title: The segregation of different submicroscopic imbalances underlying the clinical variability associated with a familial karyotypically balanced translocation.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.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.
authors.forename: Ana Carolina S
authors.initials: AC
authors.lastname: Fonseca
authors.affiliation: Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Rua do Matão, 277, 05508-090 São Paulo, SP Brazil.
authors.forename: Adriano
authors.initials: A
authors.lastname: Bonaldi
authors.affiliation: Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Rua do Matão, 277, 05508-090 São Paulo, SP Brazil.
authors.forename: Simone A S
authors.initials: SA
authors.lastname: Fonseca
authors.affiliation: Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Rua do Matão, 277, 05508-090 São Paulo, SP Brazil.
authors.forename: Paulo A
authors.initials: PA
authors.lastname: Otto
authors.affiliation: Department of Neurology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Kok
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, 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, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.affiliation: Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Rua do Matão, 277, 05508-090 São Paulo, SP Brazil.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Vianna-Morgante
keywords: 2p14 deletion; 2p14p15 microdeletion syndrome; 5q23.2-23.3 duplication; CEP68, RAB1A and ACTR2 deletion; Familial karyotypically balanced translocation; LMNB1 duplication