Mutations associated with neuropsychiatric conditions contributing to psychiatric dysfunction

PRAGYA SANTRA, AMITY UNIVERSITY KOLKATA

Mutation and copy number variants (CNV) are a great risk-factor for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD). But its association with functional brain connectivity (FC) is unknown. FC-changes may not surely represent an intermediate brain phenotype but a secondary impact of psychiatric illnesses. Individuals with a high frequency of deletion and duplication of gene exhibit worse cognitive and behavioural status. Increase genetic variation and CNV burden results in neurodevelopmental and psychiatric disorder. 

CNVs at the genomic loci 16p11.2 and 22q11.2 are more prone to genetic variations. Precisely, deletion of 37 and 24 genes in the 22q11.2 and 16p11.2 respectively resulted in changing expressions. They grant to high risk for ASD. Gene dosage resulted in structural alterations of the cingulate, insula, precuneus, and superior temporal gyrus. Other large size mutations confer genetic risks connected to brain endophenotypes representing intrinsic low-frequency synchronization to neuroanatomical arenas. 

43.2% deletion of 22q11.2 targets to dysconnectivity of thalamic-hippocampal circuitry, predictive of prodromal psychotic symptoms. The connections among anterior and lateral DMN, limbic network temporal pole, the ventral anterior insula and peri-insular sulcus, the amygdala-hippocampal complex, the dorsal anterior cingulate cortex, and pregenual anterior cingulate cortex are altered drastically. Besides duplication of 22q11.2 leads to over-connectivity in the posterior medial and lateral visual network, cerebellum I-V and lateral fusiform gyrus.

24.2% deletion of 16p11.2 focuses on alteration of connectivity among frontoparietal, somatomotor, ventral attention and basal ganglia networks. SZ individuals direct on increased similarities of thalamic-sensorimotor dysconnectivity across CNVs and psychiatric conditions. But for the duplication of 16p11.2, none of the patients survives. 

Individuals having autism shows greater similarity with 6-regional FC-signatures of 16p11.2 deletion and greater similarity with 6-region-level FC-signatures of the 22q11.2 deletion. 8 &6 out of the top 10 regions altered by 22q11.2 and 16p11.2 respectively alters psychiatric conditions. Among the idiopathic conditions due to the mutation, the connectivity alteration is maximum in SZ followed by autism and ADHD. Regional FC-signatures of gene dosage, in particular, those compromising the thalamus, somatomotor, posterior insula and cingulate showed marked coincidence with the complex architecture of idiopathic ASD, SZ, autism but not ADHD. 

Individuals with all over-connectivities and under-connectivities witness sensory-motor, auditory and visual disbalances with psychiatric illness. The thought process and perseverance of situations vary in such patients. Auditory and visuals hallucinations, impairments in gestalt visual perception and discrimination of visual motion, disturbances in auditory and tactile discrimination are serious threats to the genetic mutations.

Apart from these studies, the mechanism of psychiatric control under genetic manifestation is still a miracle. Large-scale research on common psychiatric outcomes associated with genetic variants and FC-signatures are still in progress.

Also read: Bluetongue Disease: a viral disease

SOURCE

1. Mutations associated with neuropsychiatric conditions delineate functional brain connectivity dimensions contributing to autism and schizophrenia; Clara A. Moreau et al; 19 October 2020, Nature Communications, Volume: 11, Pg no.: 5272 doi:  https://doi.org/10.1038/s41467-020-18997-2 

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