Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder

Abstract

Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

Autism spectrum disorder and schizophrenia: An updated conceptual review

“…These include 1q21.1 deletion and duplication (Bernier et al, 2016), 7q11.23 duplication (Jennifer Gladys Mulle et al, 2014; Sanders et al, 2011), 17q12 deletion (Moreno‐De‐Luca et al, 2010), 15q13.3 deletion (Lowther et al, 2015), 2p16.3 deletion (Viñas‐Jornet et al, 2014), and 16p21.32 duplication (Larson et al, 2018). Recent and ongoing work that makes comparisons across disorders in patients with these and other CNVs has begun to identify shared biological pathways common to autism and schizophrenia, including those that involve genomic integrity, lipid metabolism, protein phosphorylation, and the oxidative stress response (Kato et al, 2020; Kushima et al, 2018).…”

Autosomal recessive SLC30A9 variants in a Proband with a Cerebro-Renal Syndrome and No Parental Consanguinity

“…This duplication includes KDM4C, which encodes a lysine demethylase that has been previously implicated in the development and/or progression of certain cancers such as esophageal squamous cell carcinoma (Yang et al 2000). A recent analysis of a Japanese sample set found significant associations between CNVs involving KDM4C and neuropsychiatric disorders such as schizophrenia and autism spectrum disorder (Kato et al 2020). However, given the paternal inheritance of this CNV in an unaffected father, it seems likely that this CNV is not contributing to the phenotype described herein.…”

Autosomal recessive SLC30A9 Mutations in a Proband with a Cerebro-Renal Syndrome and No Parental Consanguinity

“…Challenges with obtaining paternal DNA samples provide further uncertainty regarding the significance of a 9p24.1-p24.1 interstitial duplication (which contains KDM4C) found in the proband. While the variant was not present in the mother, paternal inheritance cannot be ruled in or out; however, the proband's clinical presentation aligns more with the phenotype seen in the Bedouin family, rather than KDM4C-associated disorders such as schizophrenia and autism (Kato et al 2020). Furthermore, it is also generally accepted that genome duplications tend to be better tolerated than deletions (Brewer et al 1999).…”