Federici, G. & Soddu, S. Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers. J. Exp. Clin. Cancer Res 39, 46 (2020).

Article  Google Scholar 

Harrison, S. M. & Rehm, H. L. Is ‘likely pathogenic’ really 90% likely? Reclassification data in ClinVar. Genome Med 11, 72 (2019).

Article  Google Scholar 

Weston, K. P. et al. Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis. Nat. Commun. 12, 6809 (2021).

Article  Google Scholar 

Rehm, H. L. et al. ClinGen–the Clinical Genome Resource. N. Engl. J. Med 372, 2235–2242 (2015).

Article  Google Scholar 

Spielmann, M. & Kircher, M. Computational and experimental methods for classifying variants of unknown clinical significance. Cold Spring Harb. Mol. Case Stud 8, a006196 (2022).

Kremer, L. S. et al. Genetic diagnosis of Mendelian disorders via RNA sequencing. Nat. Commun. 8, 15824 (2017).

Article  Google Scholar 

Marwaha, S., Knowles, J. W. & Ashley, E. A. A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Med 14, 23 (2022).

Article  Google Scholar 

Alaimo, J. T. et al. Integrated analysis of metabolomic profiling and exome data supplements sequence variant interpretation, classification, and diagnosis. Genet Med 22, 1560–1566 (2020).

Article  Google Scholar 

Almontashiri, N. A. M. et al. Clinical Validation of Targeted and Untargeted Metabolomics Testing for Genetic Disorders: A 3 Year Comparative Study. Sci. Rep. 10, 9382 (2020).

Article  Google Scholar 

Adams, D. R. & Eng, C. M. Next-Generation Sequencing to Diagnose Suspected Genetic Disorders. N. Engl. J. Med 380, 201 (2019).

Google Scholar 

Fung, J. L. F. et al. A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis. NPJ Genom. Med 5, 37 (2020).

Article  Google Scholar 

Lionel, A. C. et al. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med 20, 435–443 (2018).

Article  Google Scholar 

Investigators, G. P. P. et al. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report. N. Engl. J. Med 385, 1868–1880 (2021).

Article  Google Scholar 

Cummings, B. B. et al. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci Transl Med 9, aal5209 (2017).

Gonorazky, H. D. et al. Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease. Am. J. Hum. Genet 104, 466–483 (2019).

Article  Google Scholar 

Fresard, L. et al. Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts. Nat. Med 25, 911–919 (2019).

Article  Google Scholar 

Lee, H. et al. Diagnostic utility of transcriptome sequencing for rare Mendelian diseases. Genet Med 22, 490–499 (2020).

Article  Google Scholar 

Murdock, D. R. et al. Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing. J Clin Invest 131, I141500 (2021).

Maddirevula, S. et al. Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics. Genome Biol. 21, 145 (2020).

Article  Google Scholar 

Wai, H. A. et al. Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance. Genet Med 22, 1005–1014 (2020).

Article  Google Scholar 

Yépez, V. A. et al. Clinical implementation of RNA sequencing for Mendelian disease diagnostics. Genome Med 14, 38 (2022).

Article  Google Scholar 

Yépez, V. A. et al. Detection of aberrant gene expression events in RNA sequencing data. Nat. Protoc. 16, 1276–1296 (2021).

Article  Google Scholar 

Zwemer, L. M. & Bianchi, D. W. The amniotic fluid transcriptome as a guide to understanding fetal disease. Cold Spring Harb. Perspect. Med. 5, a023101 (2015).

Liu, P. & Vossaert, L. Emerging technologies for prenatal diagnosis: The application of whole genome and RNA sequencing. Prenat. Diagn. 42, 686–696 (2022).

Article  Google Scholar 

Consortium, G. T. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).

Article  Google Scholar 

Park, H. J., Cho, H. Y. & Cha, D. H. The Amniotic Fluid Cell-Free Transcriptome Provides Novel Information about Fetal Development and Placental Cellular Dynamics. Int. J. Mol. Sci. 22, h52612 (2021).

Hui, L., Slonim, D. K., Wick, H. C., Johnson, K. L. & Bianchi, D. W. The amniotic fluid transcriptome: a source of novel information about human fetal development. Obstet. Gynecol. 119, 111–118 (2012).

Article  Google Scholar 

Sorber, L. et al. Circulating Cell-Free DNA and RNA Analysis as Liquid Biopsy: Optimal Centrifugation Protocol. Cancers (Basel) 11,40458 (2019).

Alfirevic, Z., Navaratnam, K. & Mujezinovic, F. Amniocentesis and chorionic villus sampling for prenatal diagnosis. Cochrane Database Syst. Rev. 9, CD003252 (2017).

Google Scholar 

Underwood, M. A., Gilbert, W. M. & Sherman, M. P. Amniotic fluid: not just fetal urine anymore. J. Perinatol. 25, 341–348 (2005).

Article  Google Scholar 

Hu, M. S. et al. Embryonic skin development and repair. Organogenesis 14, 46–63 (2018).

