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David Dezso1; João Parente Freixo2; Bárbara Marques1; Inês Carvalho2; Nataliya Tkachenko3; Natália Oliva-Teles3; Mariana Marques1; Manuela Cardoso1; José Fino1; Ana Cristina Alves1; Ana Fortuna3; Sofia Dória4; Carla Pinto de Moura4; Hildeberto Correia1; Marques Carreira5; Joaquim Sá6; Rui Gonçalves2; João Lavinha1; Teresa Kay2; ME Talkowski7,8,9; CC Morton8,9,10,11

1- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, INSA IP. Lisboa;
2- Serviço de Genética Médica, Centro Hospitalar de Lisboa Central, Lisboa, Portugal;
3- Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto;
4- Faculdade de Medicina, Universidade do Porto;
5- Faculdade de Medicina, Universidade de Coimbra;
6- Centro Hospitalar de Coimbra, Universidade de Coimbra;
7- Center for Human Genetic Research, Departments of Neurology, Pathology and Psychiatry, Massachusetts General Hospital, Boston, USA;
8- Harvard Medical School, Boston;
9- Broad Institute of MIT and Harvard, Cambridge;
10- Departments of Obstetrics and Gynecology, and of Pathology, Brigham and Women’s Hospital, Boston;
11- University of Manchester, Manchester Academic Health Science Center, Manchester, UK

European Human Genetics Conference 2016, Barcelona. Nov 2016
Oral comunication

Research grant: FCT HMSP-ICT/0016/2013

Background: Most approaches are insensitive to the full mutational spectrum of chromosome rearrangements associated with human developmental abnormalities. Therefore, our aim is to introduce next-generation sequencing (NGS) into clinical cytogenetics, creating a sequence-based Next-Gen Cytogenetics to catalyze a dramatic advancement in clinical diagnostics.
Methods: Twenty families with chromosome rearrangement-associated diseases, including two prenatal (PN) cases, have been enrolled. Fourteen of these were also analyzed by NGS using large-insert paired-end libraries.
Results: The majority of these cases were confirmed to be balanced reciprocal rearrangements, whereas 4 were complex chromosomal rearrangements including 1 of chromothripsis. Thus far, over 50 breakpoints were identified disrupting protein coding genes, lncRNAs, or intergenic regions, thus revealing candidate genes or genomic loci. These cases are further assessed for pathogenicity from positional effects on genes located within topological domains (TADs) containing the breakpoints using DECIPHER predictions of haploinsufficiency. In one PN case, the 16q24 breakpoint disrupts ANKRD11, etiologic in the autosomal dominant KBG syndrome (OMIM #148050), predicting an abnormal phenotype. The chromothripsis case, submitted as 46,XY,t(7;14)(q22;q32.1),inv(15)(q21.2q26.1), proved by NGS to carry two further deletions, at 3p12 (5.3 Mb) and 15q14 (488 kb), as well as an insertion of 644.4 kb from 15q14 into 3p14. The inv(15) is in fact a complex rearrangement of 15q with eight breakpoints.
Conclusions: We demonstrate that NGS-based chromosomal rearrangement characterization leads to major improvements in identification of chromosomal aberrations and in prediction of clinical outcomes of postnatally and prenatally detected genomic rearrangements, and to contributions to human genome annotation.

Palavras Chave: Next-Generation Citogenetics; Chromosome Rearrangement; TAD