Dataset Information

A case with concurrent duplication, triplication, and uniparental isodisomy at 1q42.12-qter supporting microhomology-mediated break-induced replication model for replicative rearrangements.

ABSTRACT:

Background

Complex genomic rearrangements (CGRs) consisting of interstitial triplications in conjunction with uniparental isodisomy (isoUPD) have rarely been reported in patients with multiple congenital anomalies (MCA)/intellectual disability (ID). One-ended DNA break repair coupled with microhomology-mediated break-induced replication (MMBIR) has been recently proposed as a possible mechanism giving rise to interstitial copy number gains and distal isoUPD, although only a few cases providing supportive evidence in human congenital diseases with MCA have been documented.

Case presentation

Here, we report on the chromosomal microarray (CMA)-based identification of the first known case with concurrent interstitial duplication at 1q42.12-q42.2 and triplication at 1q42.2-q43 followed by isoUPD for the remainder of chromosome 1q (at 1q43-qter). In distal 1q duplication/triplication overlapping with 1q42.12-q43, variable clinical features have been reported, and our 25-year-old patient with MCA/ID presented with some of these frequently described features. Further analyses including the precise mapping of breakpoint junctions within the CGR in a sequence level suggested that the CGR found in association with isoUPD in our case is a triplication with flanking duplications, characterized as a triplication with a particularly long duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure. Because microhomology was observed in both junctions between the triplicated region and the flanking duplicated regions, our case provides supportive evidence for recently proposed replication-based mechanisms, such as MMBIR, underlying the formation of CGRs?+?isoUPD implicated in chromosomal disorders.

Conclusions

To the best of our knowledge, this is the first case of CGRs?+?isoUPD observed in 1q and having DUP-TRP/INV-DUP structure with a long proximal duplication, which supports MMBIR-based model for genomic rearrangements. Molecular cytogenetic analyses using CMA containing single-nucleotide polymorphism probes with further analyses of the breakpoint junctions are recommended in cases suspected of having complex chromosomal abnormalities based on discrepancies between clinical and conventional cytogenetic findings.

SUBMITTER: Kohmoto T

PROVIDER: S-EPMC5410019 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

A case with concurrent duplication, triplication, and uniparental isodisomy at 1q42.12-qter supporting microhomology-mediated break-induced replication model for replicative rearrangements.

Kohmoto Tomohiro T Okamoto Nana N Naruto Takuya T Murata Chie C Ouchi Yuya Y Fujita Naoko N Inagaki Hidehito H Satomura Shigeko S Okamoto Nobuhiko N Saito Masako M Masuda Kiyoshi K Kurahashi Hiroki H Imoto Issei I

Molecular cytogenetics 20170428

<h4>Background</h4>Complex genomic rearrangements (CGRs) consisting of interstitial triplications in conjunction with uniparental isodisomy (isoUPD) have rarely been reported in patients with multiple congenital anomalies (MCA)/intellectual disability (ID). One-ended DNA break repair coupled with microhomology-mediated break-induced replication (MMBIR) has been recently proposed as a possible mechanism giving rise to interstitial copy number gains and distal isoUPD, although only a few cases pro ...[more]

PMID: 28465723

Similar Datasets

Project description:Background:Uniparental disomy (UPD) is a rare condition in which a child inherits both copies of a chromosome or chromosome segment from one parent. Medical consequences of UPD may include abnormal imprinting, unmasking of genetic disease, and somatic mosaicism; alternatively, the condition may be clinically silent. We present a case of maternal UPD for chromosome 6, a rare condition previously reported less than 20 times. In our patient with a normal phenotype, the condition was discovered through abnormal paternity testing results. Uniparental isodisomy is a rare cause of discordant parentage testing results, but it is an important phenomenon to recognize. Case presentation:We present a female born at 32?weeks gestational age with birth weight 10-25%ile when corrected for prematurity. Paternity testing was obtained for legal reasons, and initial results appeared to exclude the alleged father. However, the lab performed additional testing which indicated that the patient was homozygous for maternal alleles for all three tested loci located on chromosome 6. Based on these results, the patient was referred for a medical genetics evaluation for possible maternal uniparental disomy. She presented for her consultation at 10?months of age and appeared to be developing appropriately. Her age-adjusted weight, length, and head circumference were <3%ile, 10%ile, and 25%ile respectively. Chromosomal microarray testing confirmed maternal UPD6. The patient was seen again at 14?months of age, and her weight and length were 10-25%ile. She had not developed concerning symptoms or physical exam findings. Conclusions:The presence of UPD, especially in asymptomatic patients, has implications for paternity testing, as standard methods may miss cases of both isodisomy and heterodisomy. This rare inheritance pattern should be considered when discordant paternity results come under suspicion. It is unusual for a parentage testing lab to perform the amount of testing done for this case, but the initial inconsistencies necessitated further investigation. UPD6 has uncertain effects and variable phenotypes, so this patient's genetic abnormality likely would have gone undiscovered if not for the non-medical indication for the laboratory analysis. Her asymptomatic presentation raises the possibility that UPD may be more common than previously estimated.

Dataset Information

A case with concurrent duplication, triplication, and uniparental isodisomy at 1q42.12-qter supporting microhomology-mediated break-induced replication model for replicative rearrangements.

Background

Case presentation

Conclusions

Publications

A case with concurrent duplication, triplication, and uniparental isodisomy at 1q42.12-qter supporting microhomology-mediated break-induced replication model for replicative rearrangements.

Similar Datasets

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