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

• Published in: European journal of human genetics : EJHG Vol. 21; no. 5; pp. 522 - 527
• Main Authors: Ellaway, Carolyn J, Ho, Gladys, Bettella, Elisa, Knapman, Alisa, Collins, Felicity, Hackett, Anna, McKenzie, Fiona, Darmanian, Artur, Peters, Gregory B, Fagan, Kerry, Christodoulou, John
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2013
• Subjects: Age; Bioinformatics; Child; Chromosome Deletion; Chromosomes, Human, Pair 14 - genetics; Clonal deletion; Comparative Genomic Hybridization; Congenital diseases; Corpus callosum; Cytogenetic Analysis; DNA Mutational Analysis; Fatal Outcome; Female; Females; Forkhead Transcription Factors - genetics; Foxg1 protein; Frameshift mutation; Gene deletion; Gene expression; Gene Expression Profiling; Gene Expression Regulation - genetics; Genetics; Genomes; Genotype & phenotype; Hospitals; Humans; Kinases; Male; MeCP2 protein; Methyl-CpG binding protein; Microarray Analysis; Microcephaly; Microencephaly; Mutation; Nerve Tissue Proteins - genetics; Neurodevelopmental disorders; Ostomy; Patients; Phenotype; Phenotypes; Protein Kinase C - genetics; Proteins; Rett syndrome; Rett Syndrome - genetics; Rett Syndrome - pathology; Australia; Western Australia Australia; New South Wales Australia
• DOI: 10.1038/ejhg.2012.208
• ISSN: 1018-4813

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 ∼90-95% 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.