14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype

Carolyn J. Ellaway, Gladys Ho, Elisa Bettella, Alisa Knapman, Felicity Collins, Anna Hackett, Fiona McKenzie, Artur Darmanian, Gregory B. Peters, Kerry Fagan, John Christodoulou

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Rett syndrome is a clinically defined neurodevelopmental disorder almost exclusively affecting females. Usually sporadic, Rett syndrome is caused by mutations in the X-linked MECP2 gene in B90-95% of classic cases and 40-60% of individuals with atypical Rett syndrome. Mutations in the CDKL5 gene have been associated with the early-onset seizure variant of Rett syndrome and mutations in FOXG1 have been associated with the congenital Rett syndrome variant. We report the clinical features and array CGH findings of three atypical Rett syndrome patients who had severe intellectual impairment, early-onset developmental delay, postnatal microcephaly and hypotonia. In addition, the females had a seizure disorder, agenesis of the corpus callosum and subtle dysmorphism. All three were found to have an interstitial deletion of 14q12. The deleted region in common included the PRKD1 gene but not the FOXG1 gene. Gene expression analysis suggested a decrease in FOXG1 levels in two of the patients. Screening of 32 atypical Rett syndrome patients did not identify any pathogenic mutations in the PRKD1 gene, although a previously reported frameshift mutation affecting FOXG1 (c.256dupC, p.Gln86ProfsX35) was identified in a patient with the congenital Rett syndrome variant. There is phenotypic overlap between congenital Rett syndrome variants with FOXG1 mutations and the clinical presentation of our three patients with this 14q12 microdeletion, not encompassing the FOXG1 gene. We propose that the primary defect in these patients is misregulation of the FOXG1 gene rather than a primary abnormality of PRKD1.

Original languageEnglish
Pages (from-to)522-527
Number of pages6
JournalEuropean Journal of Human Genetics
Volume21
Issue number5
DOIs
Publication statusPublished - May 2013
Externally publishedYes

    Fingerprint

Cite this

Ellaway, C. J., Ho, G., Bettella, E., Knapman, A., Collins, F., Hackett, A., ... Christodoulou, J. (2013). 14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype. European Journal of Human Genetics, 21(5), 522-527. https://doi.org/10.1038/ejhg.2012.208