Sharp, A.J. et al. Characterization of a recurrent 15q24 microdeletion syndrome. Hum. Mol. Genet. 16, 567-572

University of Naples Federico II, Napoli, Campania, Italy
Human Molecular Genetics (Impact Factor: 6.39). 03/2007; 16(5):567-72. DOI: 10.1093/hmg/ddm016
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We describe multiple individuals with mental retardation and overlapping de novo submicroscopic deletions of 15q24 (1.7-3.9 Mb in size). High-resolution analysis showed that in three patients both proximal and distal breakpoints co-localized to highly identical segmental duplications (>51 kb in length, > 94% identity), suggesting non-allelic homologous recombination as the likely mechanism of origin. Sequencing studies in a fourth individual provided base pair resolution and showed that both breakpoints in this case were located in unique sequence. Despite the differences in the size and location of the deletions, all four individuals share several major features (growth retardation, microcephaly, digital abnormalities, hypospadias and loose connective tissue) and resemble one another facially (high anterior hair line, broad medial eyebrows, hypertelorism, downslanted palpebral fissures, broad nasal base, long smooth philtrum and full lower lip), indicating that this represents a novel syndrome caused by haploinsufficiency of one or more dosage-sensitive genes in the minimal deletion region. Our results define microdeletion of 15q24 as a novel recurrent genomic disorder.

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Available from: Orsetta Zuffardi, Dec 28, 2014
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    • "15q24, 16p11.2, and 17q21.31 (Koolen et al. 2006; Redon et al. 2006; Sharp et al. 2006; Shaw-Smith et al. 2006; Ballif et al. 2007; Shaffer et al. 2007; Sharp et al. 2007, 2008). Refinement of the critical region of a known syndrome by the identification of atypical deletion (Cooper et al. 2011) may facilitate the detection of a dosage-sensitive gene(s) related to ID (Vissers et al. 2010); however, there are many CNVs for which the clinical significance may still remain unknown (Rodriguez-Revenga et al. 2007). "
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    ABSTRACT: We used whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) in a cohort of 256 patients with developmental delay (DD)/intellectual disability (ID) with or without dysmorphic features, additional neurodevelopmental abnormalities, and/or congenital malformations. In 69 patients, we identified 84 non-polymorphic copy-number variants, among which 41 are known to be clinically relevant, including two recently described deletions, 4q21.21q21.22 and 17q24.2. Chromosomal microarray analysis revealed also 15 potentially pathogenic changes, including three rare deletions, 5q35.3, 10q21.3, and 13q12.11. Additionally, we found 28 copy-number variants of unknown clinical significance. Our results further support the notion that copy-number variants significantly contribute to the genetic etiology of DD/ID and emphasize the efficacy of the detection of novel candidate genes for neurodevelopmental disorders by whole-genome array CGH. Electronic supplementary material The online version of this article (doi:10.1007/s13353-013-0181-x) contains supplementary material, which is available to authorized users.
    Journal of applied genetics 12/2013; 55(1). DOI:10.1007/s13353-013-0181-x · 1.48 Impact Factor
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    • "Patient six had an interstitial deletion of 15q24.1q24.2. This is a known pathogenic abnormality as the 15q24 microdeletion syndrome was first described by Sharp et al. in 2007.[23] Phenotypic features include mild to moderate developmental delay, characteristic facial features, growth retardation, hypotonia, joint laxity, digital abnormalities and genital abnormalities. "
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    ABSTRACT: Mental retardation (MR) has a prevalence of 1-3% and genetic causes are present in more than 50% of patients. Chromosomal abnormalities are one of the most common genetic causes of MR and are responsible for 4-28% of mental retardation. However, the smallest loss or gain of material visible by standard cytogenetic is about 4 Mb and for smaller abnormalities, molecular cytogenetic techniques such as array comparative genomic hybridization (array CGH) should be used. It has been shown that 15-25% of idiopathic MR (IMR) has submicroscopic rearrangements detectable by array CGH. In this project, the genomic abnormalities were investigated in 32 MR patients using this technique. Patients with IMR with dysmorphism were investigated in this study. Karyotype analysis, fragile X and metabolic tests were first carried out on the patients. The copy number variation was then assessed in a total of 32 patients with normal results for the mentioned tests using whole genome oligo array CGH. Multiple ligation probe amplification was carried out as a confirmation test. In total, 19% of the patients showed genomic abnormalities. This is reduced to 12.5% once the two patients with abnormal karyotypes (upon re-evaluation) are removed. The array CGH technique increased the detection rate of genomic imbalances in our patients by 12.5%. It is an accurate and reliable method for the determination of genomic imbalances in patients with IMR and dysmorphism.
    Indian Journal of Human Genetics 10/2013; 19(4):443-8. DOI:10.4103/0971-6866.124373
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    • "Recently, others recurrent microdeletion syndromes (15q13.3 and 15q24), all mapping to large blocks of segmental duplications, were reported in other regions of chromosome 15 [16], [6]. The most important features among the individuals with microdeletion 15q13.3 were mild to moderate mental retardation and epilepsy and/or abnormal EEG findings, but a number of phenotypically normal parents were also reported [6], [17]. "
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    ABSTRACT: Microarray-based comparative genomic hybridization (array-CGH) led to the discovery of genetic abnormalities among patients with complex phenotype and normal karyotype. Also several apparently normal individuals have been found to be carriers of cryptic imbalances, hence the importance to perform parental investigations after the identification of a deletion/duplication in a proband. Here, we report the molecular cytogenetic characterization of two individuals in which the microdeletions/duplications present in their parents could have predisposed and facilitated the formation of de novo pathogenic different copy number variations (CNVs). In family 1, a 4-year-old girl had a de novo pathogenic 10.5 Mb duplication at 15q21.2q22.2, while her mother showed a 2.262 Mb deletion at 15q13.2q13.3; in family 2, a 9-year-old boy had a de novo 1.417 Mb deletion at 22q11.21 and a second paternal deletion of 247 Kb at 22q11.23 on the same chromosome 22. Chromosome 22 at band q11.2 and chromosome 15 at band q11q13 are considered unstable regions. We could hypothesize that 15q13.2q13.3 and 22q11.21 deletions in the two respective parents might have increased the risk of rearrangements in their children. This study highlights the difficulty to make genetic counseling and predict the phenotypic consequences in these situations.
    PLoS ONE 03/2013; 8(3):e57910. DOI:10.1371/journal.pone.0057910 · 3.23 Impact Factor
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