RESUMO

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.

RESUMO

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.

Assuntos

Transtorno Bipolar , Lipofuscinoses Ceroides Neuronais , Humanos , Proteínas de Membrana/genética , Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/genética

RESUMO

Abstract Introduction: Neuronal ceroid lipofuscinosis (NCLs) is an autosomal recessive neurodegenerative disorders group. We report the first case in Colombia involving a new genetically confirmed variant of a homozygous CLN6 mutation. Case report: 12-year-old male, history of blood parents and average growth until 5 years of age. At this age began focal crises, progressive regression of neurodevelopment, severe cognitive deficit, and swallowing disorder that led to gastrostomy. Clinical exome + CNVs + mitochondrial DNA genetic study identified variant NM_017882.3 (CLN6): c. 22C>T, p. (Gln8*) in homozygous, deleterious. Late-onset infantile neuronal ceroid lipofuscinosis was diagnosed. Discussion: Mutations in the CLN6 gene are associated with late-onset infantile lipofuscinosis of autosomal recessive inheritance. This variant has not been previously described in the medical literature nor is it listed in the population databases, which indicates that it is extremely rare. The treatment focuses on the control of seizures, sleep disturbances, extrapyramidal symptoms, behavioral disorders, anxiety, and psychosis. Conclusion: To date, this variant of the CLN6 gene has not been reported in the world. There are currently no etiological or disease-specific therapeutic approaches. The use of exome/whole genome sequencing can be very useful for etiological diagnosis and differential diagnosis. An early diagnosis opens the door to future care and treatment.