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

Author(s)

Fonseca, Ana Carolina S. ^{[1, 2]} ; Bonaldi, Adriano ^[1] ; Fonseca, Simone A. S. ^[1] ; Otto, Paulo A. ^[1] ; Kok, Fernando ^[3] ; Bak, Mads ^[2] ; Tommerup, Niels ^[2] ; Vianna-Morgante, Angela M. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biosci, Dept Genet & Evolutionary Biol, BR-05508090 Sao Paulo, SP - Brazil

^[2] Univ Copenhagen, Dept Cellular & Mol Med, Wilhelm Johannsen Ctr Funct Genome Res, Copenhagen - Denmark

^[3] Univ Sao Paulo, Sch Med, Dept Neurol, Sao Paulo - Brazil

• Document type: Journal article
• Source: MOLECULAR CYTOGENETICS; v. 8, DEC 30 2015.
• Web of Science Citations: 2

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. (AU)

• FAPESP's process: 13/01146-9 - Characterization of apparently balanced chromosomal rearrangements and its association with the phenotype of carriers: breakpoint mapping by mate pair sequencing
• Grantee: Ana Carolina dos Santos Fonseca
• Support type: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 11/14293-4 - Characterization of apparently balanced chromosomal rearrangements and of its association to the phenotype of carriers
• Grantee: Ana Carolina dos Santos Fonseca
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC