Biomedical subjects

Pankaj B Agrawal

Publications and source records attributed to Pankaj B Agrawal.

3 recordsLinked to original sources

PubMed2026

Abnormal ClC-3/TMEM9-mediated endosomal ion transport in CLCN3-associated neurodevelopmental disease.

Endolysosomal abnormalities are particularly detrimental to the nervous system and have been implicated in neuropsychiatric disorders. Key regulators of the lysosomal and endosomal luminal ion homeostasis are CLC chloride/proton exchangers. We report 15 individuals carrying variants in CLCN3, encoding a ubiquitous endosomal 2Cl-/H+ exchanger, and provide updated clinical information for 5 previously reported individuals. Subjects displayed a broad spectrum of neuropsychiatric symptoms, including developmental delay, intellectual disability, and epilepsy. To reveal the pathogenic mechanism, we investigated ClC-3 variants-mediated ion transport and its regulation by the recently discovered inhibitory beta subunit TMEM9. 12/20 missense variants exhibited altered properties and fell into two classes: those affecting the region binding inhibitory TMEM9 carboxy-termini, and those that broaden the voltage range over which ClC-3 conducts ions. Surprisingly, the latter variants also attenuated TMEM9-mediated inhibition. Both classes produced a toxic gain-of-function, as evident from endolysosomal vacuolization by mutant ClC-3/TMEM9 overexpression. Our results expand the genetic and clinical spectrum of CLCN3-related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9.

Chloride Channels↗

PubMed2025

Implementing customized genomic sequencing reports to empower providers in safety-net neonatal intensive care units.

PURPOSE: Through our implementation study providing rapid genomic sequencing (rGS) in safety-net neonatal intensive care units (NICUs), we investigated the feasibility and perceived usefulness of customized "clinical interpretive reports" (CIRs) to help neonatal providers with interpreting, disclosing, and managing care based on rGS results. METHODS: Enrolled infants received rGS through a clinically accredited vendor. We developed 5 CIR types to provide customized interpretation of rGS results and link results to clinical management considerations, research opportunities, and resources. We developed workflows to triage, create, and deliver CIRs within 3 business days. Providers received the vendor reports and CIRs, disclosed results, and completed post-disclosure surveys. We analyzed summary statistics for the first 100 cases. RESULTS: We delivered 97 of 100 CIRs (97%) within our goal time frame (average 1.3 days) and provided clinical management recommendations in 40 of 100 (40%). Neonatal providers completed the post-disclosure surveys for 86 of 100 disclosures (86%). Most reported using the CIR before disclosure (80/86, 93%) and found it helpful at providing useful information beyond the vendor report (79/80, 99%). CONCLUSION: It is feasible and useful to develop customized rGS reports to assist non-genetics providers in safety-net NICU settings. Similar approaches may hold promise for equitably advancing genomic care in non-NICU settings.

Humans↗

PubMed2025

Unique signatures of highly constrained genes across publicly available genomic databases.

PURPOSE: Publicly available genomic databases are critical in understanding human genetic variation. They also provide unique insights into patterns of genetic constraints and their relationship with human disease. METHODS: We utilized one of the largest publicly available databases, Genome Aggregate Database, to determine genes that are highly constrained for only loss-of-function, only missense, and both loss-of-function/missense variants. We identified their unique signatures and explored their causal relationship with human diseases. Those genes were also evaluated for chromosomal location, tissue-level expression, Gene Ontology analysis, and gene family categorization using multiple publicly available databases. RESULTS: We identified unique patterns of inheritance, protein size, and enrichment in distinct molecular pathways for those constrained genes associated with human disease. In addition, we identified genes that are currently not known to cause human disease, which may be excellent gene discovery candidates. CONCLUSION: We elucidate biological pathways of highly constrained genes that expand our understanding of critical cellular proteins. The findings can also advance research in rare diseases.

Humans↗