Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder

Abstract

Objective: Bipolar disorder is a heritable chronic mental disorder that causes psychosocial impairment through depressive/manic episodes. Familial transmission of bipolar disorder does not follow simple Mendelian patterns of inheritance. The aim of this study was to describe a large family with 12 members affected by bipolar disorder. Whole-exome sequencing was performed for eight members, three of whom were diagnosed with bipolar disorder, and another reported as “borderline.” Methods: Whole-exome sequencing data allowed us to select variants that the affected members had in common, including and excluding the “borderline” individual with moderate anxiety and obsessive-compulsive traits. Results: The results favored designating certain genes as predispositional to bipolar disorder: a heterozygous missense variant in CLN6 resulted in a “borderline” phenotype that, if combined with a heterozygous missense variant in ZNF92 , is responsible for the more severe bipolar disorder phenotype. Both rare missense changes are predicted to disrupt protein function. Conclusions: Loss of both alleles in CLN6 causes neuronal ceroid lipofuscinosis, a severe progressive childhood neurological disorder. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder later in life if associated with additional variants in ZNF92 .

Weak evidence for a relation between bipolar disorder and heterozygous

“…We read with interest the article by Privitera et al 1 about a study of a five-generation family in which 12 members have bipolar disorder, eight of whom underwent whole exome sequencing to detect a common underlying genetic defect. Three patients who underwent whole exome sequencing had bipolar disorder and one was a “borderline” case.…”

“…Three patients who underwent whole exome sequencing had bipolar disorder and one was a “borderline” case. 1 It was found that a heterozygous missense variant in CLN6 was associated with the “borderline” phenotype and the combination of heterozygous missense variants in CLN6 and ZNF92 was associated with the bipolar phenotype. 1 The study is appealing but raises concerns that should be discussed.…”

“…We disagree with the conclusions that the “borderline” case was due to the heterozygous CLN6 variant and that the bipolar disorder was due to the combination of the heterozygous ZNF92 variant and the heterozygous CLN6 variant. 1 No studies were conducted to confirm that either the CLN6 or ZNF92 gene products were dysfunctional. Furthermore, previous studies have shown that heterozygous variants in either gene are not pathogenic.…”