Introduction. Bipolar Disorder (BD) is an heritable chronic mental disorder causing psychosocial impairment, affecting patients with depressive/manic episodes. The familial transmission of BD does not follow any of the simple Mendelian patterns of inheritance, demonstrating the involvement of multiple susceptibility genes. Materials and Method. Whole Exome Sequencing (WES) was performed in eight subjects of a large family counting twelve BD affected people. We selected variants in common between the affected subjects, once including and once excluding a “borderline” subject with moderate anxiety and traits of obsessive- compulsive disorder.  Results. Results were in favour of a Digenic model of transmission, with a heterozygous missense variant in CLN6 resulting in a “borderline” phenotype that if combined with a heterozygous missense variant in ZNF92 is responsible for the more severe BD phenotype. Both rare missense changes are predicted to disrupt the protein function. Conclusions. Loss of both alleles in CLN6 causes Neuronal Ceroid Lipofuscinosis, a severe progressive neurological disorder of childhood. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder late in life. Additional variants, such as that in ZNF92 reported here, may further worsen the phenotype in a setting of digenic disorder. Further investigation on a larger cohort should be performed in order to better characterize the contribution of each gene.

Trusso, M.A. (2022). THE GENETICS OF BIPOLAR DISORDER AND THE ROLE OF HETEROZYGOSITY FOR NEURONAL CEROID LIPOFUSCINOSIS.

THE GENETICS OF BIPOLAR DISORDER AND THE ROLE OF HETEROZYGOSITY FOR NEURONAL CEROID LIPOFUSCINOSIS

Trusso, Maria Allegra
2022

Abstract

Introduction. Bipolar Disorder (BD) is an heritable chronic mental disorder causing psychosocial impairment, affecting patients with depressive/manic episodes. The familial transmission of BD does not follow any of the simple Mendelian patterns of inheritance, demonstrating the involvement of multiple susceptibility genes. Materials and Method. Whole Exome Sequencing (WES) was performed in eight subjects of a large family counting twelve BD affected people. We selected variants in common between the affected subjects, once including and once excluding a “borderline” subject with moderate anxiety and traits of obsessive- compulsive disorder.  Results. Results were in favour of a Digenic model of transmission, with a heterozygous missense variant in CLN6 resulting in a “borderline” phenotype that if combined with a heterozygous missense variant in ZNF92 is responsible for the more severe BD phenotype. Both rare missense changes are predicted to disrupt the protein function. Conclusions. Loss of both alleles in CLN6 causes Neuronal Ceroid Lipofuscinosis, a severe progressive neurological disorder of childhood. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder late in life. Additional variants, such as that in ZNF92 reported here, may further worsen the phenotype in a setting of digenic disorder. Further investigation on a larger cohort should be performed in order to better characterize the contribution of each gene.
Trusso, M.A. (2022). THE GENETICS OF BIPOLAR DISORDER AND THE ROLE OF HETEROZYGOSITY FOR NEURONAL CEROID LIPOFUSCINOSIS.
Trusso, Maria Allegra
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/1214195