272. Detection of an ultra-rare missense mutation (E263G) in the DRD5 gene segregating with multiple psychiatric diagnoses in a family

Abstract

Abstract Background Genetic variants play a critical role in the pathogenesis of psychiatric disorders. These include common variants with small effects and rare variants with significant clinical impact. Rare variants may arise de novo in patients or be transmitted within families according to Mendelian inheritance patterns. The combination of next-generation sequencing (NGS) technologies and family-based studies provides an opportunity to identify rare variants associated with psychiatric disorders. In our molecular genetics study series on psychiatric disorders, we recruited a nuclear family with three children. The father was diagnosed with delusional disorder in his fifties, while the mother had no psychiatric history. Among the children, the son and one daughter were diagnosed with schizophrenia in their twenties, and the other daughter was diagnosed with bipolar II disorder in her twenties. Aims & Objectives The aim of this study was to identify genetic variants that may underlie the psychiatric conditions observed in this family and to explore their potential pathogenic mechanisms through bioinformatic analysis. Method We performed whole-genome sequencing (WGS) for all family members and conducted segregation analysis to identify variants associated with psychiatric disorders. Candidate variants were validated by Sanger sequencing. Bioinformatic analysis and literature review were carried out to assess the pathogenicity of the identified variants. Results Assuming a dominant mode of inheritance, we identified an A-to-G substitution at nucleotide position 9,782,817 on chromosome 4 (GRCh38.p14) that segregated with psychiatric conditions in this family. The authenticity of this variant was confirmed by repeated PCR and Sanger sequencing. This substitution occurred at cDNA position 788 of the dopamine receptor D5 gene (DRD5), resulting in an amino acid change from glutamic acid to glycine at position 263 (E263G). The variant is catalogued as rs752776884 in the SNP database with an extremely low global frequency (<0.00002). However, in the Taiwan BioBank, the allele frequency was reported as 0.0003. Functional prediction tools indicated potential pathogenicity: PolyPhen-2 classified the variant as “probably damaging” with a score of 1.000, while SIFT predicted it to be deleterious with a score of 0.01. No phenotype has yet been reported for this variant in the ClinVar database. Discussion & Conclusions Dopamine receptors are central to the pharmacotherapy of psychiatric disorders such as schizophrenia, major depression, bipolar disorder, and attention-deficit/hyperactivity disorder (ADHD). Association studies have linked common variants in dopamine receptor genes to various psychiatric conditions. However, only a few rare variants in these genes have been reported in relation to neuropsychiatric disorders. To our knowledge, E263G may represent the first DRD5 variant associated with psychiatric disorders. Although bioinformatic predictions suggest a deleterious effect, functional studies are required to clarify its biological consequences. To further investigate the role of DRD5 variants in psychiatric disorders, we are conducting a mutation screening study in a larger cohort of psychiatric patients.