Bringing science to bedside for physicians

July 16, 2018 0 By CH Unnikrishnan

Emerging neuro-genetic architecture can enable better understanding of disease networks and possible improvement of patient care
Dr Rajanikanth Vangala

There have been several scientific and technological advances which are revolutionizing the understanding of mental and neurological diseases. These discoveries have a direct impact on the diagnosis and treatment protocols and clinical management of patients. However, there are significant gaps in translating these complex data into clinically relevant tools for physicians, healthcare providers and patients/families. The most important first step in bridging the gap and unlocking the potential of genomic tests for neurological, neurodevelopmental and other diseases is to bring the science to the bedside.

With the advent and validation of whole genome sequencing by Next Generation Sequencing and other genomic technologies in clinical diagnostics, clinicians are now capable of identifying specific disorders more clearly. The use of genomic technologies almost becomes a mandatory adaptation, especially in clinically, biologically and phenotypically heterogeneous neurological diseases. These innovations allow us to locate previously untraceable genetic variations associated with these disorders. The emerging neuro-genetic architecture or wiring can enable a better understanding of disease networks and a possible improvement in patient care.

Using the gene interaction networks and their overlap with pathogenic genetic variations, association with disease burden as well as statistical, clinical and biological factors, scientists are able to prioritize biomarkers. These validated biomarkers could improve the diagnosis and management of neurodevelopmental diseases such as autism, intellectual disability and schizophrenia. Glessner JT et al and Jensen M et al (Genome Medicine) have performed a large-scale meta-analysis of genome wide studies and discovered copy number variation (CNV) of DOC8/ KANK1 as a common shared genetic etiology between five diseases: autism spectrum disease, bipolar disease, attention deficit disorder, depression and schizophrenia. This also shows that CNV map could help in elucidating common functional pathways in clinically heterogeneous groups of patients, thus providing guidance for interpreting the potential diagnosis.

Multiple approaches are being implemented in understanding and using the wiring or genetic architecture in neurological diseases, of which neuroimaging-genomics is a fast upcoming field. With methodological and rigorous clinical studies, this field can have a significant impact on how risk-variants are affecting the functioning of the brain. Large-scale genetic studies (Genome Wide Association Studies – GWAS) like Enhancing Neuroimaging Genetics through Meta- Analysis (ENIGMA) and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) have data from almost 21,151 subjects. These global consortia based studies have truly built collaborations between scientists and clinicians, resulting in high quality research. The studies of brain images for association between common variants and volumes of important regions of brain like hippocampus detected not only the well-known ApoE marker, but also that carriers of HMGA2 allele, averaged 9cm3 larger brain volumes per allele. Furthermore, association studies of voxels (unit measurement of 3 dimensional data points of brain image) with GWAS or v-GWAS by Stein et al (Neuroimage journal), suggested that 31622 voxels were associated with 448,293 single nucleotide polymorphisms for brain volume phenotype in Alzheimer’s disease.

Therefore, emerging collective interdisciplinary and integrative efforts will lead to uncovering of important genomics variations influencing the disease initiation and progression, thus helping us in improving our diagnosis, patient risk stratification and clinical outcomes.

Gene variants linked to synesthesia identified

European researchers have identified more than three dozen genetic variants that could be involved in the biology of synesthesia.

Scientists from the Max Planck Institute for Psycholinguistics and the University of Cambridge analysed the DNA of three families in which multiple members, across several different generations, have the genetic disorder where they experience colour when listening to sounds.

The team identified 37 genes that harboured variants predictive of whether a person had synesthesia or not. No variants were shared across families.

Gene ontology analyses highlighted six genes—COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2— associated with axonogenesis and expressed during early childhood when synesthetic associations are formed, the researchers noted in their study, are related to neuronal development.

These genes are all expressed during early childhood, the time when “synesthetic associations” are formed, the authors wrote in their paper published in PNAS.

Variants preferentially fell within genes tied to the processes of axonogenesis and cell migration, forming a common theme across families, one that aligns with contemporary theories about the neurodevelopmental origins of synesthesia. These results suggest that molecular approaches can help increase understanding of the neurobiology of our sensory experiences, beyond pathology.

Over 130 years after the first reports of familial synesthesia, these results provide a molecular starting point for studies addressing the origins of healthy variation in sensory integration, according to the researchers.

Three families with sound–colour (auditory–visual) synesthesia, without a history of drug use or any neurological, ophthalmological, or psychiatric disorder, were identified from the Cambridge Synaesthesia Research Group database.