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The segregation of different submicroscopic imbalances underlying the clinical variability associated with a familial karyotypically balanced translocation.

Fonseca AC, Bonaldi A, Fonseca SA, Otto PA, Kok F, Bak M, Tommerup N, Vianna-Morgante AM - Mol Cytogenet (2015)

Bottom Line: About 7 % of karyotypically balanced chromosomal rearrangements (BCRs) are associated with congenital anomalies due to gene or regulatory element disruption, and cryptic imbalances on rearranged chromosomes.A 5p15.1 deletion, encompassing 1.47 Mb, also detected in the family, did not segregate with the clinical phenotype.The disclosing of the complexity of an apparently simple two-break familial rearrangement illustrates the importance of reconstructing the precise structure of derivative chromosomes for establishing genotype-phenotype correlations.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Rua do Matão, 277, 05508-090 São Paulo, SP Brazil ; Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT

Background: About 7 % of karyotypically balanced chromosomal rearrangements (BCRs) are associated with congenital anomalies due to gene or regulatory element disruption, and cryptic imbalances on rearranged chromosomes. Rare familial BCRs segregating with clinical features are a powerful source for the identifying of causative genes due to the presence of several affected carriers.

Case presentation: We report on a karyotypically balanced translocation t(2;22)(p13;q12.2) associated with variable learning disabilities, and craniofacial and hand dysmorphisms, detected in six individuals in a three-generation family. Combined a-CGH, FISH and mate-pair sequencing revealed a ten-break complex rearrangement, also involving chromosome 5. As the consequence of the segregation of the derivative chromosomes der(2), der(5) and der(22), different imbalances were present in affected and clinically normal family members, thus contributing to the clinical variability. A 6.64 Mb duplication of a 5q23.2-23.3 segment was the imbalance common to all affected individuals. Although LMNB1, implicated in adult-onset autosomal dominant leukodystrophy (ADLD) when overexpressed, was among the 18 duplicated genes, none of the adult carriers manifested ADLD, and LMNB1 overexpression was not detected in the two tested individuals, after qRT-PCR. The ectopic location of the extra copy of the LMBN1 gene on chromosome 22 might have negatively impacted its expression. In addition, two individuals presenting with more severe learning disabilities carried a 1.42 Mb 2p14 microdeletion, with three genes (CEP68, RAB1A and ACTR2),which are candidates for the intellectual impairment observed in the previously described 2p14p15 microdeletion syndrome, mapping to the minimal overlapping deleted segment. A 5p15.1 deletion, encompassing 1.47 Mb, also detected in the family, did not segregate with the clinical phenotype.

Conclusion: The disclosing of the complexity of an apparently simple two-break familial rearrangement illustrates the importance of reconstructing the precise structure of derivative chromosomes for establishing genotype-phenotype correlations.

No MeSH data available.


Related in: MedlinePlus

Chromosome 5 microdeletion and microduplication detected in the proband. (a) a-CGH (105 K, Agilent): Probes within a 1.45 Mb segment at 5p15.1 were deleted (chr5: 15,097,402-16,551,445; Human GRCh37 Assembly, hg19). The UCSC profile of the region depicts the deletion identified by a-CGH, which was extended to 1.47 Mb by MPS (chr5:15,073,606-16,552,845) (red), with the four genes mapping to this segment. (b) FISH probes RP1-137K24 (red signal) and RP1-167G20 (green signal) from the deleted segment, showed signals only on the normal chromosome 5. (c) a-CGH (105 K, Agilent): Probes within a 6.63 Mb segment on 5q23.2-23.3 were duplicated (chr5: 123,798,118-130,432,974). The UCSC profile depicts the duplication identified by a-CGH, which was extended to a 6.64 Mb interval by MPS (chr5:123,790,174-130,437,756) (blue), with the 18 genes mapping to this segment. (d) The additional segment of chromosome 5 was found to be inserted into the der(22) breakpoint region, by FISH, using the probes R11-48C14 (red signal) and RP1-236L2 (green signal) from the duplicated segment. This result was confirmed by MPS analysis (Table 1 and Additional file 7: Table S4)
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Fig2: Chromosome 5 microdeletion and microduplication detected in the proband. (a) a-CGH (105 K, Agilent): Probes within a 1.45 Mb segment at 5p15.1 were deleted (chr5: 15,097,402-16,551,445; Human GRCh37 Assembly, hg19). The UCSC profile of the region depicts the deletion identified by a-CGH, which was extended to 1.47 Mb by MPS (chr5:15,073,606-16,552,845) (red), with the four genes mapping to this segment. (b) FISH probes RP1-137K24 (red signal) and RP1-167G20 (green signal) from the deleted segment, showed signals only on the normal chromosome 5. (c) a-CGH (105 K, Agilent): Probes within a 6.63 Mb segment on 5q23.2-23.3 were duplicated (chr5: 123,798,118-130,432,974). The UCSC profile depicts the duplication identified by a-CGH, which was extended to a 6.64 Mb interval by MPS (chr5:123,790,174-130,437,756) (blue), with the 18 genes mapping to this segment. (d) The additional segment of chromosome 5 was found to be inserted into the der(22) breakpoint region, by FISH, using the probes R11-48C14 (red signal) and RP1-236L2 (green signal) from the duplicated segment. This result was confirmed by MPS analysis (Table 1 and Additional file 7: Table S4)

