Nallur Basappa Ramachandra

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with a strong genetic basis. Most genetic studies on ASD emphasize de novo mutations, while inherited rare variants remain understudied. We hypothesize that subtle, inherited ASD-related traits accumulate across generations and clinically manifest as ASD in offspring. To investigate this, we extracted inherited variations from trio-based Whole Exome Sequences (WES) of 23 simplex ASD families (accession number PRJNA1071313 and PRJNA1072259). Data was processed in BWA, GATK and VarScan. Variants were annotated, filtered for functional impact, and scored using a 'weighted scoring' approach based on intolerance to genetic alterations. Overall 751 'weighted-genes' with evolutionary and neuronal functions hosting deleterious inherited variations were functionally annotated for ASD-linked behaviours and comorbidities. We found 149 (20%) genes enriched for core ASD-behaviours like social-interaction and restrictive repetitive behaviours (RRB), 200 genes (26.6%) for associated-behaviours like hyperactivity, communication, intelligence and mood and 225 genes displayed neuronal-functions (p = 3.799E-20). Importantly, 62% of RRB genes displayed sensory functions and 71.43% of genes associated to social interaction deficits were also linked to seizures. Brain tissue expression analysis of all 751 genes revealed 95 prenatally and 195 postnatally upregulated genes were enriched with neurodevelopmental and neurotransmission functions, respectively; protein-protein-interactions suggested genes BUB1, HMGA2, HDAC2, KALRN, SORL1, IGF2, FASN, WFS1 as promising new-candidates for ASD. In our ASD cohort, inherited variations in genes regulating sensory function and neurodevelopment were also RRB producing genes- supporting a multigenic, subdued but additive genetic load being passed down from unrelated parents to their offsprings- promising an underexplored avenue for autism genetic research.

Genomic variations in GRIN2B have been linked to various neurodevelopmental disorders including autism spectrum disorders (ASD). Unraveling variations that modify the protein's structure and function is essential for the possible treatment of diseases. Here, we report in silico analysis of all the ASD-specific genomic variations found in GRIN2B and their roles in the pathogenesis of ASD. GRIN2B variations were collected through databases and text mining. These variants were predicted for pathogenicity scores using Varsome tools, and protein domains were predicted using InterPro. Mapping of these variants was done manually. A structural and functional analysis of GRIN2B was also conducted. The GRIN2B gene has 14 exons, and the transcripts expressed in the brain encode 1484 amino acids. Among the 379 ASD-specific variants collected, 54 had a pathogenicity score >60%. Of these, four variants, p.G459E, p.G459R, p.E657G, and p.G820R, showed pathogenic scores >80%. The homology modeling built for these variants indicated that the variants can disrupt the GRIN2B protein. The network analysis revealed that the GRIN2B protein is biologically connected. Among all the variations, 13 variations are key to consider for possible diagnostic and therapeutic approaches. Hence, the in silico analysis reveals that the most deleterious variations impair the function of GRIN2B, resulting in altered CNS development that contributes to ASD. Received: 23 April 2025 | Revised: 22 August 2025 | Accepted: 22 September 2025 Conflicts of Interest The authors declare that they have no conflicts of interest to this work. Data Availability Statement The data supporting the findings of this study are available upon request from the corresponding author. Author Contribution Statement Srushti S. Chavadapur: Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Writing – review & editing, Visualization. Nallur B. Ramachandra: Conceptualization, Methodology, Validation, Resources, Supervision, Project administration.

