Fifty microdeletions among 112 cases of Sotos syndrome: low copy repeats possibly mediate the common deletion

Sotos syndrome (SoS) is an autosomal dominant overgrowth syndrome with characteristic craniofacial dysmorphic features and various degrees of mental retardation. We previously showed that haploinsufficiency of the NSD1 gene is the major cause of SoS, and submicroscopic deletions at 5q35, including NSD1, were found in about a half (20/42) of our patients examined. Since the first report, an additional 70 SoS cases consisting of 53 Japanese and 17 non-Japanese have been analyzed. We found 50 microdeletions (45%) and 16 point mutations (14%) among all the 112 cases. A large difference in the frequency of microdeletions between Japanese and non-Japanese patients was noted: 49 (52%) of the 95 Japanese patients and only one (6%) of the 17 non-Japanese had microdeletions. A sequence-based physical map was constructed to characterize the microdeletions. Most of the microdeletions were confirmed to be identical by FISH analysis. We identified highly homologous sequences, i.e., possible low copy repeats (LCRs), in regions flanking proximal and distal breakpoints of the common deletion, This suggests that LCRs may mediate the deletion. Such LCRs seem to be present in different populations. Thus the different frequency of microdeletions between Japanese and non-Japanese cases in our study may have been caused by patient-selection bias.     

A novel third type of recurrent NF1 microdeletion mediated by nonallelic homologous recombination between LRRC37B‐containing low‐copy repeats in 17q11.2

Large microdeletions encompassing the neurofibromatosis type‐1 (NF1) gene and its flanking regions at 17q11.2 belong to the group of genomic disorders caused by aberrant recombination between segmental duplications. The most common NF1 microdeletions (type‐1) span 1.4‐Mb and have breakpoints located within NF1‐REPs A and C, low‐copy repeats (LCRs) containing LRRC37‐core duplicons. We have identified a novel type of recurrent NF1 deletion mediated by nonallelic homologous recombination (NAHR) between the highly homologous NF1‐REPs B and C. The breakpoints of these ～1.0‐Mb (“type‐3”) NF1 deletions were characterized at the DNA sequence level in three unrelated patients. Recombination regions, spanning 275, 180, and 109‐bp, respectively, were identified within the LRRC37B‐P paralogues of NF1‐REPs B and C, and were found to contain sequences capable of non‐B DNA formation. Both LCRs contain LRRC37‐core duplicons, abundant and highly dynamic sequences in the human genome. NAHR between LRRC37‐containing LCRs at 17q21.31 is known to have mediated the 970‐kb polymorphic inversions of the MAPT‐locus that occurred independently in different primate species, but also underlies the syndromes associated with recurrent 17q21.31 microdeletions and reciprocal microduplications. The novel NF1 microdeletions reported here provide further evidence for the unusually high recombinogenic potential of LRRC37‐containing LCRs in the human genome. Hum Mutat 31:742–751, 2010. © 2010 Wiley‐Liss, Inc.     

Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype-phenotype correlations

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation, absent speech, ataxia, and a happy disposition. Deletions of the 15q11q13 region are found in approximately 70% of AS patients. The deletions are sub-classified into class I and class II based on their sizes of approximately 6.8 and approximately 6.0, respectively, with two different proximal breakpoints and a common distal breakpoint. Utilizing a chromosome 15-specific comparative genomic hybridization genomic microarray (array-CGH), we have identified, determined the deletion sizes, and mapped the breakpoints in a cohort of 44 cases, to relate those breakpoints to the genomic architecture and derive more precise genotype-phenotype correlations. Interestingly four patients of the 44 studied (9.1%) had novel and unusually large deletions, and are reported here. This is the first report of very large deletions of 15q11q13 resulting in AS; the largest deletion being >10.6 Mb. These novel deletions involve three different distal breakpoints, two of which have been earlier shown to be involved in the generation of isodicentric 15q chromosomes (idic15). Additionally, precise determination of the deletion breakpoints reveals the presence of directly oriented low-copy repeats (LCRs) flanking the recurrent and novel breakpoints. The LCRs are adequate in size, orientation, and homology to enable abnormal recombination events leading to deletions and duplications. This genomic organization provides evidence for a common mechanism for the generation of both common and rare deletion types. Larger deletions result in a loss of several genes outside the common Angelman syndrome-Prader-Willi syndrome (AS-PWS) critical interval, and a more severe phenotype.     

Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms

Genomic disorders contribute significantly to genetic disease and, as detection methods improve, greater numbers are being defined. Paralogous low copy repeats (LCRs) mediate many of the chromosomal rearrangements that underlie these disorders, predisposing chromosomes to recombination errors. Deletions of proximal 22q11.2 comprise the most frequently occurring microdeletion syndrome, DiGeorge/Velocardiofacial syndrome (DGS/VCFS), in which most breakpoints have been localized to a 3 Mb region containing four large LCRs. Immediately distal to this region, there are another four related but smaller LCRs that have not been characterized extensively. We used paralog-specific primers and long-range PCR to clone, sequence, and examine the distal deletion breakpoints from two patients with de novo deletions mapping to these distal LCRs. Our results present definitive evidence of the direct involvement of LCRs in 22q11 deletions and map both breakpoints to the BCRL module, common to most 22q11 LCRs, suggesting a potential region for LCR-mediated rearrangement both in the distal LCRs and in the DGS interval. These are the first reported cases of distal 22q11 deletions in which breakpoints have been characterized at the nucleotide level within LCRs, confirming that distal 22q11 LCRs can and do mediate rearrangements leading to genomic disorders.     

Atypical 22q11.2 deletion in a patient with DGS/VCFS spectrum

Deletions in region 22q11.2 usually occur between two low copy repeat regions (LCRs), which are preferred chromosome sites for rearrangements. Most of the deletions encompass the same 3 or 1.5 Mb region, with breakpoints at LCR A and D or at LCR A and B, respectively. We report on a patient with clinical features of the 22q deletion syndrome who presents a novel, atypical deletion, smaller than 1.5 Mb, with distal breakpoint in LCR B and proximal breakpoint within no known LCR site.     

Absence of cutaneous neurofibromas in an NF1 patient with an atypical deletion partially overlapping the common 1.4 Mb microdeleted region

The majority of neurofibromatosis type 1 (NF1) microdeletions in 17q11.2 span approximately 1.4 Mb and have breakpoints that lie within the proximal and distal NF1-low copy repeats, termed NF1-REPs. Less frequent are patients with atypical deletions and non-recurring breakpoints. NF1 patients with gross deletions have been reported to manifest a more severe clinical phenotype than NF1 patients with intragenic mutations, and display early onset and extensive growth of neurofibromas. It has been suggested that the deletion of a neighboring gene or genes in addition to the NF1 gene may modify the expression of the disease, particularly with regard to the high burden of cutaneous neurofibromas. Thus, atypical deletions partially overlapping with the common 1.4 Mb microdeletion interval could prove useful in identifying possible genetic modifiers in the NF1 gene region whose haploinsufficiency might promote neurofibroma growth. Here we report a 20-year-old female who has an atypical deletion with a proximal breakpoint in NF1 intron 21 and a distal deletion breakpoint in the ACCN1 gene. The deletion spans 2.7 Mb and was mediated by an intrachromosomal non-homology-driven mechanism, for example, non-homologous end-joining (NHEJ). Remarkably, this patient did not exhibit cutaneous neurofibromas. However, genotype-phenotype comparisons in this and other previously reported patients with atypical deletions partially overlapping the commonly deleted 1.4 Mb interval do not identify a specific deleted region that is associated with increased neurofibroma growth.     

Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis

The 22q11.2 deletion syndrome, which includes DiGeorge and velocardiofacial syndromes (DGS/VCFS), is the most common microdeletion syndrome. The majority of deleted patients share a common 3 Mb hemizygous deletion of 22q11.2. The remaining patients include those who have smaller deletions that are nested within the 3 Mb typically deleted region (TDR) and a few with rare deletions that have no overlap with the TDR. The identification of chromosome 22-specific duplicated sequences or low copy repeats (LCRs) near the end-points of the 3 Mb TDR has led to the hypothesis that they mediate deletions of 22q11.2. The entire 3 Mb TDR has been sequenced, permitting detailed investigation of the LCRs and their involvement in the 22q11.2 deletions. Sequence analysis has identified four LCRs within the 3 Mb TDR. Although the LCRs differ in content and organization of shared modules, those modules that are common between them share 97-98% sequence identity with one another. By fluorescence in situ hybridization (FISH) analysis, the end-points of four variant 22q11.2 deletions appear to localize to the LCRs. Pulsed-field gel electrophoresis and Southern hybridization have been used to identify rearranged junction fragments from three variant deletions. Analysis of junction fragments by PCR and sequencing of the PCR products implicate the LCRs directly in the formation of 22q11.2 deletions. The evolutionary origin of the duplications on chromosome 22 has been assessed by FISH analysis of non-human primates. Multiple signals in Old World monkeys suggest that the duplication events may have occurred at least 20-25 million years ago.     

