title: Accurate Breakpoint Mapping in Apparently Balanced Translocation Families with Discordant Phenotypes Using Whole Genome Mate-Pair Sequencing.
abstract: Familial apparently balanced translocations (ABTs) segregating with discordant phenotypes are extremely challenging for interpretation and counseling due to the scarcity of publications and lack of routine techniques for quick investigation. Recently, next generation sequencing has emerged as an efficacious methodology for precise detection of translocation breakpoints. However, studies so far have mainly focused on de novo translocations. The present study focuses specifically on familial cases in order to shed some light to this diagnostic dilemma. Whole-genome mate-pair sequencing (WG-MPS) was applied to map the breakpoints in nine two-way ABT carriers from four families. Translocation breakpoints and patient-specific structural variants were validated by Sanger sequencing and quantitative Real Time PCR, respectively. Identical sequencing patterns and breakpoints were identified in affected and non-affected members carrying the same translocations. PTCD1, ATP5J2-PTCD1, CADPS2, and STPG1 were disrupted by the translocations in three families, rendering them initially as possible disease candidate genes. However, subsequent mutation screening and structural variant analysis did not reveal any pathogenic mutations or unique variants in the affected individuals that could explain the phenotypic differences between carriers of the same translocations. In conclusion, we suggest that NGS-based methods, such as WG-MPS, can be successfully used for detailed mapping of translocation breakpoints, which can also be used in routine clinical investigation of ABT cases. Unlike de novo translocations, no associations were determined here between familial two-way ABTs and the phenotype of the affected members, in which the presence of cryptic imbalances and complex chromosomal rearrangements has been excluded. Future whole-exome or whole-genome sequencing will potentially reveal unidentified mutations in the patients underlying the discordant phenotypes within each family. In addition, larger studies are needed to determine the exact percentage for phenotypic risk in families with ABTs.
authors.affiliation: Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.|The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: Constantia
authors.initials: C
authors.lastname: Aristidou
authors.affiliation: Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: Costas
authors.initials: C
authors.lastname: Koufaris
authors.affiliation: Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: Athina
authors.initials: A
authors.lastname: Theodosiou
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen N., Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Bak
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen N., Denmark.
authors.forename: Mana M
authors.initials: MM
authors.lastname: Mehrjouy
authors.affiliation: Cytogenetics Unit, University of Social Welfare and Rehabilitation Sciences, Genetics Research Center, Tehran, Iran.
authors.forename: Farkhondeh
authors.initials: F
authors.lastname: Behjati
authors.affiliation: Department of Clinical Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: George
authors.initials: G
authors.lastname: Tanteles
authors.affiliation: Department of Clinical Genetics, The Cyprus Institute of Neurology and Genetics and Archbishop Makarios III Medical Centre, Nicosia, Cyprus.
authors.forename: Violetta
authors.initials: V
authors.lastname: Christophidou-Anastasiadou
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen N., Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.affiliation: Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.|The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: Carolina
authors.identifier: http://orcid.org/0000-0002-9296-8347
authors.initials: C
authors.lastname: Sismani
mesh_terms: D000293:Adolescent; D000328:Adult; D002135:Calcium-Binding Proteins / Q000235:genetics; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D025063:Chromosome Disorders / Q000175:diagnosis / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods*; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics; D010086:Oxidative Phosphorylation Coupling Factors / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods; D014178:Translocation, Genetic / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics
chemical_list: C479428:CADPS2 protein, human; D002135:Calcium-Binding Proteins; D024101:Mitochondrial Proteins; D010086:Oxidative Phosphorylation Coupling Factors; C544933:PTCD1 protein, human; D033921:Vesicular Transport Proteins; C000628217:F(6) ATPase; D025261:Mitochondrial Proton-Translocating ATPases