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Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome
Author(s) -
Olson Heather E.,
Tambunan Dimira,
LaCoursiere Christopher,
Goldenberg Marti,
Pinsky Rebecca,
Martin Emilie,
Ho Eugenia,
Khwaja Omar,
Kaufmann Walter E.,
Poduri Annapurna
Publication year - 2015
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.37132
Subject(s) - rett syndrome , mecp2 , genetic testing , frameshift mutation , proband , medicine , epilepsy , intellectual disability , neurodevelopmental disorder , pediatrics , genetics , mutation , bioinformatics , phenotype , biology , gene , psychiatry
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. © 2015 Wiley Periodicals, Inc.