1 mutations is heterogeneous, overlaps with other NDDs, and complicated by a high mutation burden. Dysregulation of chromatin structure and abnormal excitatory synaptic signaling may form two common pathological bases of RTT.Genet Med 19 1, 13-19.

Figure 1

An interaction network of genes with likely pathogenic mutations contributing to RTT in our cases. Black circles are input genes and gray circles are genes highly related to the input genes chosen by the network-building algorithm to maximize connectivity. The network was generated by using an input list of 46 genes with likely pathogenic mutations listed in Table 2 as well as the 3 known RTT genes MECP2, CDKL5, and FOXG1. Of the 46 genes, 23 were found to interact amongst each other either directly or indirectly through at least one of three ways: physical interactions (orange lines), co-localization of protein products (light blue lines), and participating in the same step of a given pathway (light green lines). Asterisks indicate genes related to input genes that have been reported to either carry de novo mutations in at least one patient with other NDDs (TBL1XR1, MTMR2, AKR1C4) or whose expression has been reported to be significantly altered in a MECP2 mutant model system (DAB1, ITGA2, LAMA5), or both (GLIS2, LAMC3, SMARCE1). Network weighting was assigned based on query genes so as to maximize connectivity among input genes, and at most 20 related genes and 10 related attributes were allowed to be incorporated in the network.