Title : Tautology of neurological diseases
Abstract:
Introduction:
We use “tautology” to denote the effect of mutations capable of producing diverse phenotypes, which shared genes, common pathways, gene interaction, pleiotropy, and epistasis could explain. We evaluated a large family in which six different neurological diseases: intellectual disability, dementia, epilepsy, myelomeningocele, cleft lip, cerebellar atrophy, neurodevelopmental and neurodegenerative, cosegregate and coined the term ‘tautological factor” underpinning its etiology.
Methods:
Clinical characterization of the phenotypes (medical, neuropsychological, imaging evaluation). Whole exome sequencing to several family members was applied. Forty individuals were analyzed, prioritizing variants according to ACMG guidelines, MAF<0.01, predictors of pathogenicity and phenotype-genotype relationship. Segregation analysis was performed. The identified genes and their functions were analyzed in search of common mechanisms, using databases and the GENEMANIA tool to determine a possible interaction network between them. Structural analysis of variants in the protein was performed.
Results:
Ten genes associated with the observed phenotypes were identified, carrying possible pathogenic mutations and forming a genetic interaction network. SPAG9 (p.Tyr914Ter), PCLO (p.Gln375_His5142delinsHisSerTrpSerCys), CNTN5 (p.Phe89AsnfsTer2), CCT7 (p.Arg126Cys), CHMP4C (p.Gly58Arg), VPS13B (p.Ala3716Thr), NOTCH3 (p.Asn1588His), ZIC5 (p.Ala238_Pro251del), MTHFR (p.Arg132His) and CTBP2 (p.Pro569Thr) and (p.Pro391_Leu392insAlaAlaProAlaCysGlyPro). Of these genes, mutations in the CTBP2 gene were identified in most affected patients. The CTBP2 gene is expressed early in neurodevelopment and is essential in the closure of the neural tube. There are few reports of mutations in this gene, which is a key point where many neuro-ontogeny pathways collide, crucial for regulating pluripotent cells during the development of the three germ layers.
Other of the identified genes are involved in functions such as interactions on the cell surface during neurodevelopment, synaptic vesicle trafficking, neural crest development, retrograde trafficking of lysosomes, autophagosome flow, formation of multivesicular bodies and repression of the transcription in neurodevelopment. Additionally, several of the genes we identified were found to form an interaction gene network closely related to the Wnt pathway that is of great importance in embryogenesis.
Conclusions:
A genetic interaction network that explains the possible tautology by combinatorial pleiotropy mechanisms is identified. CTBP2 interacts with various partners, resulting in variability in phenotype. A clinical follow-up and a complete genealogy allowed us to go beyond the mere description of the individual mutations of the family nuclei to understand the entire family as a possible alteration of shared biological pathways grouped by the CTBP2 transcription factor, which may have broader applicability to other complex genetic disorders. We identify common genetic factors in a family group, which are related to pathological mechanisms leading to different neurological diseases, which is the first report of a tautological genetic effect in neurological diseases.
