Genotype-Phenotype Correlation in Four 15q24 Deleted Patients Identified by Array-CGH

Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU, Lille, France.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 11/2009; 149A(12):2813-9. DOI: 10.1002/ajmg.a.33097
Source: PubMed


Microdeletion 15q24 is an emerging syndrome recently described, mainly due to increased use of array-CGH. Clinical features associate mild to moderate developmental delay, typical facial characteristics (high forehead and frontal hairline, broad eyebrows, downslanting palpebral features, long philtrum), hands (particularly proximal implanted thumbs) and genital anomalies (micropenis, hypospadias). We report here on four de novo cases having 2.5-6.1 Mb deletions involving 15q24: one 15q23q24.2 (Patient 1) and three 15q24.1q24.2 deletions (Patients 2-4). We correlate phenotype to genotype according to molecular boundaries of these deletions. Since bilateral iris coloboma and severe ano-rectal malformation were only present in Patient 1, we could link these anomalies to haploinsufficiency of 15q23 genes. Neither hypospadias nor micropenis were present in Patient 3 bearing the smallest deletion, therefore we could define 500 kb 15q24.1 region linked to these anomalies.

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Available from: Bruno Delobel, Sep 25, 2015
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    • "Further analyses will be needed to demonstrate the underlying mechanism by which this SNP might influence the inter-individual variations in sensitivity to the effect of low-dose BPA and increased risk of HS. It is known that ARNT2 is located on 15q24-25, while 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with developmental delay, craniofacial dysmorphism, digital and genital abnormalities (including HS) [30], [31], [32]. Other possible interpretations of our findings include the interactions between genetic loci located on 15q24-25, although further study is necessary to investigate this possibility. "
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    ABSTRACT: We hypothesized that polymorphic differences among individuals might cause variations in the effect that environmental endocrine disruptors (EEDs) have on male genital malformations (MGMs). In this study, individual variation in the genetic response to low-dose bisphenol A (BPA) was investigated in human foreskin fibroblast cells (hFFCs) derived from child cryptorchidism (CO) and hypospadias (HS) patients. hFFCs were collected from control children without MGMs (n = 5) and child CO and HS patients (n = 8 and 21, respectively). BPA exposure (10 nM) was found to inhibit matrix metalloproteinase-11 (MMP11) expression in the HS group (0.74-fold, P = 0.0034) but not in the control group (0.93-fold, P = 0.84) and CO group (0.94-fold, P = 0.70). Significantly lower levels of MMP11 expression were observed in the HS group compared with the control group (0.80-fold, P = 0.0088) and CO group (0.79-fold, P = 0.039) in response to 10 nM BPA. The effect of single-nucleotide polymorphism rs5000770 (G>A), located within the aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) locus, on individual sensitivity to low-dose BPA was investigated in the HS group. A significant difference in neurotensin receptor 1 (NTSR1) expression in response to 10 nM BPA was observed between AA and AG/GG groups (n = 6 and 15, respectively. P = 0.031). However, no significant difference in ARNT2 expression was observed (P = 0.18). This study advances our understanding of the specificity of low-dose BPA effects on human reproductive health. Our results suggest that genetic variability among individuals affects susceptibility to the effects of EEDs exposure as a potential cause of HS.
    Full-text · Article · Dec 2012 · PLoS ONE
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    • "Other CGH arrays revealed a novel recurrent 15q24 microdeletion syndrome with the deletions being between 1.7 and 3.9 Mb in size. The syndrome is characterized, amongst other features, by genital anomalies in male, including micropenis and hypospadias (Sharp et al. 2007; Andrieux et al. 2009), but the causative genes have not been identified. "
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    • "Birth defects have been reported in several individuals including congenital heart defects (such as tetralogy of Fallot and ventricular septal defects) in four (~20%), intestinal atresia in two, imperforate anus in one [5], iris coloboma in one, myelomeningocele in one, and diaphragmatic hernia in two individuals. Other features that have been reported in a minority of cases include strabismus [1-3,6,10] nystagmus [1,5,8] and dental abnormalities [1]. "
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