Genetic studies of Prader-Willi patients provide evidence for conservation of genomic architecture in proximal chromosome 15q

Prader-Willi syndrome (PWS) is a neurogenetic disorder associated with recurrent genomic recombination involving low copy repeats (LCRs) located in the human chromosome 15q11-q13. Previous studies of PWS patients from Asia suggested that there is a higher incidence of deletion and lower incidence of maternal uniparental disomy (mUPD) compared to that of Western populations. In this report, we present genetic etiology of 28 PWS patients from Taiwan. Consistent with the genetic etiology findings from Western populations, the type II deletion appears to be the most common deletion subtype. Furthermore, the ratio of the two most common deletion subtypes and the ratio of the maternal heterodisomy to isodisomy cases observed from this study are in agreement with previous findings from Western populations. In addition, we identified and further mapped the deletion breakpoints in two patients with atypical deletions using array CGH (comparative genomic hybridization). Despite the relatively small numbers of patients in each subgroup, our findings suggest that the genomic architecture responsible for the recurrent recombination in PWS is conserved in Taiwanese of the Han Chinese heritage and Western populations, thereby predisposing chromosome 15q11-q13 to a similar risk of rearrangements.     

Identification of recurrent type‐2 NF1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder

Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number variation in the human genome. Although several disease‐associated meiotic NAHR breakpoints have been analyzed in great detail, hotspots for mitotic NAHR are not well characterized. Type‐2 NF1 microdeletions, which are predominantly of postzygotic origin, constitute a highly informative model with which to investigate the features of mitotic NAHR. Here, a custom‐designed MLPA‐ and PCR‐based approach was used to identify 23 novel NAHR‐mediated type‐2 NF1 deletions. Breakpoint analysis of these 23 type‐2 deletions, together with 17 NAHR‐mediated type‐2 deletions identified previously, revealed that the breakpoints are nonuniformly distributed within the paralogous SUZ12 and SUZ12P sequences. Further, the analysis of this large group of type‐2 deletions revealed breakpoint recurrence within short segments (ranging in size from 57 to 253‐bp) as well as the existence of a novel NAHR hotspot of 1.9‐kb (termed PRS4). This hotspot harbored 20% (8/40) of the type‐2 deletion breakpoints and contains the 253‐bp recurrent breakpoint region BR6 in which four independent type‐2 deletion breakpoints were identified. Our findings indicate that a combination of an open chromatin conformation and short non‐B DNA‐forming repeats may predispose to recurrent mitotic NAHR events between SUZ12 and its pseudogene. Hum Mutat 33:1599–1609, 2012. © 2012 Wiley Periodicals, Inc.     

Rearrangements involving 12q in myeloproliferative disorders: possible role of HMGA2 and SOCS2 genes

We report two cases of translocation associated with deletion on derivative chromosomes in atypical myeloproliferative disorder (MPD). In a MPD with t(3;12)(q29;q14), the rearrangement targeted the HMGA2 locus at 12q14 and deleted a region of about 1.5 megabases (Mb) at 3q29. In an MPD with t(9;12)(q13 approximately q21;q22) and JAK2 V617F mutation, array comparative genomic hybridization delineated a deletion of about 3 Mb at 9q13 approximately q21 and a deletion of about 2 Mb at 12q22 containing SOCS2. These results show that close examination of translocations in hematopoietic diseases may reveal associated microdeletions. The role of these deletions is discussed.     

A previously unrecognized microdeletion syndrome on chromosome 22 band q11.2 encompassing the BCR gene

Susceptibility of the chromosome 22q11.2 region to rearrangements has been recognized on the basis of common clinical disorders such as the DiGeorge/velocardiofacial syndrome (DG/VCFs). Recent evidence has implicated low-copy repeats (LCRs); also known as segmental duplications; on 22q as mediators of nonallelic homologous recombination (NAHR) that result in rearrangements of 22q11.2. It has been shown that both deletion and duplication events can occur as a result of NAHR caused by unequal crossover of LCRs. Here we report on the clinical, cytogenetic and array CGH studies of a 15-year-old Hispanic boy with history of learning and behavior problems. We suggest that he represents a previously unrecognized microdeletion syndrome on chromosome 22 band q11.2 just telomeric to the DG/VCFs typically deleted region and encompassing the BCR gene. Using a 32K BAC array CGH chip we were able to refine and precisely narrow the breakpoints of this microdeletion, which was estimated to be 1.55-1.92 Mb in size and to span approximately 20 genes. This microdeletion region is flanked by LCR clusters containing several modules with a very high degree of sequence homology (>95%), and therefore could play a causal role in its origin.     

Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes

Four unrelated families with the same unbalanced translocation der(4)t(4;11)(p16.2;p15.4) were analyzed. Both of the breakpoint regions in 4p16.2 and 11p15.4 were narrowed to large ～359-kb and ～215-kb low-copy repeat (LCR) clusters, respectively, by aCGH and SNP array analyses. DNA sequencing enabled mapping the breakpoints of one translocation to 24 bp within interchromosomal paralogous LCRs of ～130 kb in length and 94.7% DNA sequence identity located in olfactory receptor gene clusters, indicating nonallelic homologous recombination (NAHR) as the mechanism for translocation formation. To investigate the potential involvement of interchromosomal LCRs in recurrent chromosomal translocation formation, we performed computational genome-wide analyses and identified 1143 interchromosomal LCR substrate pairs, >5 kb in size and sharing >94% sequence identity that can potentially mediate chromosomal translocations. Additional evidence for interchromosomal NAHR mediated translocation formation was provided by sequencing the breakpoints of another recurrent translocation, der(8)t(8;12)(p23.1;p13.31). The NAHR sites were mapped within 55 bp in ～7.8-kb paralogous subunits of 95.3% sequence identity located in the ～579-kb (chr 8) and ～287-kb (chr 12) LCR clusters. We demonstrate that NAHR mediates recurrent constitutional translocations t(4;11) and t(8;12) and potentially many other interchromosomal translocations throughout the human genome. Furthermore, we provide a computationally determined genome-wide "recurrent translocation map."     

Intrachromosomal mitotic nonallelic homologous recombination is the major molecular mechanism underlying type‐2 NF1 deletions

Nonallelic homologous recombination (NAHR) is responsible for the recurrent rearrangements that give rise to genomic disorders. Although meiotic NAHR has been investigated in multiple contexts, much less is known about mitotic NAHR despite its importance for tumorigenesis. Because type‐2 NF1 microdeletions frequently result from mitotic NAHR, they represent a good model in which to investigate the features of mitotic NAHR. We have used microsatellite analysis and SNP arrays to distinguish between the various alternative recombinational possibilities, thereby ascertaining that 17 of 18 type‐2 NF1 deletions, with breakpoints in the SUZ12 gene and its highly homologous pseudogene, originated via intrachromosomal recombination. This high proportion of intrachromosomal NAHR causing somatic type‐2 NF1 deletions contrasts with the interchromosomal origin of germline type‐1 NF1 microdeletions, whose breakpoints are located within the NF1‐REPs (low‐copy repeats located adjacent to the SUZ12 sequences). Further, meiotic NAHR causing type‐1 NF1 deletions occurs within recombination hotspots characterized by high GC‐content and DNA duplex stability, whereas the type‐2 breakpoints associated with the mitotic NAHR events investigated here do not cluster within hotspots and are located within regions of significantly lower GC‐content and DNA stability. Our findings therefore point to fundamental mechanistic differences between the determinants of mitotic and meiotic NAHR. Hum Mutat 31:1163–1173, 2010. © 2010 Wiley‐Liss, Inc.     

Atypical copy number abnormalities in 22q11.2 region: Report of three cases

The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, with a highly variable phenotype. This chromosomal region contains low copy repeat (LCR) sequences that mediate non-allelic homologous recombination which predispose to copy number abnormalities at this locus. This article describes three patients investigated for suspicion of 22q11.2DS presenting atypical copy number abnormalities overlapping or not with the common ～3 Mb deletion. They were investigated by G-banding karyotype, Multiplex-ligation dependent probe amplification (MLPA) and array Genomic Hibridization (aGH). Clinical and molecular data were compared with literature, in order to contribute to genotype–phenotype correlation. Atypical chromosomal abnormalities were detected: 3.6 Mb deletion at 22q11.21-q11.23 between LCRs B–F in patient 1 and approximately 1.5 Mb deletion at 22q11.21-q11.22 between LCRs D–E in patients 2 and 3. The breakpoints detected in patient 1 have not been previously described. These findings exemplify the complexity and genetic heterogeneity observed in 22q11.2 region and corroborates the idea that genetic modifiers contribute to the phenotypic variability observed in proximal and distal 22q11.2 deletion syndromes.     