Background: Ventricular septal defect (VSD) is one of the common congenital heart malformations. Potential risk genes involved in the manifestation of VSD still need to be identified. Methods: The whole exome sequencing was performed on 24 congenital heart disease (CHD) subjects, 19 with VSD, two with VSD-associated atrial septal defects (ASD), and three with tetralogy of fallot (ToF). Besides, data mining using two CHD databases, a knowledgebase for nonsyndromic congenital heart disease-associated risk factors (CHD-RF-KB), and CHDbase and PubMed using medical subject headings were performed to prioritize the genes for further analysis in our study. The functional effects of variations of the selected genes were assessed using prediction tools to check the variant pathogenicity. The protein–protein network was established to identify the interactions among the proteins and their role in heart developmental pathways. Results: The whole exome sequencing analysis identified 628 genes with variants of minor allele frequency < 1%. In addition, the data mining yielded 50 genes, and of these, 34 genes were common in our 24 CHD subjects with new variations. Of the 34 genes, 11 genes, such as DLC1, MTRR, EVC, HOMEZ, EPRS, HOXB1, MTHFD1, MTHFR, NOS3, TRDN, and TBX18 recurrently occurred in more than 15 CHD subjects. The variant, c.524C > T in MTRR, recurrently occurred in nine CHD subjects, which resulted in the change of an amino acid from serine to leucine, suggesting a change in the functionality of the protein. Besides, four variations in GATA4 and one in TBX20 showed high pathogenicity scores. The protein–protein network showed high interactions among 26 transcription factors, and the TNNT2, MYL7, and ZFPM2 were the newly identified proteins in the network. Conclusions: The present study identified 37 potential risk genes through exome sequencing and interaction network analysis based on strong evidence from previously reported studies. From these genes, 176 variations were identified, of which 166 were newly reported from our samples, and 10 were previously reported, indicating that these are novel variants for the Indian population. Therefore, these genes and the variations can be a potential biomarker for creating the gene panel for CHD.

Human genetic diseases significantly burden the family and society. The key concern is understanding the diseases’ etiology, prevention, treatment, and management. Even though there are many analytical methods and tools available, overall knowledge of these has yet to reach needy families. Here, we systematically narrated the methods and techniques such as pedigree analysis, the pattern of inheritance, cytogenetic analysis, next-generation sequencing, drug discovery, personalized genomic medicine and artificial intelligence employed to diagnose and treat genetic diseases, particularly complex diseases. These techniques help unravel the high-risk causal genes and their variants, further enabling drug discovery research groups and leading to personalized, targeted therapeutic interventions.

Centrioles are subcellular organelles found at the cilia base with an evolutionarily conserved structure and a shock absorber-like function. In sperm, centrioles are found at the flagellum base and are essential for embryo development in basal animals. Yet, sperm centrioles have evolved diverse forms, sometimes acting like a transmission system, as in cattle, and sometimes becoming dispensable, as in house mice. How the essential sperm centriole evolved to become dispensable in some organisms is unclear. Here, we test the hypothesis that this transition occurred through a cascade of evolutionary changes to the proteins, structure, and function of sperm centrioles and was possibly driven by sperm competition. We found that the final steps in this cascade are associated with a change in the primary structure of the centriolar luminal protein FAM161A in rodents. This information provides the first insight into the molecular mechanisms and adaptive evolution underlying a major evolutionary transition within the internal structure of the mammalian sperm neck. Graphical Highlights: – Barrel-shaped centrioles are present in all rodents except members of the Muridae taxonomical family. – The FAM161A sequence evolved selectively in rodents and specifically in a murid subgroup. – The evolution of centriole degradation is correlated with the expression of a novel FAM161A isoform. – The ancestral centriole remodeling program involves elongation followed by redistribution. – The mouse centriole degradation program involves elongation followed by elimination.

ADAM33 has been linked to airway structural changes in patients with asthma, leading to airway hyperresponsiveness, narrowing, and ultimately poor treatment responsiveness. This study aimed to evaluate the genetic association of ADAM33 SNPs with asthma, disease severity, and treatment responsiveness to ICS+LABA in the South Indian population. In this case–control study (486 controls and 503 cases), we performed genotyping using MassArray for six SNPs of ADAM33, namely rs2280091, rs2787094, rs3918396, rs67044, rs2853209, and rs3918392. We studied the association with asthma and treatment responsiveness to ICS+LABA, using genotype, allele frequency distribution, and haplotype analysis. A significant clinical finding of the study was that certain patients in the disease severity group (moderate and mild) showed poor or no improvement after a three-month follow-up of regular ICS+LABA therapy. Of the studied ADAM33 SNPs, rs2853209 showed an association with asthma. The further analysis of asthma patients according to disease severity suggested an association between moderate disease and the minor allele “T” for rs2853209. The homozygous minor allele of SNP rs2787094 was found to be associated with poorer lung function and the least lung-function improvement after three months of ICS+LABA therapy. The haplotype analysis of six SNPs showed a significant association between the rs2853209 and rs3918396 blocks and asthma. ADAM33 gene polymorphism has clinical relevance in terms of disease association and response to treatment. SNP rs2853209 seemed most relevant to asthma, and SNP rs2787094 could be a genetic marker for predicting response to ICS+LABA therapy in the study population.