Strict network analysis of evolutionary conserved and brain-expressed genes reveals new putative candidates implicated in Intellectual Disability and in Global Development Delay

Abstract

Objectives

Intellectual Disability (ID) and Global Development Delay (GDD) are frequent reasons for referral to genetic services and although they present overlapping phenotypes concerning cognitive, motor, language, or social skills, they are not exactly synonymous. Aiming to better understand independent or shared mechanisms related to these conditions and to identify new candidate genes, we performed a highly stringent protein-protein interaction network based on genes previously related to ID/GDD in the Human Phenotype Ontology portal.

Methods

ID/GDD genes were searched for reliable interactions through STRING and clustering analysis was applied to detect biological complexes through the MCL algorithm. Six coding hub genes (TP53, CDC42, RAC1, GNB1, APP, and EP300) were recognised by the Cytoscape NetworkAnalyzer plugin, interacting with 1625 proteins not yet associated with ID or GDD. Genes encoding these proteins were explored by gene ontology, associated diseases, evolutionary conservation, and brain expression.

Results

One hundred and seventy-two new putative genes playing a role in enriched processes/pathways previously related to ID and GDD were revealed, some of which were already postulated to be linked to ID/GDD in additional databases.

Conclusions

Our findings expanded the aetiological genetic landscape of ID/GDD and showed evidence that both conditions are closely related at the molecular and functional levels.

Keywords:

• Intellectual disability
• Global Developmental Delay
• protein-protein interaction
• brain development
• genetics

Acknowledgements

The authors thank the original studies’ authors for making their data available in a FAIR way.

Statement of interest

The authors declare that they have no conflict of interest.

Web resources

The URLs for data presented herein are as follows:

DECIPHER v9.30: https://decipher.sanger.ac.uk/ddd/ddgenes

GTEx portal version 8: https://www.gtexportal.org/home/

Greenwood Genetic Centre, X-Linked Intellectual Disability, jan 2020, https://www.ggc.org/xlid-genetic-research/

Human Phenotype Ontology (April 2019 HPO Release), https://hpo.jax.org/

INTERSPIA: http://bioinfo.konkuk.ac.kr/INTERSPIA/

Mouse Genome Informatics (6.15): http://www.informatics.jax.org/

Online Mendelian Inheritance in Man (OMIM), https://www.omim.org/

PanelApp Intellectual disability (Version 3.62): https://panelapp.genomicsengland.co.uk/panels/285/

STRING version 11.0: https://string-db.org/

SysID database (update on March 26th, 2020): https://sysid.cmbi.umcn.nl/

WebGestalt: http://www.webgestalt.org/

Additional information

Funding

This work was supported by funds from Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001 and Inovation Department of State University of Rio de Janeiro (Qualitec/InovUERJ).