A rare missense variant in Bruton’s tyrosine kinase is associated with bipolar disorder accompanied by psychosis

INTRODUCTION: Bipolar disorder is a mental disorder associated with extreme mood shifts. Psychosis (hallucinations, delusions, and thought disorder) can also co-occur in some patients. Although highly heritable, the genetic etiology of bipolar disorder remains unclear. METHODS: We visited outpatient departments of mental hospitals and recruited all members of a consanguineous family in which multiple siblings had psychosis. Clinical assessments using standardized rating tools were administered. Whole-exome sequencing was performed for all participants. RESULTS: Three male siblings were identified to have bipolar disorder with psychosis, while their sister was affected with bipolar disorder without psychosis. Other relatives were unaffected. Analysis of exome data identified six variants segregating with psychosis. Only one hemizygous variant, Bruton's tyrosine kinase (BTK) c.410A>G, p.(Asp137Gly), was predicted deleterious. The variant was rare in all publicly available databases (gnomAD allele frequency = 0.00001094) and was absent from the DNA of at least 400 unrelated ethnically matched controls. The amino acid affected by this variant was conserved among orthologs. The mutated BTK p.Gly137 residue was predicted to lack the interacting bond with p.Ser136. DISCUSSION: Most reported BTK variants are known to cause agammaglobulinemia. A de-novo variant in BTK p.(Arg255Gln) was previously associated with schizophrenia in one female patient. Multigenic deletions, including BTK, can cause deafness-dystonia-optic neuropathy syndrome, sometimes accompanied by psychosis. Taken together, these studies indicate that BTK may have a role in some mental disorders that needs to be investigated further. Use of animal models may elucidate any BTK function in the brain.