Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome.
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.
Epilepsy Genetics Program, Division of Epilepsy & Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Neurogenetics Program, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
Heather E
HE
Olson
Epilepsy Genetics Program, Division of Epilepsy & Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts.
Dimira
D
Tambunan
Epilepsy Genetics Program, Division of Epilepsy & Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts.
Christopher
C
LaCoursiere
Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
Marti
M
Goldenberg
Epilepsy Genetics Program, Division of Epilepsy & Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts.
Rebecca
R
Pinsky
Epilepsy Genetics Program, Division of Epilepsy & Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts.
Emilie
E
Martin
Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.|Rett Syndrome Program, Boston Children's Hospital, Boston, Massachusetts.
Eugenia
E
Ho
Neurogenetics Program, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.|Rett Syndrome Program, Boston Children's Hospital, Boston, Massachusetts.
Omar
O
Khwaja
Harvard Medical School, Boston, Massachusetts.|Neurogenetics Program, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.|Rett Syndrome Program, Boston Children's Hospital, Boston, Massachusetts.
Walter E
WE
Kaufmann
Epilepsy Genetics Program, Division of Epilepsy & Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Neurogenetics Program, Boston Children's Hospital, Boston, Massachusetts.|Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.|F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts.
Annapurna
A
Poduri
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics*; D059472:Exome / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051938:Munc18 Proteins / Q000235:genetics; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D015518:Rett Syndrome / Q000235:genetics*; D055815:Young Adult
C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D020662:Guanine Nucleotide Exchange Factors; C550083:IQSEC2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D051938:Munc18 Proteins; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C100681:SCN8A protein, human; C497937:STXBP1 protein, human
CDKL5; FOXG1; MECP2; Rett syndrome; SCN8A; STXBP1; deletions; genetic; mutations; whole exome sequencing