Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome

Abstract

Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently remain unexplained in patients without clinically identified MECP2 mutations. We recruited a cohort of 11 patients with features of Rett syndrome and negative initial clinical testing for mutations in MECP2. We analyzed their phenotypes to determine whether patients met formal criteria for Rett syndrome, reviewed repeat clinical genetic testing, and performed exome sequencing of the probands. Using 2010 diagnostic criteria, three patients had classical Rett syndrome, including two for whom repeat MECP2 gene testing had identified mutations. In a patient with neonatal onset epilepsy with atypical Rett syndrome, we identified a frameshift deletion in STXBP1. Among seven patients with features of Rett syndrome not fulfilling formal diagnostic criteria, four had suspected pathogenic mutations, one each in MECP2, FOXG1, SCN8A, and IQSEC2. MECP2 mutations are highly correlated with classical Rett syndrome. Genes associated with atypical Rett syndrome, epilepsy, or intellectual disability should be considered in patients with features overlapping with Rett syndrome and negative MECP2 testing. While most of the identified mutations were apparently de novo, the SCN8A variant was inherited from an unaffected parent mosaic for the mutation, which is important to note for counseling regarding recurrence risks.

A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability

“…Regarding clinical features in females, these are less severe due to the presence of a normal X-chromosome, which has been previously described. 9,11 I2 II2 II4 II5 II6 III1 Olson et al 30 Gandomi et al 31 Tran Mau-Them et al 5 Tran Mau-Them et al 5 Gilissen et al 32 33 Moey et al 34 Moey et al 34 Moey et al 34 Moey et al 34 Froyen et al 35 Froyen et al 35 Froyen et al 35 Gedeon et al 36 Froyen et al 37 Froyen et al 37 Froyen et al 37 Froyen et al 37 Patient 1 IQSEC2 splicing mutation and ID I Madrigal et al…”

“…2,5,[30][31][32][33][34][35][36][37][38][39][40][41] Tables 1 and 2 summarize the clinical manifestations of patients with deletions or duplications in the IQSEC2 gene and Table 3 summarizes the clinical manifestations of patients with point variants in this gene. It has been proposed that non-synonymous variants in this gene are responsible for non-syndromic ID, whereas truncating variants may generate a more severe neurodevelopmental phenotype related to the loss of function of IQSEC2.…”

Monogenic disorders that mimic the phenotype of Rett syndrome

“…She had a likely pathogenic de novo IQSEC2 frameshift deletion (c.273_282del; p.Asn91Lysfs*112). Though she did not fulfill requirements for a clinical diagnosis of typical or atypical RTT, she met 3/4 of the main criteria and 3/11 of the supportive criteria [19]. Another report mentions an IQSEC2 nonsense mutation in a female with severe ID, developmental regression with loss of acquired language, stereotyped hand movements, and inappropriate laughing/screaming spells [20].…”

Identification of novel genetic causes of Rett syndrome-likephenotypes

“…Recently, two publications described the application of WES to smaller series of patients with features of RTT, where, if we exclude the variants found in MECP2 and FOXG1 genes, an yield of 27% was found 45 46. However, important questions such as (1) what other genes may lead to an RTT-like similar phenotype and (2) which pathways and genetic mechanisms can lead to such a specific phenotype still remain unanswered.…”