Mentions: After G-banding, a karyotypically balanced translocation t(2;22)(p13;q12.2) was detected in the proband (III-4), his older brother (III-3), mother (II-4), maternal grandmother (I-2), aunt (II-3) and uncle (II-6) (Fig. 1b). They shared similar clinical signs, although in variable degrees, II-6 and III-3 presenting with more severe learning disabilities. The clinically normal brother of the proband (III-5) had a normal karyotype. In the proband, a-CGH analysis revealed a 1.45 Mb deletion at 5p15.1 and a 6.63 Mb duplication at 5q23.2-23.3 (Fig. 2a-d). The deletion was confirmed by FISH (Fig. 2b), and the extra segment of chromosome 5 was found to be inserted into the der(22) breakpoint region (Fig. 2d). a-CGH and/or FISH detected the 5p15.1 deletion in three affected individuals [the mother (II-4), maternal grandmother (I-2) and aunt (II-3)], but also in the phenotypically normal brother (III-5) of the proband (Additional file 4: Figure S1). The insertion of 5q23.2-23.3 into the der(22), however, was detected only in the affected individuals (Additional file 5: Figure S2). Four and 18 genes are located within the deleted and duplicated segments of chromosome 5, respectively (Fig. 2a and c). In addition, a 1.24 Mb 2p14 deletion was identified by a-CGH in the proband’s affected brother (III-3; Figs. 1b and 3a-b). This deletion was also detected in the proband’s affected uncle (II-6; Figs. 1b and 3c). Five genes map to the deleted segment of chromosome 2 (Fig. 3d). In the phenotypically normal brother of the proband (III-5; Fig. 1b), this same 2p14 segment was duplicated, inserted into the short arm of the der(5) (Additional file 6: Figure S3). As expected, the other carriers of the der(5) – the proband (III-4), his grandmother (I-2), mother(II-4) and aunt (II-3), had the 2p14 segment inserted into der(5) as well (Additional file 6: Figure S3); they did not have any imbalance of chromosome 2, since they also carried the der(2). The affected brother (III-3) and uncle (II-6) of the proband both carried the deletion, since they inherited the normal chromosome 5 and not the der(5) from their respective mothers. No copy number variations were detected on chromosome 22.Fig. 2


The segregation of different submicroscopic imbalances underlying the clinical variability associated with a familial karyotypically balanced translocation.

Fonseca AC, Bonaldi A, Fonseca SA, Otto PA, Kok F, Bak M, Tommerup N, Vianna-Morgante AM - Mol Cytogenet (2015)

