Human developmental abnormalities are devastating conditions that account for almost half of all full-term neonatal deaths in developed countries. For individuals who survive, congenital anomalies often confer lifelong disability and their impact on public health is profound. Yet the genetic etiology and genomic architecture contributing to the vast majority of these conditions remains unknown. Although these are rare conditions, annual health care costs of these subjects are staggering. Separately, and in addition, the genetic etiologies of recurrent infertility (not due to chromosomal aneuploidies) remain poorly elucidated.

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The premises of this research program are that current low resolution diagnostic techniques are:

1. Insensitive to the full mutational spectrum contributing to human developmental disorders and infertility;

2. Our understanding of the molecular alterations introduced by genomic rearrangements is poor;

3. The lack of a fully annotated human genome including a Haploinsufficiency Map (HipMap) hinders predictive diagnostics.

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Therefore, this research program proposes to introduce Next-Generation Sequencing (NGS) into clinical cytogenetics, leveraging the unique innovations in the detection of genomic structural variation to create high-throughput, sequence-based Next-Gen Cytogenetics to catalyze a dramatic advancement in clinical diagnostics. Furthermore, extending the aim of this program to an understanding of the molecular pathology of these chromosome rearrangement-associated developmental disorders and infertilities will contribute to an improved prediction of the phenotypic consequences of de novo chromosomal translocations and inversions in prenatal and postnatal diagnostics not previously possible.

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This project is included in the Harvard Medical School Portugal - Program In Translational Research and Information.

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This project is being funded by Portuguese Fundação para a Ciência e a Tecnologia (FCT)  (HMSP-ICT/0016/2013), and  has been authorized by the Ethics Committee at National Institute of Health Doutor Ricardo Jorge, as well as by the Portuguese Data Protection Authority.

 

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