Genotype-phenotype studies in neurosensory diseases: a blood based personalized disease modeling platform for neurosensory hearing loss
Abstract
BackgroundGenetic testing has substantially improved the diagnosis of sensorineural hearing loss (SNHL); however, genomic findings alone often fail to explain patient-specific functional phenotypes, particularly in cases involving variants of uncertain significance (VUSs) or genetically unresolved disease. We evaluated whether an in-house Plasma-Induced Transcriptomic and epi-Transcriptomic Reprogramming (PITTRep) platform could bridge this gap by providing a functional, patient-specific model of disease biology.MethodsFollowing validation of PITTRep as a reproducible plasma-driven transdifferentiation platform using autologous plasma and peripheral blood cells, seven clinically distinct SNHL cases were investigated, comprising hereditary POU3F4-associated hearing loss, MYO7A-associated congenital SNHL, three GJB2-associated cases representing truncating and missense variants with distinct clinical phenotypes, FGF3-associated congenital hearing loss, and acquired ototoxic SNHL without detectable pathogenic variants. Patient-derived blood cultures were evaluated using immunofluorescence, genomic and regulatory analyses, and phenotypic assessment of adipocyte-to-neurogenic transdifferentiation (ATN).ResultsDespite distinct clinical presentations and genetic backgrounds, all seven cases demonstrated a reproducible disruption of the ATN continuum. Healthy controls consistently underwent adipogenic niche formation followed by neuronal differentiation with organized neurite networks, whereas patient-derived cultures exhibited arrested adipogenic remodelling, compact cellular aggregates, reduced neuronal marker expression, and impaired neurite development. In the MYO7A case, functional remodelling occurred predominantly through untranslated regulatory regions, developmental transcription factors, long non-coding RNAs, and chromosome 11-associated sensory-developmental pathways while the coding variant remained unchanged. The ototoxic case revealed similar impairment of ATN despite the absence of pathogenic genomic variants, demonstrating persistent neuroinflammatory activation and defective neurogenic plasticity independent of inherited mutations. In contrast, POU3F4-associated cultures exhibited partial functional rescue following artificial endolymph supplementation, highlighting the influence of microenvironmental modulation.ConclusionPITTRep reproducibly models patient-specific functional phenotypes across hereditary and acquired SNHL and identifies disruption of the adipocyte-to-neurogenic transdifferentiation continuum as a common systems-level feature of auditory dysfunction. These findings demonstrate the potential of PITTRep to complement genomic diagnostics by functionally interpreting disease-associated variants, stratifying genomically unresolved cases, and providing a scalable platform for precision diagnostics and regenerative medicine.
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BibTeX
@article{arora2026genotypephenotype,
title = {{Genotype-phenotype studies in neurosensory diseases: a blood based personalized disease modeling platform for neurosensory hearing loss}},
author = {Rhythm Arora and Naresh Kumar Panda and Ramandeep Singh Virk and Jaimanti Bakshi and Mohit Dogra and Shubham Kaushik and Maryada Sharma},
journal = {Frontiers in Molecular Biosciences},
year = {2026},
month = nov,
doi = {10.3389/fmolb.2026.1922984},
url = {https://www.frontiersin.org/articles/10.3389/fmolb.2026.1922984},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Genotype-phenotype studies in neurosensory diseases: a blood based personalized disease modeling platform for neurosensory hearing loss
AU - Rhythm Arora
AU - Naresh Kumar Panda
AU - Ramandeep Singh Virk
AU - Jaimanti Bakshi
AU - Mohit Dogra
AU - Shubham Kaushik
AU - Maryada Sharma
PY - 2026
DA - 2026/11/03
JO - Frontiers in Molecular Biosciences
DO - 10.3389/fmolb.2026.1922984
UR - https://www.frontiersin.org/articles/10.3389/fmolb.2026.1922984
AB - BackgroundGenetic testing has substantially improved the diagnosis of sensorineural hearing loss (SNHL); however, genomic findings alone often fail to explain patient-specific functional phenotypes, particularly in cases involving variants of uncertain significance (VUSs) or genetically unresolved disease. We evaluated whether an in-house Plasma-Induced Transcriptomic and epi-Transcriptomic Reprogramming (PITTRep) platform could bridge this gap by providing a functional, patient-specific model of disease biology.MethodsFollowing validation of PITTRep as a reproducible plasma-driven transdifferentiation platform using autologous plasma and peripheral blood cells, seven clinically distinct SNHL cases were investigated, comprising hereditary POU3F4-associated hearing loss, MYO7A-associated congenital SNHL, three GJB2-associated cases representing truncating and missense variants with distinct clinical phenotypes, FGF3-associated congenital hearing loss, and acquired ototoxic SNHL without detectable pathogenic variants. Patient-derived blood cultures were evaluated using immunofluorescence, genomic and regulatory analyses, and phenotypic assessment of adipocyte-to-neurogenic transdifferentiation (ATN).ResultsDespite distinct clinical presentations and genetic backgrounds, all seven cases demonstrated a reproducible disruption of the ATN continuum. Healthy controls consistently underwent adipogenic niche formation followed by neuronal differentiation with organized neurite networks, whereas patient-derived cultures exhibited arrested adipogenic remodelling, compact cellular aggregates, reduced neuronal marker expression, and impaired neurite development. In the MYO7A case, functional remodelling occurred predominantly through untranslated regulatory regions, developmental transcription factors, long non-coding RNAs, and chromosome 11-associated sensory-developmental pathways while the coding variant remained unchanged. The ototoxic case revealed similar impairment of ATN despite the absence of pathogenic genomic variants, demonstrating persistent neuroinflammatory activation and defective neurogenic plasticity independent of inherited mutations. In contrast, POU3F4-associated cultures exhibited partial functional rescue following artificial endolymph supplementation, highlighting the influence of microenvironmental modulation.ConclusionPITTRep reproducibly models patient-specific functional phenotypes across hereditary and acquired SNHL and identifies disruption of the adipocyte-to-neurogenic transdifferentiation continuum as a common systems-level feature of auditory dysfunction. These findings demonstrate the potential of PITTRep to complement genomic diagnostics by functionally interpreting disease-associated variants, stratifying genomically unresolved cases, and providing a scalable platform for precision diagnostics and regenerative medicine.
SN - 2296-889X
ER -