Chromosome 5 microdeletion and microduplication detected in the proband. (a) a-CGH (105 K, Agilent): Probes within a 1.45 Mb segment at 5p15.1 were deleted (chr5: 15,097,402-16,551,445; Human GRCh37 Assembly, hg19). The UCSC profile of the region depicts the deletion identified by a-CGH, which was extended to 1.47 Mb by MPS (chr5:15,073,606-16,552,845) (red), with the four genes mapping to this segment. (b) FISH probes RP1-137K24 (red signal) and RP1-167G20 (green signal) from the deleted segment, showed signals only on the normal chromosome 5. (c) a-CGH (105 K, Agilent): Probes within a 6.63 Mb segment on 5q23.2-23.3 were duplicated (chr5: 123,798,118-130,432,974). The UCSC profile depicts the duplication identified by a-CGH, which was extended to a 6.64 Mb interval by MPS (chr5:123,790,174-130,437,756) (blue), with the 18 genes mapping to this segment. (d) The additional segment of chromosome 5 was found to be inserted into the der(22) breakpoint region, by FISH, using the probes R11-48C14 (red signal) and RP1-236L2 (green signal) from the duplicated segment. This result was confirmed by MPS analysis (Table 1 and Additional file 7: Table S4)
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Fig2: Chromosome 5 microdeletion and microduplication detected in the proband. (a) a-CGH (105 K, Agilent): Probes within a 1.45 Mb segment at 5p15.1 were deleted (chr5: 15,097,402-16,551,445; Human GRCh37 Assembly, hg19). The UCSC profile of the region depicts the deletion identified by a-CGH, which was extended to 1.47 Mb by MPS (chr5:15,073,606-16,552,845) (red), with the four genes mapping to this segment. (b) FISH probes RP1-137K24 (red signal) and RP1-167G20 (green signal) from the deleted segment, showed signals only on the normal chromosome 5. (c) a-CGH (105 K, Agilent): Probes within a 6.63 Mb segment on 5q23.2-23.3 were duplicated (chr5: 123,798,118-130,432,974). The UCSC profile depicts the duplication identified by a-CGH, which was extended to a 6.64 Mb interval by MPS (chr5:123,790,174-130,437,756) (blue), with the 18 genes mapping to this segment. (d) The additional segment of chromosome 5 was found to be inserted into the der(22) breakpoint region, by FISH, using the probes R11-48C14 (red signal) and RP1-236L2 (green signal) from the duplicated segment. This result was confirmed by MPS analysis (Table 1 and Additional file 7: Table S4)
Mentions: After G-banding, a karyotypically balanced translocation t(2;22)(p13;q12.2) was detected in the proband (III-4), his older brother (III-3), mother (II-4), maternal grandmother (I-2), aunt (II-3) and uncle (II-6) (Fig. 1b). They shared similar clinical signs, although in variable degrees, II-6 and III-3 presenting with more severe learning disabilities. The clinically normal brother of the proband (III-5) had a normal karyotype. In the proband, a-CGH analysis revealed a 1.45 Mb deletion at 5p15.1 and a 6.63 Mb duplication at 5q23.2-23.3 (Fig. 2a-d). The deletion was confirmed by FISH (Fig. 2b), and the extra segment of chromosome 5 was found to be inserted into the der(22) breakpoint region (Fig. 2d). a-CGH and/or FISH detected the 5p15.1 deletion in three affected individuals [the mother (II-4), maternal grandmother (I-2) and aunt (II-3)], but also in the phenotypically normal brother (III-5) of the proband (Additional file 4: Figure S1). The insertion of 5q23.2-23.3 into the der(22), however, was detected only in the affected individuals (Additional file 5: Figure S2). Four and 18 genes are located within the deleted and duplicated segments of chromosome 5, respectively (Fig. 2a and c). In addition, a 1.24 Mb 2p14 deletion was identified by a-CGH in the proband’s affected brother (III-3; Figs. 1b and 3a-b). This deletion was also detected in the proband’s affected uncle (II-6; Figs. 1b and 3c). Five genes map to the deleted segment of chromosome 2 (Fig. 3d). In the phenotypically normal brother of the proband (III-5; Fig. 1b), this same 2p14 segment was duplicated, inserted into the short arm of the der(5) (Additional file 6: Figure S3). As expected, the other carriers of the der(5) – the proband (III-4), his grandmother (I-2), mother(II-4) and aunt (II-3), had the 2p14 segment inserted into der(5) as well (Additional file 6: Figure S3); they did not have any imbalance of chromosome 2, since they also carried the der(2). The affected brother (III-3) and uncle (II-6) of the proband both carried the deletion, since they inherited the normal chromosome 5 and not the der(5) from their respective mothers. No copy number variations were detected on chromosome 22.Fig. 2

Bottom Line: About 7 % of karyotypically balanced chromosomal rearrangements (BCRs) are associated with congenital anomalies due to gene or regulatory element disruption, and cryptic imbalances on rearranged chromosomes.A 5p15.1 deletion, encompassing 1.47 Mb, also detected in the family, did not segregate with the clinical phenotype.The disclosing of the complexity of an apparently simple two-break familial rearrangement illustrates the importance of reconstructing the precise structure of derivative chromosomes for establishing genotype-phenotype correlations.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Rua do Matão, 277, 05508-090 São Paulo, SP Brazil ; Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT

Background: About 7 % of karyotypically balanced chromosomal rearrangements (BCRs) are associated with congenital anomalies due to gene or regulatory element disruption, and cryptic imbalances on rearranged chromosomes. Rare familial BCRs segregating with clinical features are a powerful source for the identifying of causative genes due to the presence of several affected carriers.

Case presentation: We report on a karyotypically balanced translocation t(2;22)(p13;q12.2) associated with variable learning disabilities, and craniofacial and hand dysmorphisms, detected in six individuals in a three-generation family. Combined a-CGH, FISH and mate-pair sequencing revealed a ten-break complex rearrangement, also involving chromosome 5. As the consequence of the segregation of the derivative chromosomes der(2), der(5) and der(22), different imbalances were present in affected and clinically normal family members, thus contributing to the clinical variability. A 6.64 Mb duplication of a 5q23.2-23.3 segment was the imbalance common to all affected individuals. Although LMNB1, implicated in adult-onset autosomal dominant leukodystrophy (ADLD) when overexpressed, was among the 18 duplicated genes, none of the adult carriers manifested ADLD, and LMNB1 overexpression was not detected in the two tested individuals, after qRT-PCR. The ectopic location of the extra copy of the LMBN1 gene on chromosome 22 might have negatively impacted its expression. In addition, two individuals presenting with more severe learning disabilities carried a 1.42 Mb 2p14 microdeletion, with three genes (CEP68, RAB1A and ACTR2),which are candidates for the intellectual impairment observed in the previously described 2p14p15 microdeletion syndrome, mapping to the minimal overlapping deleted segment. A 5p15.1 deletion, encompassing 1.47 Mb, also detected in the family, did not segregate with the clinical phenotype.

Conclusion: The disclosing of the complexity of an apparently simple two-break familial rearrangement illustrates the importance of reconstructing the precise structure of derivative chromosomes for establishing genotype-phenotype correlations.

No MeSH data available.


Related in: MedlinePlus