TY - JOUR
T1 - Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome
AU - Olson, Heather E.
AU - Tambunan, Dimira
AU - Lacoursiere, Christopher
AU - Goldenberg, Marti
AU - Pinsky, Rebecca
AU - Martin, Emilie
AU - Ho, Eugenia
AU - Khwaja, Omar
AU - Kaufmann, Walter E.
AU - Poduri, Annapurna
N1 - Publisher Copyright:
© 2015 Wiley Periodicals, Inc.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
KW - CDKL5
KW - Deletions
KW - FOXG1
KW - Genetic
KW - MECP2
KW - Mutations
KW - Rett syndrome
KW - SCN8A
KW - STXBP1
KW - Whole exome sequencing
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U2 - 10.1002/ajmg.a.37132
DO - 10.1002/ajmg.a.37132
M3 - Article
C2 - 25914188
AN - SCOPUS:84939466790
SN - 1552-4825
VL - 167
SP - 2017
EP - 2025
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 9
ER -