A linkage and exome study implicates rare variants of KANK4 and CAP2 in bipolar disorder in a multiplex family

Abstract

Objectives Bipolar disorder (BD) is a neuropsychiatric disorder with a complex pattern of inheritance. Although many genetic studies have been conducted on BD, its genetic correlates remain uncertain. This study was aimed at identifying the genetic underpinnings of the disorder in an Indian family, which has been under comprehensive clinical evaluation and follow‐up for over 12 years. Methods We analysed a four‐generation family with several of its members diagnosed for BD employing a combination of genetic linkage and exome analysis. Results We obtained suggestive LOD score for a chromosome 1 and a chromosome 6 marker (D1S410; LOD = 3.01, Ө = 0; and D6S289; LOD = 1.58, Ө = 0). Manual haplotyping of the regions encompassing these two markers helped delimit a critical genomic interval of 32.44 Mb (D1S2700‐D1S435; chromosome 1p31.1‐13.2) and another of 10.34 Mb (D6S470‐D6S422; chromosome 6p22.3‐22.2). We examined the exomic sequences corresponding to these two intervals and found rare variants, NM_181712.4: c.2461G>T (p.Asp821Tyr) in KANK4 at 1p31.1‐13.2; and NM_006366:c.‐93G>A, in the 5' UTR of CAP2 at 6p22.3‐22.2. Conclusions Our studysuggests involvement of KANK4 or CAP2 or both in BD in this family. Further analysis of these two genes in BD patients and functional evaluation of the allelic variants identified are suggested.

Genomic and neuroimaging approaches to bipolar disorder

“…The authors suggested that KANK4 and CAP2, which are also expressed in the brain, alone or together are involved in bipolar disorder in the investigated family. 71 In their 2020 publication, Forstner et al described their findings from WES of 81 patients with bipolar disorder from 23 Spanish and four German multigenerational, multiply affected families (three members from each family). The analysis considered only variants shared by all three investigated family members.…”

“…The authors suggested that KANK4 and CAP2 , which are also expressed in the brain, alone or together are involved in bipolar disorder in the investigated family. 71 …”

Exome sequencing of Japanese schizophrenia multiplex families supports the involvement of calcium ion channels

“…Therefore, it is also essential to investigate variants shared among patients in order to elucidate the association between transmitted variants and SCZ. Indeed, several sequencing studies have focused on shared variants associated with bipolar disorder [ 18 , 19 ] and autism spectrum disorder [ 20 , 21 ] in patients in the same multiplex family. A previous WES study of SCZ multiplex families demonstrated that several loci could potentially affect synaptic plasticity and neurocognitive performance [ 22 ] and that variants in genes related to metabotropic glutamate receptor 5 (mGlu5) are more common in affected family members [ 23 ].…”