Recurrent deletion of ZNF630 at Xp11.23 is not associated with mental retardation
Dorien LugtenbergLuiz Zangrande‐VieiraMaria KirchhoffAnnabel WhibleyAstrid OudakkerSusanne KjærgaardAngela Maria Vianna‐MorganteTjitske KleefstraMariken RuiterFernanda Sarquis JeheeReinhard UllmannCharles E. SchwartzMichael StrattonF. Lucy RaymondJoris A. VeltmanTerry VrijenhoekRolph PfundtJanneke Schuurs-HoeijmakersJayne Y. Hehir‐KwaGuy FroyenJamel ChellyHans Hilger RopersClaude MoraineJozef GéczJeroen KnijnenburgSarina G. KantBen C.J. HamelCarla RosenbergHans van BokhovenArjan P.M. de Brouwer
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Abstract ZNF630 is a member of the primate‐specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41 , ZNF81 , and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating that the deletions resulted from non‐allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6‐fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant ( P ‐value = 0.174). Conversely, a 1.9‐fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either ( P ‐value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation. © 2010 Wiley‐Liss, Inc.Keywords:
Non-allelic homologous recombination
Breakpoint
Segmental duplication
Non-allelic homologous recombination
Comparative genomic hybridization
Segmental duplication
Gene dosage
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Non-allelic homologous recombination
Segmental duplication
dup
Breakpoint
Comparative genomic hybridization
Gene rearrangement
Chromosomal rearrangement
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Breakpoint
Non-allelic homologous recombination
Comparative genomic hybridization
Segmental duplication
Gene rearrangement
Gene dosage
genomic DNA
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Abstract Background Segmental duplications (SDs) on 22q11.2 (LCR22), serve as substrates for meiotic non-allelic homologous recombination (NAHR) events resulting in several clinically significant genomic disorders. Results To understand the duplication activity leading to the complicated SD structure of this region, we have applied the A-Bruijn graph algorithm to decompose the 22q11.2 SDs to 523 fundamental duplication sequences, termed subunits. Cross-species syntenic analysis of primate genomes demonstrates that many of these LCR22 subunits emerged very recently, especially those implicated in human genomic disorders. Some subunits have expanded more actively than others, and young Alu SINEs, are associated much more frequently with duplicated sequences that have undergone active expansion, confirming their role in mediating recombination events. Many copy number variations (CNVs) exist on 22q11.2, some flanked by SDs. Interestingly, two chromosome breakpoints for 13 CNVs (mean length 65 kb) are located in paralogous subunits, providing direct evidence that SD subunits could contribute to CNV formation. Sequence analysis of PACs or BACs identified extra CNVs, specifically, 10 insertions and 18 deletions within 22q11.2; four were more than 10 kb in size and most contained young AluY s at their breakpoints. Conclusions Our study indicates that AluY s are implicated in the past and current duplication events, and moreover suggests that DNA rearrangements in 22q11.2 genomic disorders perhaps do not occur randomly but involve both actively expanded duplication subunits and Alu elements.
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Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of the NF1 gene region. To date, only nine unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple café au lait spots (CALS), Lisch nodules, freckling, or neurofibromas, the hallmark signs of NF1. Here, we have characterized two novel NF1 duplications, one sporadic and one familial. Both index patients with NF1 duplications exhibited learning disabilities and atypical CALS. Additionally, patient R609021 had Lisch nodules, whereas patient R653070 exhibited two inguinal freckles. The mother and sister of patient R609021 also harbored the NF1 duplication and exhibited cognitive dysfunction but no CALS. The breakpoints of the nine NF1 duplications reported previously have not been identified and hence their underlying generative mechanisms have remained unclear. In this study, we performed high-resolution breakpoint analysis that indicated that the two duplications studied were mediated by nonallelic homologous recombination (NAHR) and that the duplication breakpoints were located within the NAHR hotspot paralogous recombination site 2 (PRS2), which also harbors the type-1 NF1 deletion breakpoints. Hence, our study indicates for the first time that NF1 duplications are reciprocal to type-1 NF1 deletions and originate from the same NAHR events.
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Abstract Chromosomal band 17q12 is a gene‐rich region flanked by segmental duplications, making the region prone to deletions and duplications via the non‐allelic homologous recombination mechanism. While deletions cause a well‐described disorder with a specific phenotype called renal cysts and diabetes mellitus, the phenotype caused by reciprocal duplications is less specific, primarily because of variable expressivity, and incomplete penetrance. We present an unusual family with four children carrying the 17q12 microduplication inherited from their clinically healthy mother, who was a carrier of both the duplication and, interestingly, also of an atypical deletion of the 17q12 region. The duplication was inherited from her diabetic father and the deletion from her diabetic mother who also suffered from a renal disorder. Clinical manifestations in the family were variable, but all children showed some degree of a neurodevelopmental disorder, such as epilepsy, intellectual disability, delayed speech development, or attention deficit disorder. The simultaneous occurrence of a deletion and duplication in the same chromosomal region in one family is very rare, and to our knowledge, individuals carrying both a deletion and a duplication of this region have never been described.
Non-allelic homologous recombination
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Breakpoint
Non-allelic homologous recombination
Segmental duplication
Comparative genomic hybridization
Structural Variation
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Non-allelic homologous recombination
Comparative genomic hybridization
Segmental duplication
Gene dosage
Gene rearrangement
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Segmental duplication
Non-allelic homologous recombination
Gene rearrangement
Comparative genomic hybridization
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Citations (95)