Article  Google Scholar 

Mahoney, M. G., Muller, E. J. & Koch, P. J. Desmosomes and desmosomal cadherin function in skin and heart diseases-advancements in basic and clinical research. Dermatol Res Pract 2010, 725647 (2010).

Nazzaro, V. [Normal development of human fetal skin]. G Ital. Dermatol Venereol. 124, 421–427 (1989).

Google Scholar 

Lord, J. et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 393, 747–757 (2019).

Article  Google Scholar 

Wright, C. F. et al. Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1133 families with developmental disorders. Genet Med 20, 1216–1223 (2018).

Article  Google Scholar 

Wright, C. F. et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet 385, 1305–1314 (2015).

Article  Google Scholar 

Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).

Article  Google Scholar 

Normand, E. A. et al. Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder. Genome Med 10, 74 (2018).

Article  Google Scholar 

Petrovski, S. et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet 393, 758–767 (2019).

Article  Google Scholar 

Chung, C. C. Y. et al. Rapid whole-exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs. Lancet Reg. Health West Pac. 1, 100001 (2020).

Article  Google Scholar 

Kingsmore, S. F. et al. A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants. Am. J. Hum. Genet 105, 719–733 (2019).

Article  Google Scholar 

Wells, C. et al. A case of mild CHARGE syndrome associated with a splice site mutation in CHD7. Eur. J. Med Genet 59, 195–197 (2016).

Article  Google Scholar 

Smirnov, D., Schlieben, L. D., Peymani, F., Berutti, R. & Prokisch, H. Guidelines for clinical interpretation of variant pathogenicity using RNA phenotypes. Hum. Mutat. 43, 1056–1070 (2022).

Article  Google Scholar 

Layman, W. S., Hurd, E. A. & Martin, D. M. Chromodomain proteins in development: lessons from CHARGE syndrome. Clin. Genet 78, 11–20 (2010).

Article  Google Scholar 

Meisner, J. K. & Martin, D. M. Congenital heart defects in CHARGE: The molecular role of CHD7 and effects on cardiac phenotype and clinical outcomes. Am. J. Med Genet C. Semin Med Genet 184, 81–89 (2020).

Article  Google Scholar 

Asad, Z. et al. Rescue of neural crest-derived phenotypes in a zebrafish CHARGE model by Sox10 downregulation. Hum. Mol. Genet 25, 3539–3554 (2016).

Article  Google Scholar 

Lettieri, A. et al. Semaphorin Regulation by the Chromatin Remodeler CHD7: An Emerging Genetic Interaction Shaping Neural Cells and Neural Crest in Development and Cancer. Front Cell Dev. Biol. 9, 638674 (2021).

Article  Google Scholar 

Feng, W. et al. The chromatin remodeler CHD7 regulates adult neurogenesis via activation of SoxC transcription factors. Cell Stem Cell 13, 62–72 (2013).

Article  Google Scholar 

Bajpai, R. et al. CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature 463, 958–962 (2010).

Article  Google Scholar 

Yan, S. et al. CHD7 regulates cardiovascular development through ATP-dependent and -independent activities. Proc. Natl Acad. Sci. USA 117, 28847–28858 (2020).

Article  Google Scholar 

An, H. et al. Functional mechanism and pathogenic potential of MYRF ICA domain mutations implicated in birth defects. Sci. Rep. 10, 814 (2020).

Article  Google Scholar 

Li, Z., Park, Y. & Marcotte, E. M. A Bacteriophage tailspike domain promotes self-cleavage of a human membrane-bound transcription factor, the myelin regulatory factor MYRF. PLoS Biol. 11, e1001624 (2013).

Article  Google Scholar 

Lee, K. S. et al. Mutational spectrum of type I collagen genes in Korean patients with osteogenesis imperfecta. Hum. Mutat. 27, 599 (2006).

Article  Google Scholar 

Odibo, A. O. 68-97 (John Wiley & Sons, Inc, 2015).

Enzensberger, C. et al. Fetal loss rate and associated risk factors after amniocentesis, chorionic villus sampling and fetal blood sampling. Ultraschall Med 33, E75–E79 (2012).

Article  Google Scholar 

Bournazos, A. M. et al. Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants. Genet Med 24, 130–145 (2022).

Article  Google Scholar 

Brnich, S. E. et al. Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework. Genome Med 12, 3 (2019).

Article  Google Scholar 

Pervolaraki, E., Dachtler, J., Anderson, R. A. & Holden, A. V. The developmental transcriptome of the human heart. Sci. Rep. 8, 15362 (2018).

Article  Google Scholar 

Ware, S. M. et al. The genetic architecture of pediatric cardiomyopathy. Am. J. Hum. Genet 109, 282–298 (2022).

Article  Google Scholar 

Loukogeorgakis, S. P. & De Coppi, P. Stem cells from amniotic fluid–Potential for regenerative medicine. Best. Pr. Res Clin. Obstet. Gynaecol. 31, 45–57 (2016).

Article