title: 14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype.
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 ∼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.
authors.affiliation: Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, New South Wales, Australia. carolyn.ellaway@health.nsw.gov.au
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Ellaway
authors.forename: Gladys
authors.initials: G
authors.lastname: Ho
authors.forename: Elisa
authors.initials: E
authors.lastname: Bettella
authors.forename: Alisa
authors.initials: A
authors.lastname: Knapman
authors.forename: Felicity
authors.initials: F
authors.lastname: Collins
authors.forename: Anna
authors.initials: A
authors.lastname: Hackett
authors.forename: Fiona
authors.initials: F
authors.lastname: McKenzie
authors.forename: Artur
authors.initials: A
authors.lastname: Darmanian
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Peters
authors.forename: Kerry
authors.initials: K
authors.lastname: Fagan
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
mesh_terms: D002648:Child; D002872:Chromosome Deletion; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D011493:Protein Kinase C / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics* / Q000473:pathology
chemical_list: C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; C089212:protein kinase D; D011493:Protein Kinase C