The proximal chromosome 14q microdeletion syndrome: Delineation of the phenotype using high resolution SNP oligonucleotide microarray analysis (SOMA) and review of the literature

Abstract

We report on two patients with overlapping small interstitial deletions involving regions 14q12 to 14q13.1. Both children had severe developmental delay, failure to thrive, microcephaly, and distinctive facial features, including abnormal spacing of the eyes, epicanthal folds, sloping forehead, low-set ears, rounded eyebrows with triangular media aspect and outer tapering, depressed and broad nasal bridge, small mouth, a long philtrum, and a prominent Cupid's bow. Brain MRI of both children showed partial agenesis of the corpus callosum. Our first patient had bilateral hypoplastic optic nerves causing blindness, mild hearing impairment, sinus arrhythmia, abnormal temperature regulation, frequent apneic episodes, myoclonic jerks, and opisthotonus. Our second patient had a seizure disorder confirmed by EEG, sleep apnea, chronic interstitial lung disease, and several episodes of pneumonia and gastroenteritis. Cytogenetic analysis showed a normal karyotype in Patient 1 and a unique apparently balanced three-way translocation in Patient 2 involving chromosomes 4, 14, and 11. High resolution SNP Oligonucleotide Microarray Analysis (SOMA) revealed a deletion in the proximal region of chromosome 14q overlapping with the deletion of our first patient, and no copy number changes in chromosomes 4 and 11. Here, we review and compare published cases with a deletion involving the 14q12-22.1 chromosomal region in an effort to correlate phenotype and genotype. We also examine the underlying genomic architecture to identify the possible mechanism of the chromosomal abnormality. Our review found a patient with a mirror duplication of our first patient's deletion, confirming the existence of an underlying genomic structural instability in the region. © 2011 Wiley-Liss, Inc.

Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement ofFOXG1appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus

“…In some cases, this is sufficiently explained by haploinsufficiency of FOXG1 as in the recent publication by Torgyekes et al ,14 and patient 5 in the paper by Kamnasaran et al 20 The severity of the phenotype of patients 4 and 6 described in the latter paper might well be explained by the positional effect of these deletions on FOXG1 as these deletions span the region with putative cis -regulatory elements25 (figure 2). …”

“…Indeed, it is our opinion that inclusion of these patients in genotype–phenotype correlation studies confounds the ‘true’ phenotype of patients with a 14q13 deletion. A recent paper14 which claims to describe the phenotype of patients with a 14q deletion is therefore not representative for patients whose 14q13 deletion does not include FOXG1 .…”

“…However, clinical data are often sparse and most of these publications rely on conventional karyotyping or focus on only one or two genes ( NKX2-1 , PAX9 ) in the deletion. Recently, two papers have appeared describing additional patients with a deletion including 14q13 and a severe phenotype,13 14 although the patients in the latter paper14 have much larger deletions including chromosome band 14q12 and FOXG1. …”

A de novo 14q12q13.3 interstitial deletion in a patient affected by a severe neurodevelopmental disorder of unknown origin

“…Patients affected by chromosomal rearrangements that completely or partially encompass the 14q12q13.3 genomic region display heterogeneous clinical features. These features include microcephaly, facial dysmorphisms (e.g., micrognathia, ocular hypotelorism, hypodontia), cryptorchidism, generalized muscular hypertonicity, delayed psychomotor development, holoprosencephaly, and seizures [Grammatico et al, 1994; Shapira et al, 1994; Govaerts et al, 1996; Chen et al, 1997; Schuffenhauer et al, 1999; Ramelli et al, 2000; Kamnasaran et al, 2001; Breedveld et al, 2002; Das et al, 2002; Petek et al, 2003; Su et al, 2004; Kamnasaran et al, 2005; Shimojima et al, 2009; Caliebe et al, 2011; Torgyekes et al, 2011]. In order to map the breakpoints of the deleted regions, these studies were initially performed using microsatellite markers and fluorescence in situ hybridization (FISH).…”

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

“…1,17,[30][31][32] On the other hand, overexpression of Foxg1 in chicken brain results in thickening of the neuroepithelium and large outgrowth of the telencephalon and mesencephalum, due to reduction of neuroepithelial apoptosis rather than increased cell proliferation. 33 Similarly, in humans, intragenic mutations and gene deletions leading to haploinsufficiency [11][12][13][14][15]34,35 are associated with the congenital variant of Rett syndrome. The importance of FOXG1 dosage during brain development is further suggested by the association of chromosome 14q12 duplications harboring FOXG1 with epilepsy, mental retardation, and severe speech impairment.…”