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2018

ANUÁRIO DO HOSPITAL DONA ESTEFÂNIA
REPOSITÓRIO MÉDICO CIENTÍFICO

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DETECTION OF DE NOVO STRUCTURAL CHROMOSOMAL REARRANGEMENTS WITH NUCLEOTIDE LEVEL RESOLUTION FOR ASSESSMENT OF THEIR CLINICAL OUTCOME IN PRENATAL DIAGNOSIS

Inês Carvalho*1, João Freixo*1, Mariana Marques2, Manuela Cardoso2, Joana Fino2, Ana Cristina Alves2, Bárbara Marques2, Michael E. Talkowski3-5, Hildeberto Correia2, Cynthia C. Morton4-7, Dezső David2

*These two authors contributed equally
1Central Lisbon Hospital Center, Lisbon, Portugal
Department of Human Genetics, National Health Institute Doutor Ricardo Jorge, Lisbon, Portugal;
3Center for Human Genetic Research, Departments of Neurology, Pathology and Psychiatry, Massachusetts General Hospital, Boston, MA, United States;
4Harvard Medical School, Boston, MA, United States;
5Broad Institute of MIT and Harvard, Cambridge, MA, United States;
6Departments of Obstetrics and Gynecology, and of Pathology, Brigham and Women’s Hospital, Boston, MA, United States;
7University of Manchester, Manchester Academic Health Science Center, Manchester, UK

- European Society of Human Genetics Conference 2017. Sob a forma de Apresetação oral na sessão “best poster”.

Resumo:
Introdução e Objectivo
Recognition of de novo (dn) balanced chromosomal aberrations (BCAs) leading potentially to congenital anomalies constitutes a huge challenge in prenatal diagnosis (PND). Therefore, cytogenetic and cytogenomic approaches, including chromosome microarray analysis (CMA) have to be complemented by methods allowing identification of breakpoints at nucleotide resolution within the actionable time frame of a prenatal diagnosis.
Métodos
Concomitantly with the conventional PND protocol, we apply large-insert whole-genome sequencing (liWGS) for identification of dnBCA breakpoints in two prenatal samples.
Resultados
The first fetus, referred for PND because of increased risk at combined first trimester screening, is a female with a t(16;17)(q24;q21.3)dn. Sequencing identified the 16q24 and 17q21.3 breakpoints within IVS3 of ANKRD11 and IVS1 of WNT3, respectively. Haploinsufficiency of ANKRD11 causes dominant KBG syndrome (OMIM #148050), whereas of WNT3 result in recessive tetraamelia syndrome (OMIM #165330). Although the translocation results in two fusion genes no evidence of chimeric transcripts was found.The second fetus, referred for PND due to maternal anxiety, is a male with a t(2;19)(p13.3;q13.11)dn. The 2p13.3 breakpoint is localized within IVS1 of ATP6V1B1 whereas that of 19q13.11 adjacent to CEP89ATP6V1B1 causes a recessive form of renal tubular acidosis with progressive sensorineural deafness (OMIM #192132).
Conclusões
Clinical features of the newborns corroborate the predicted outcome in the light of chromatin topologically associated domains (TADs); KBG syndrome in the first case and a normal phenotype in the second case.Although prediction of the phenotypic outcomes highlights the gaps in our current knowledge, this approach allows improved genetic counselling. Therefore, we recommend inclusion of this approach into current PND care.

Palavras Chave: Balanced chromosomal aberrations; Haploinsufficiency; Prenatal