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.
    PLoS ONE 12/2012; 7(12):e52756. DOI:10.1371/journal.pone.0052756 · 3.23 Impact Factor
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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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    ABSTRACT: Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Many of the genes required for gonad development have been identified by analysis of DSD patients. However, the use of knockout and transgenic mouse strains have contributed enormously to the study of gonad gene function and interactions within the development network. Although the genetic basis of mammalian sex determination and differentiation has advanced considerably in recent years, a majority of 46,XY gonadal dysgenesis patients still cannot be provided with an accurate diagnosis. Some of these unexplained DSD cases may be due to mutations in novel DSD genes or genomic rearrangements affecting regulatory regions that lead to atypical gene expression. Here, we review our current knowledge of mammalian sex determination drawing on insights from human DSD patients and mouse models.
    Chromosome Research 01/2012; 20(1):215-38. DOI:10.1007/s10577-012-9274-3 · 2.48 Impact Factor
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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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    ABSTRACT: Chromosome 15q24 microdeletion syndrome is a recently described rare microdeletion syndrome that has been reported in 19 individuals. It is characterized by growth retardation, intellectual disability, and distinct facial features including long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, small mouth, long smooth philtrum, and full lower lip. Other common findings include skeletal and digital abnormalities, genital abnormalities in males, hypotonia, behavior problems, recurrent infections, and eye problems. Other less frequent findings include hearing loss, growth hormone deficiency, hernias, and obesity. Congenital malformations, while rare, can be severe and include structural brain anomalies, cardiovascular malformations, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and myelomeningocele. Karyotypes are typically normal, and the deletions were detected in these individuals by array comparative genomic hybridization (aCGH). The deletions range in size from 1.7-6.1 Mb and usually result from nonallelic homologous recombination (NAHR) between paralogous low-copy repeats (LCRs). The majority of 15q24 deletions have breakpoints that localize to one of five LCR clusters labeled LCR15q24A, -B, -C, -D, and -E. The smallest region of overlap (SRO) spans a 1.2 Mb region between LCR15q24B to LCR15q24C. There are several candidate genes within the SRO, including CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK, that may predispose to many of the clinical features observed in individuals with 15q24 deletion syndrome. The deletion occurred as a de novo event in all of the individuals when parents were available for testing. Parental aCGH and/or FISH studies are recommended to provide accurate genetic counseling and guidance regarding prognosis, recurrence risk, and reproductive options. Management involves a multi-disciplinary approach to care with the primary care physician and clinical geneticist playing a crucial role in providing appropriate screening, surveillance, and care for individuals with this syndrome. At the time of diagnosis, individuals should receive baseline echocardiograms, audiologic, ophthalmologic, and developmental assessments. Growth and feeding should be closely monitored. Other specialists that may be involved in the care of individuals with 15q24 deletion syndrome include immunology, endocrine, orthopedics, neurology, and urology. Chromosome 15q24 microdeletion syndrome should be differentiated from other genetic syndromes, particularly velo-cardio-facial syndrome (22q11.2 deletion syndrome), Prader-Willi syndrome, and Noonan syndrome. These conditions share some phenotypic similarity to 15q24 deletion syndrome yet have characteristic features specific to each of them that allows the clinician to distinguish between them. Molecular genetic testing and/or aCGH will be able to diagnose these conditions in the majority of individuals. Disease name and synonyms Chromosome 15q24 deletion syndrome 15q24 deletion syndrome 15q24 microdeletion syndrome
    Orphanet Journal of Rare Diseases 01/2012; 7(1):2. DOI:10.1186/1750-1172-7-2 · 3.36 Impact Factor
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