The 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 c...

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Published in:American journal of human genetics Vol. 111; no. 5; p. 841
Main Authors: Li, Shenglan, Zhao, Sen, Sinson, Jefferson C, Bajic, Aleksandar, Rosenfeld, Jill A, Neeley, Matthew B, Pena, Mezthly, Worley, Kim C, Burrage, Lindsay C, Weisz-Hubshman, Monika, Ketkar, Shamika, Craigen, William J, Clark, Gary D, Lalani, Seema, Bacino, Carlos A, Machol, Keren, Chao, Hsiao-Tuan, Potocki, Lorraine, Emrick, Lisa, Sheppard, Jennifer, Nguyen, My T T, Khoramnia, Anahita, Hernandez, Paula Patricia, Nagamani, Sandesh Cs, Liu, Zhandong, Eng, Christine M, Lee, Brendan, Liu, Pengfei
Format: Journal Article
Language:English
Published: United States 02.05.2024
Subjects:
Cell Transdifferentiation - genetics
Female
Fibroblasts - cytology
Fibroblasts - metabolism
Humans
Male
Nervous System Diseases - diagnosis
Nervous System Diseases - genetics
Neurons - cytology
Neurons - metabolism
Reproducibility of Results
RNA-Seq - methods
Sequence Analysis, RNA - methods
Transcriptome
RNA sequencing
clinically accessible tissue
fibroblast
RNA-seq
transcriptome
transdifferentiation
genetic diagnosis
induced neuron
isoform
neurological disorder
ISSN:1537-6605, 1537-6605
Online Access:Get more information
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Summary: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 individuals with primary neurological phenotypes recruited to the Undiagnosed Diseases Network. The overall diagnostic yield was 25.4%. Over a quarter of the diagnostic findings benefited from transdifferentiation and could not be achieved by fibroblast RNA-seq alone. This iNeuron transcriptomic approach can be effectively integrated into diagnostic whole-transcriptome evaluation of individuals with genetic disorders.
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ISSN:1537-6605
1537-6605
DOI:10.1016/j.ajhg.2024.03.007