A 3 Mb deletion in 14q12 causes severe mental retardation, mild facial dysmorphisms and Rett‐like features

Abstract

The present report describes a 7-year-old girl with a de novo 3 Mb interstitial deletion of chromosome 14q12, identified by oligo array-CGH. The region is gene poor and contains only five genes two of them, FOXG1B and PRKD1 being deleted also in a previously reported case with a very similar phenotype. Both patients present prominent metopic suture, epicanthic folds, bulbous nasal tip, tented upper lip, everted lower lip and large ears and a clinical course like Rett syndrome, including normal perinatal period, postnatal microcephaly, seizures, and severe mental retardation. FOXG1B (forkhead box G1B) is a very intriguing candidate gene since it is known to promote neuronal progenitor proliferation and to suppress premature neurogenesis and its disruption is reported in a patient with postnatal microcephaly, corpus callosum agenesis, seizures, and severe mental retardation.

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

“…13 In most of the reported 14q12 microdeletions thus far, the PRKD1 gene has also been disrupted. 8,[12][13][14] Including this report, only four cases of 14q12 microdeletions have found FOXG1 gene to be intact, the other being reported by Kortüm et al 13 In earlier reports and mutation analyses, FOXG1 has been considered the primary pathogenic cause in the patients because of its role in the formation of the developing brain. 9 FOXG1 is a transcriptional repressor with expression restricted to fetal and adult brain and testis.…”

“…7,8,12,14 Of these, there has only been one previous microdeletion of 14q12 not involving FOXG1. 13 In addition, there were two translocations affecting chromosome 14 identified in patients with similar phenotypes, although the breakpoints on chromosome 14 mapped 5 and 265 kb downstream of the primary transcript of FOXG1.…”

“…6 Recent reports of microdeletions in the 14q12 region found in Rett syndrome patients have found a third gene, forkhead box protein G1 (FOXG1), to be highly associated with the congenital variant. 7,8 The FoxG1 protein is a winged-helix transcription factor and its expression is highest in fetal and infant brain. It is involved in telencephalic development, 9 promotes neurogenesis and antagonises neuronal differentiation.…”

“…10,11 At least eight instances of 14q12 microdeletions have been reported. 7,8,[12][13][14] Mutation analyses have identified de novo loss-of-function point mutations in FOXG1, particularly in patients with the congenital form of Rett syndrome. [15][16][17] Duplications of FOXG1 are also found in patients with epilepsy and intellectual impairment, [18][19][20][21] highlighting the importance of gene dosage at this locus, although more recently the pathogenicity of FOXG1 duplications has been questioned.…”

Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12

“…8 In differentiated postmitotic neurons, FOXG1 promotes cell survival through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and has a protective effect against the neurotoxic effect of Mecp2. 9,10 In humans, intragenic mutations and gene deletions leading to haploinsufficiency [11][12][13][14][15] cause a developmental encephalopathy originally described as a congenital variant of Rett syndrome (MIM 613454) but recently redefined as the FOXG1 syndrome. 16 Also, a complex chromosome 14q12 rearrangement consisting of a translocation with adjacent inversion was described in a patient with intellectual disability, brain malformations, and microcephaly.…”