Multiple New Genes Affecting Developmental Brain Disorders Identified Interview with:

Andrea J. Gonzalez-Mantilla, M.D. Postdoctoral Fellow

Andrea J. Gonzalez-Mantilla, M.D.

Andrea J. Gonzalez-Mantilla, M.D.
Postdoctoral Fellow

Andres Moreno-De-Luca, M.D. Investigator I

Andres Moreno-De-Luca, M.D.

Andres Moreno-De-Luca, M.D.
Investigator I
Autism & Developmental Medicine Institute
Department of Radiology
Geisinger Health System
Danville, PA 17822

Medical Research: What is the background for this study? What are the main findings?

Response: Developmental brain disorders (DBD), such as autism, intellectual disability, and schizophrenia are a group of heterogeneous conditions characterized by deficits that affect multiple functional domains, such as cognition, behavior, communication, and motor skills. Previous studies provide strong evidence of common underlying molecular pathways and shared genetic causes among apparently different DBDs.

Large-scale genomic studies of individuals with developmental brain disorders have found that identifying multiple, independent de novo pathogenic loss-of-function (pLOF) variants in the same gene among unrelated individuals is a powerful statistical approach to reliably identify disease-causing genes. However, genomic data from smaller cohorts and case reports are not routinely pooled with data from larger studies. Moreover, most previous studies have been restricted to cohorts of individuals ascertained based on a single diagnosis (e.g., a study will focus on only individuals with a diagnosis of autism and not consider other genomic data from individuals with a different diagnosis). Therefore, genomic data from individuals across DBD are not being jointly analyzed in search of pLOF variants in the same gene that may help build evidence for a causative role in developmental brain disorders.

In this study, we carried out data mining of previously published data to identify genes related to the DBD phenotype. We expanded the aforementioned method and developed a multilevel data-integration approach, which capitalizes on three genotype-phenotype data sources:
(1) genomic data from structural and sequence pLOF variants,
(2) phenotype data from six apparently distinct DBD (autism, intellectual disability, epilepsy, schizophrenia, bipolar disorder and attention-deficit/hyperactivity disorder), and
(3) data from large scale studies, smaller cohorts, and case reports.

We identified 241 candidate genes for developmental brain disorders, including 17 genes that had not previously been associated with developmental brain disorders.

Medical Research: What should clinicians and patients take away from your report?

Response: The main take home point from our study is that jointly analyzing genomic data from individuals with seemingly different developmental brain disorders increases the yield of discovering genes associated with this phenotype over what would be obtained if each disorder, type of genomic variant, and study design were analyzed independently. The identification of new genetic causes of DBD is helping to increase our understanding of their underlying biology, which will ultimately lead to targeted therapies.

In addition, we have developed a a publicly available and searchable online knowledge base with all of the genotype and phenotype data from this study, which can be accessed at

Medical Research: What recommendations do you have for future research as a result of this study?

Response: We recommend to routinely pool, jointly analyze, and publicly share genotype and phenotype data from individuals with various developmental brain disorders to further increase the yield of DBD gene discovery. Then, by taking a genome-first approach to characterizing the phenotypic effects in individuals with developmental brain disorders, we will be able to improve the health and well-being of individuals with these disorders.


Gonzalez-Mantilla AJ, Moreno-De-Luca A, Ledbetter DH, Martin C. A Cross-Disorder Method to Identify Novel Candidate Genes for Developmental Brain Disorders. JAMA Psychiatry. Published online January 27, 2016. doi:10.1001/jamapsychiatry.2015.2692.

Andres Moreno-De-Luca, M.D., & Andrea J. Gonzalez-Mantilla, M.D. (2016). Multiple New Genes Affecting Developmental Brain Disorders Identified