A unique coincidence of a 17q12 deletion and duplication in a Czech family led to a refined genotype–phenotype correlation
Hana ZůnováMiroslav StolfaTereza KunikovaDrahuše NovotnáR. ValkovicovaKatalin ŠtěrbováMarkéta Vlčková
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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.Keywords:
Non-allelic homologous recombination
Penetrance
Segmental duplication
Expressivity
Non-allelic homologous recombination
Comparative genomic hybridization
Segmental duplication
Gene dosage
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Abstract Chromosomal rearrangements that alter the copy number of dosage-sensitive genes can result in genomic disorders, such as the 3q29 deletion syndrome. At the 3q29 region, non-allelic homologous recombination (NAHR) between paralogous copies of segmental duplications (SDs) leads to a recurrent ∼1.6 Mbp deletion or duplication, causing neurodevelopmental and psychiatric phenotypes. However, risk factors contributing to NAHR at this locus are not well understood. In this study, we used an optical mapping approach to identify structural variations within the 3q29 interval. We identified 18 novel haplotypes among 161 unaffected individuals and used this information to characterize this region in 18 probands with either the 3q29 deletion or 3q29 duplication syndrome. A significant amount of variation in haplotype prevalence was observed between populations. Within probands, we narrowed down the breakpoints to a ∼5 kbp segment within the SD blocks in 89% of the 3q29 deletion and duplication cases studied. Furthermore, all 3q29 deletion and duplication cases could be categorized into one of five distinct classes based on their breakpoints. Contrary to previous findings for other recurrent deletion and duplication loci, there was no evidence for inversions in either parent of the probands mediating the deletion or duplication seen in this syndrome.
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Proband
Non-allelic homologous recombination
Segmental duplication
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The Charcot-Marie-Toothtype 1A (CMT1 A) duplication was the first recurrent, large (>1 Mb), submicroscopic DNA duplication rearrangement found to be associated with a common auto-somal dominant trait. Mechanistic studies of the CMT1A duplication have set the paradigm for genomic disorders. The CMT1A-REP low-copy repeats (LCRs) were among the first identified nongenic genomic architectural features that could act as substrates for nonallelic homologous recombination (NAHR). Identification of the predicted reciprocal recombination product, the hereditary neuropathy with liability to pressure palsies (HNPP) deletion, resulted in a model for reciprocal duplication/deletion genomic disorders.
Non-allelic homologous recombination
Segmental duplication
Comparative genomic hybridization
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Abstract Background Retrotransposons have been suggested to provide a substrate for non-allelic homologous recombination (NAHR) and thereby promote gene family expansion. Their precise role, however, is controversial. Here we ask whether retrotransposons contributed to the recent expansions of the Androgen - binding protein ( Abp ) gene families that occurred independently in the mouse and rat genomes. Results Using dot plot analysis, we found that the most recent duplication in the Abp region of the mouse genome is flanked by L1Md _ T elements. Analysis of the sequence of these elements revealed breakpoints that are the relicts of the recombination that caused the duplication, confirming that the duplication arose as a result of NAHR using L1 elements as substrates. L1 and ERVII retrotransposons are considerably denser in the Abp regions than in one Mb flanking regions, while other repeat types are depleted in the Abp regions compared to flanking regions. L1 retrotransposons preferentially accumulated in the Abp gene regions after lineage separation and roughly followed the pattern of Abp gene expansion. By contrast, the proportion of shared vs. lineage-specific ERVII repeats in the Abp region resembles the rest of the genome. Conclusions We confirmed the role of L1 repeats in Abp gene duplication with the identification of recombinant L1Md _ T elements at the edges of the most recent mouse Abp gene duplication. High densities of L1 and ERVII repeats were found in the Abp gene region with abrupt transitions at the region boundaries, suggesting that their higher densities are tightly associated with Abp gene duplication. We observed that the major accumulation of L1 elements occurred after the split of the mouse and rat lineages and that there is a striking overlap between the timing of L1 accumulation and expansion of the Abp gene family in the mouse genome. Establishing a link between the accumulation of L1 elements and the expansion of the Abp gene family and identification of an NAHR-related breakpoint in the most recent duplication are the main contributions of our study.
Retrotransposon
Lineage (genetic)
Segmental duplication
Gene conversion
Non-allelic homologous recombination
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Non-allelic homologous recombination
Segmental duplication
dup
Breakpoint
Comparative genomic hybridization
Gene rearrangement
Chromosomal rearrangement
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Genomic architecture, higher order structural features of the human genome, can provide molecular substrates for recurrent sub-microscopic chromosomal rearrangements, or may result in genomic instability by forming structures susceptible to DNA double-strand breaks. Pelizaeus-Merzbacher disease (PMD) is a genomic disorder most commonly arising from genomic duplications of the dosage-sensitive proteolipid protein gene ( PLP1 ). Unlike many other genomic disorders that result from non-allelic homologous recombination utilizing flanking low-copy repeats (LCRs) as substrates, generating a common and recurrent rearrangement, the breakpoints of PLP1 duplications have been reported not to cluster, yielding duplicated genomic segments of varying lengths. This suggests a distinct molecular mechanism underlying PLP1 duplication events. To determine whether structural features of the genome also facilitate PLP1 duplication events, we analyzed extensively the genomic architecture of the PLP1 region and defined several novel LCRs (LCR–PMDs). Array comparative genomic hybridization showed that PLP1 duplication sizes differed, but revealed a subgroup of patients with apparently similar PLP1 duplication breakpoints. Pulsed-field gel electrophoresis analysis using probes adjacent to the LCR–PMDs detected unique recombination-specific junction fragments in 12 patients, enabled us to associate the LCR–PMDs with breakpoint regions, and revealed rearrangements inconsistent with simple tandem duplications in four patients. Two-color fluorescence in situ hybridization was consistent with directly oriented duplications. Our study provides evidence that PLP1 duplication events may be stimulated by LCRs, possibly non-homologous pairs at both the proximal and distal breakpoints in some cases, and further supports an alternative role of genomic architecture in rearrangements responsible for genomic disorders.
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Segmental duplication
Comparative genomic hybridization
Non-allelic homologous recombination
genomic DNA
Gene 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.
Segmental duplication
Non-allelic homologous recombination
Breakpoint
Alu element
Synteny
Structural Variation
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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
Penetrance
Segmental duplication
Expressivity
Cite
Citations (3)
Non-allelic homologous recombination
Comparative genomic hybridization
Segmental duplication
Gene dosage
Gene rearrangement
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Citations (22)