Congenital heart defects in a novel recurrent 22q11.2 deletion harboring the genes CRKL and MAPK1

The proximal region of the long arm of chromosome 22 is rich in low copy repeats (LCR). Non-allelic homologous recombination (NAHR) between these substrates explains the high prevalence of recurrent rearrangements within this region. We have performed array comparative genomic hybridization in a normally developing girl with growth delay, microcephaly, and truncus arteriosus, and have identified a novel recurrent 22q11 deletion that spans LCR22-4 and partially affects the common 22q11.2 deletion syndrome and the distal 22q11 deletion syndrome. This deletion is atypical as it did not occur by NAHR between any of the major LCRs found on 22q11.2. However, the breakpoint containing regions coincide with highly homologous regions. An identical imbalance was reported previously in a patient with striking phenotypic similarity. Computational gene prioritization methods and biological evidence denote the genes CRKL and MAPK1 as the highest ranking candidates for causing congenital heart disease within the deleted region.     

Higher frequency of uncommon 1.5-2 Mb deletions found in familial cases of 22q11.2 deletion syndrome

Familial 22q11.2 deletions have been reported as a 6%-28% of the total affected cases of 22q11.2 microdeletion syndrome (del22q11.2). Different deletion genotypes have been described for this disorder, with a predominant 3 Mb deletion present in 90% of the cases, a less common 1.5-2 Mb deletion in 8%, and atypical smaller deletions in 2%. We have studied 15 cases of del22q11.2 from 6 families (two of them three-generation families) that were previously diagnosed through FISH. We have sized the deleted region by allele genotyping of 12-16 polymorphic markers in all cases, and we have found three families affected with the 1.5-2 Mb deletion, two affected with the 3 Mb deletion, and one in which the deletion size could not be determined. This predominance of the smaller 1.5-2 Mb deletions in our familial cases differs from the minor frequency observed in sporadic cases of del22q11.2. This finding suggests that small deletions are more linked to familial inheritance than large ones, possibly due to psychosocial or biological factors associated with differences in the phenotype. Deletion sizing on routine diagnosis may help characterizing the inheritability of 22q11.2 microdeletion syndrome.     

Non-hotspot-related breakpoints of common deletions in Sotos syndrome are located within destabilised DNA regions

Background: Sotos syndrome (SoS) is a disorder characterised by excessive growth, typical craniofacial features, and developmental retardation. It is caused by haploinsuffiency of NSD1 at 5q35. There is a 3.0 kb recombination hotspot in which the breakpoints of around 80% of SoS patients with a common deletion can be mapped. Objective: To identify deletion breakpoints located outside the SoS recombination hotspot. Methods: A screening system for the directly orientated segments of the SoS LCRs was developed for 10 SoS patients with a common deletion who were negative for the SoS hotspot. Deletion-junction fragments were analysed for DNA duplex stability and their relation to scaffold/matrix attachment regions (S/MARs). These features were compared with the SoS hotspot and recombination hotspots of other genomic disorders. Results: The breakpoint was mapped in four SoS patients, two with a deletion in the maternally derived chromosome. These breakpoint regions were located ∼2.5 kb, ∼9.6 kb, ∼27.2, and ∼27.7 kb telomeric to the SoS hotspot and were confined to 164 bp, 46 bp, 256 bp, and 124 bp, respectively. Two of the regions were mapped within Alu elements. All crossover events were found to have occurred within or adjacent to a highly destabilised DNA duplex with a high S/MAR probability. In contrast, the SoS hotspot and other genomic disorders'' recombination hotspots were mapped to stabilised DNA helix regions, flanked by destabilised regions with high probability of containing S/MAR elements. Conclusions: The data suggest that a specific chromatin structure may increase susceptibility for recurrent crossover events and thus predispose to recombination hotspots in genomic disorders.     

