biostudies-literatureLi SEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD NIH HHSNHGRINHGRI NIH HHSNIH Common Fund841-862https://www.ebi.ac.uk/biostudies/studies/S-EPMC11080285biostudies-literatureUnknown111(5)RNA sequencing (RNA-seq) has recently been used in translational research settings to facilitate diagnoses of Mendelian disorders. A significant obstacle for clinical laboratories in adopting RNA-seq is the low or absent expression of a significant number of disease-associated genes/transcripts in clinically accessible samples. As this is especially problematic in neurological diseases, we developed a clinical diagnostic approach that enhanced the detection and evaluation of tissue-specific genes/transcripts through fibroblast-to-neuron cell transdifferentiation. The approach is designed specifically to suit clinical implementation, emphasizing simplicity, cost effectiveness, turnaround time, and reproducibility. For clinical validation, we generated induced neurons (iNeurons) from 71 indiAmerican journal of human geneticsThe clinical utility and diagnostic implementation of human subject cell transdifferentiation followed by RNA sequencing.PMC11080285R35 HG011311U01 HG007942P50 HD103555U01 HG007709Ketkar SUndiagnosed Diseases NetworkRosenfeld JANguyen MTTLiu PBurrage LCBajic ALee BLiu ZLalani SZhao SBacino CAHernandez PPChao HTNeeley MBNagamani SCKhoramnia AClark GDEmrick LCraigen WJWorley KCWeisz-Hubshman MPena MLi SPotocki LMachol KSheppard JEng CMSinson JCfalseThe clinical utility and diagnostic implementation of human subject cell transdifferentiation followed by RNA sequencing.RNA sequencing (RNA-seq) has recently been used in translational research settings to facilitate diagnoses of Mendelian disorders. A significant obstacle for clinical laboratories in adopting RNA-seq is the low or absent expression of a significant number of disease-associated genes/transcripts in clinically accessible samples. As this is especially problematic in neurological diseases, we developed a clinical diagnostic approach that enhanced the detection and evaluation of tissue-specific genes/transcripts through fibroblast-to-neuron cell transdifferentiation. The approach is designed specifically to suit clinical implementation, emphasizing simplicity, cost effectiveness, turnaround time, and reproducibility. For clinical validation, we generated induced neurons (iNeurons) from 71 indi2024-01-01T00:00:00Z2024 May2026-06-03T00:08:50.659Z2025-04-06T09:32:56.643ZS-EPMC110802853859381110.1016/j.ajhg.2024.03.007