Genetic insights into childhood-onset schizophrenia: The yield of clinical exome sequencing

Anna Alkelai; Lior Greenbaum; Shahar Shohat; Gundula Povysil; Ayan Malakar; Zhong Ren; Joshua E Motelow; Tanya Schechter; Benjamin Draiman; Eti Chitrit-Raveh; Daniel Hughes; Vaidehi Jobanputra; Sagiv Shifman; David B Goldstein; Yoav Kohn

doi:10.1016/j.schres.2022.12.033

Genetic insights into childhood-onset schizophrenia: The yield of clinical exome sequencing

Schizophr Res. 2023 Feb:252:138-145. doi: 10.1016/j.schres.2022.12.033. Epub 2023 Jan 14.

Authors

Affiliations

¹ Institute for Genomic Medicine, Columbia University Medical Center, New York, USA; Regeneron Genetics Center, Tarrytown, NY, USA. Electronic address: alkelai.ana@gmail.com.
² The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel; The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tal Aviv University, Tel Aviv, Israel.
³ Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁴ Institute for Genomic Medicine, Columbia University Medical Center, New York, USA.
⁵ Institute for Genomic Medicine, Columbia University Medical Center, New York, USA; Department of Pediatrics, Division of Critical Care and Hospital Medicine, Columbia University Irving Medical Center, New York-Presbyterian Morgan Stanley Children's Hospital of New York, New York, NY, USA.
⁶ Department of Child and Adolescent Psychiatry, Jerusalem Mental Health Center, Eitanim Psychiatric Hospital, Israel.
⁷ Department of Pathology and Cell Biology, Columbia University, New York, NY, USA; New York Genome Center, New York, NY, USA.
⁸ Department of Child and Adolescent Psychiatry, Jerusalem Mental Health Center, Eitanim Psychiatric Hospital, Israel; Hadassah-Hebrew University School of Medicine, Jerusalem, Israel.

PMID: 36645932
DOI: 10.1016/j.schres.2022.12.033

Abstract

Childhood-onset schizophrenia (COS) is a rare form of schizophrenia with an onset prior to 13 years of age. Although genetic factors play a role in COS etiology, only a few causal variants have been reported to date. This study presents a diagnostic exome sequencing (ES) in 37 Israeli Jewish families with a proband diagnosed with COS. By implementing a trio/duo ES approach and applying a well-established diagnostic pipeline, we detected clinically significant variants in 7 probands (19 %). These single nucleotide variants and indels were mostly inherited. The implicated genes were ANKRD11, GRIA2, CHD2, CLCN3, CLTC, IGF1R and MICU1. In a secondary analysis that compared COS patients to 4721 healthy controls, we observed that patients had a significant enrichment of rare loss of function (LoF) variants in LoF intolerant genes associated with developmental diseases. Taken together, ES could be considered as a valuable tool in the genetic workup for COS patients.

Keywords: Childhood onset schizophrenia; Diagnostic yield; Whole exome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Child
Exome Sequencing
Family
Genetic Predisposition to Disease
Humans
Phenotype
Schizophrenia* / genetics
Schizophrenia, Childhood*