Sotos syndrome common deletion is mediated by directly oriented subunits within inverted Sos-REP low-copy repeats

Sotos syndrome (Sos) is an overgrowth disorder also characterized clinically by mental retardation, specific craniofacial features and advanced bone age. As NSD1 haploinsufficiency was determined in 2002 to be the major cause of Sos, many intragenic mutations and chromosomal microdeletions involving the entire NSD1 gene have been described. In the Japanese population, half of the cases analyzed appear to have a common microdeletion; however, in the European population, deletion cases account for only 9%. Blast analysis of the Sos genomic region on 5q35 revealed two complex mosaic low-copy repeats (LCRs) that are centromeric and telomeric to NSD1. We termed these proximal Sos-REP (Sos-PREP, approximately 390 kb) and distal Sos-REP (Sos-DREP, approximately 429 kb), respectively. On the basis of the analysis of DNA sequence, we determined the size, structure, orientation and extent of sequence identity of these LCRs. We found that Sos-PREP and Sos-DREP are composed of six subunits termed A-F. Each of the homologous subunits, with the exception of one, is located in an inverted orientation and the order of subunits is different between the two Sos-REPs. Only the subunit C' in Sos-DREP is oriented directly with respect to the subunit C in Sos-PREP. These latter C' and C subunits are greater than 99% identical. Using pulsed-field gel electrophoresis analysis in eight Sos patients with a common deletion, we detected an approximately 550 kb junction fragment that we predicted according to the non-allelic homologous recombination (NAHR) mechanism using directly oriented Sos-PREP C and Sos-DREP C' subunits as substrates. This patient specific junction fragment was not present in 51 Japanese and non-Japanese controls. Subsequently, using long-range PCR with restriction enzyme digestion and DNA sequencing, we identified a 2.5 kb unequal crossover hotspot region in six out of nine analyzed Sos patients with the common deletion. Our data are consistent with an NAHR mechanism for generation of the Sos common deletion.     

Copy number variation at the breakpoint region of isochromosome 17q

Isochromosome 17q, or i(17q), is one of the most frequent nonrandom changes occurring in human neoplasia. Most of the i(17q) breakpoints cluster within a ~240-kb interval located in the Smith-Magenis syndrome common deletion region in 17p11.2. The breakpoint cluster region is characterized by a complex architecture with large (~38–49 kb), inverted and directly oriented, low-copy repeats (LCRs), known as REPA and REPB that apparently lead to genomic instability and facilitate somatic genetic rearrangements. Through the analysis of bacterial artificial chromosome (BAC) clones, pulsed-field gel electrophoresis (PFGE), and public array comparative genomic hybridization (array CGH) data, we show that the REPA/B structure is also susceptible to frequent meiotic rearrangements. It is a highly dynamic genomic region undergoing deletions, inversions, and duplications likely produced by non-allelic homologous recombination (NAHR) mediated by the highly identical SNORD3@, also known as U3, gene cluster present therein. We detected at least seven different REPA/B structures in samples from 29 individuals of which six represented potentially novel structures. Two polymorphic copy-number variation (CNV) variants, detected in 20% of samples, could be structurally described along with the likely underlying molecular mechanism for formation. Our data show the high susceptibility to rearrangements at the i(17q) breakpoint cluster region in the general population and exemplifies how large genomic regions laden with LCRs still represent a technical challenge for both determining specific structure and assaying population variation. The variant REPA/B structures identified may have different susceptibilities for inducing i(17q), thus potentially representing important risk alleles for tumor progression.     

Structures and molecular mechanisms for common 15q13.3 microduplications involving CHRNA7: benign or pathological?

We have investigated four ～1.6‐Mb microduplications and 55 smaller 350–680‐kb microduplications at 15q13.2–q13.3 involving the CHRNA7 gene that were detected by clinical microarray analysis. Applying high‐resolution array‐CGH, we mapped all 118 chromosomal breakpoints of these microduplications. We also sequenced 26 small microduplication breakpoints that were clustering at hotspots of nonallelic homologous recombination (NAHR). All four large microduplications likely arose by NAHR between BP4 and BP5 LCRs, and 54 small microduplications arose by NAHR between two CHRNA7‐LCR copies. We identified two classes of ～1.6‐Mb microduplications and five classes of small microduplications differing in duplication size, and show that they duplicate the entire CHRNA7. We propose that size differences among small microduplications result from preexisting heterogeneity of the common BP4–BP5 inversion. Clinical data and family histories of 11 patients with small microduplications involving CHRNA7 suggest that these microduplications might be associated with developmental delay/mental retardation, muscular hypotonia, and a variety of neuropsychiatric disorders. However, we conclude that these microduplications and their associated potential for increased dosage of the CHRNA7‐encoded α7 subunit of nicotinic acetylcholine receptors are of uncertain clinical significance at present. Nevertheless, if they prove to have a pathological effects, their high frequency could make them a common risk factor for many neurobehavioral disorders. Hum Mutat 31:1–11, 2010. © 2010 Wiley‐Liss, Inc.