Assigning single clinical features to their disease-locus in large deletions: the example of chromosome 1q23-25 deletion syndrome

Fichera, Marco;Saccuzzo, Lucia;Bertuzzo, Sara;Marelli, Susan;Cavallini, Anna;Romaniello, Romina;Kocova, Mirjana;Citterio, Andrea;Fanizza, Isabella;Trabacca, Antonio;Pagliazzi, Angelica;Guarducci, Silvia;Giglio, Sabrina

Membro del Collaboration Group

;Zuffardi, Orsetta;Bonaglia, Maria Clara

2020-01-01

---

Abstract

Aim: Assigning a disease-locus within the shortest regions of overlap (SRO) shared by deleted/duplicated subjects presenting this disease is a robust mapping approach, although the presence of different malformation traits and their attendance only in a part of the affected subjects can hinder the interpretation. To overcome the problem of incomplete penetrance, we developed an algorithm that we applied to the deletion region 1q23.3-q25, which contains three SROs, each contributing to the abnormal phenotype without clearly distinguishing between the different malformations. We describe six new subjects, including a healthy father and his daughter, with 1q23.3-q25 deletion of different sizes. The aim of this study was to correlate specific abnormal traits to the haploinsufficiency of specific gene/putative regulatory elements. Methods: Merging cases with those in the literature, we considered four traits, namely intellectual disability (ID), microcephaly, short-hands/feet, and brachydactyly, and conceived a mathematical model to predict with what probability the haploinsufficiency of a specific portion of the deletion region is associated with one of the four malformations. Results: The haploinsufficiency of PBX1 is strongly associated with ID. DNM3 and LHX4 are confirmed as responsible for growth retardation, whereas ATPIB1 was identified as a new candidate gene for microcephaly, short-hands/feet, and brachydactyly. Conclusion: Although our model is hampered by long-term position effects of regulatory elements, synergistic cooperation of several genes, and incomplete clinical assessment, it can be useful for contiguous gene syndromes showing a complex pattern of clinical characteristics. Obviously, functional approaches are needed to warrant its reliability.