West syndrome associated with mosaic duplication of FOXG1 in a patient with maternal uniparental disomy of chromosome 14
ABSTRACT FOXG1 on chromosome 14 has recently been suggested as a dosage-sensitive gene. Duplication of this gene could cause severe epilepsy and developmental delay, including infantile spasms. Here, we report on a female patient diagnosed with maternal uniparental disomy of chromosome 14 and West syndrome who carried a small supernumerary marker chromosome. A chromosomal analysis revealed mosaicism of 47,XX, + mar/46,XX. Spectral karyotyping multicolor fluorescence in situ hybridization analysis confirmed that the marker chromosome was derived from chromosome 14. A DNA methylation test at MEG3 in 14q32.2 and microsatellite analysis using polymorphic markers on chromosome 14 confirmed that the patient had maternal uniparental disomy 14 as well as a mosaic small marker chromosome of paternal origin containing the proximal long arm of chromosome 14. Microarray-based comparative genomic hybridization analysis conclusively defined the region of the gain of genomic copy numbers at 14q11.2-q12, encompassing FOXG1. The results of the analyses of our patient provide further evidence that not only duplication but also a small increase in the dosage of FOXG1 could cause infantile spasms.
- SourceAvailable from: Ahmed B. Hamid
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- "Recently, FOXG1 was reported to be a dose-sensitive gene whose duplication could result in severe epilepsy, infantile spasms and developmental delay [Yeung et al., 2009; Brunetti-Pierri et al., 2011], while its deletion could cause seizures, but not infantile spasms [Tohyama et al., 2011]. "
ABSTRACT: Small supernumerary marker chromosomes (sSMC) are structurally abnormal chromosomes, generally equal in size or smaller than a chromosome 20 of the same metaphase spread. Most of them are unexpectedly detected in routine karyotype analyses, and it is usually not easy to correlate them with a specific clinical picture. A small group of sSMCs is derived from more than one chromosome, called complex sSMCs. Here, we report on a patient with a de novo complex sSMC, derived from chromosomes 8 and 14. Banding karyotype analysis, multiplex ligation-dependent probe amplification (MLPA), single nucleotide polymorphism (SNP)-based array, and fluorescence in situ hybridization (FISH) were performed to investigate its origin. Array and FISH analyses revealed a der(14)t(8;14)(p23.2;q22.1)dn. The propositus presents some clinical features commonly found in patients with partial duplication or triplication of 8p and 14q. This is the first report describing a patient with a congenital der(14)t(8;14)(p23.2;q22.1)dn sSMC.Cytogenetic and Genome Research 03/2013; 139(4). DOI:10.1159/000348743 · 1.91 Impact Factor
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- "We have identified known causative CNVs in three patients with isolated epilepsy and seven patients with epilepsy and other neurodevelopmental abnormalities (Table I). A number of studies have suggested that increased dosage of FOXG1 mapping to chromosome 14q12 is pathogenic for developmental delay, cognitive impairment with speech delay, and epilepsy [Yeung et al., 2009; Brunetti-Pierri et al., 2011; Paciorkowski et al., 2011; Striano et al., 2011; Tohyama et al., 2011]. However, recently, Amor et al.  reported a familial case of an $88 kb duplication in 14q12, encompassing FOXG1, associated only with isolated hemifacial microsomia . "
ABSTRACT: Copy-number variants (CNVs) collectively represent an important cause of neurodevelopmental disorders such as developmental delay (DD)/intellectual disability (ID), autism, and epilepsy. In contrast to DD/ID, for which the application of microarray techniques enables detection of pathogenic CNVs in ∼10-20% of patients, there are only few studies of the role of CNVs in epilepsy and genetic etiology in the vast majority of cases remains unknown. We have applied whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) to a cohort of 102 patients with various types of epilepsy with or without additional neurodevelopmental abnormalities. Chromosomal microarray analysis revealed 24 non-polymorphic CNVs in 23 patients, among which 10 CNVs are known to be clinically relevant. Two rare deletions in 2q24.1q24.3, including KCNJ3 and 9q21.13 are novel pathogenic genetic loci and 12 CNVs are of unknown clinical significance. Our results further support the notion that rare CNVs can cause different types of epilepsy, emphasize the efficiency of detecting novel candidate genes by whole-genome array CGH, and suggest that the clinical application of array CGH should be extended to patients with unexplained epilepsies. © 2012 Wiley Periodicals, Inc.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2012; 159B(7):760-71. DOI:10.1002/ajmg.b.32081 · 3.27 Impact Factor
- European journal of human genetics: EJHG 01/2012; 20(6):595-6; author reply 596-7. DOI:10.1038/ejhg.2011.267 · 4.23 Impact Factor