BACKGROUND: Cardiac-urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin-related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital cardiac developmental defects, pulmonary hypoplasia, congenital diaphragmatic hernia, and urogenital malformations. CASE PRESENTATION: We present case reports of two siblings of unrelated parents in whom whole-exome sequencing was indicated due to familial occurrence of extensive developmental defects. A new, previously undescribed splicing pathogenic variant c.1388+2T>G in the MYRF gene has been identified in both patients. Both parents are unaffected, tested negative, and have another healthy daughter. The identical de novo event in siblings suggests gonadal mosaicism, which can mimic recessive inheritance. CONCLUSIONS: To our knowledge, this is the first published case of familial cardiac-urogenital syndrome indicating gonadal mosaicism.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pathology University Hospital Brno Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pediatrics University Hospital Brno Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Medical Genetics and Genomics University Hospital Brno Faculty of Medicine Masaryk University Brno Czech Republic

Zobrazit více v PubMed

Alves, D. , & Leão, M. (2020). The clinical overlap between cardiac‐urogenital syndrome, Meacham syndrome, and PAGOD syndrome. Report of a new patient with cardiac‐urogenital syndrome. American Journal of Medical Genetics Part A, 182(6), 1532–1534. 10.1002/ajmg.a.61551 PubMed DOI

An, H. , Fan, C. , Sharif, M. , Kim, D. , Poitelon, Y. , & Park, Y. (2020). Functional mechanism and pathogenic potential of MYRF ICA domain mutations implicated in birth defects. Scientific Reports, 10(1), 814. 10.1038/s41598-020-57593-8 PubMed DOI PMC

Bujalka, H. , Koenning, M. , Jackson, S. , Perreau, V. M. , Pope, B. , Hay, C. M. , Mitew, S. , Hill, A. F. , Lu, Q. R. , Wegner, M. , Srinivasan, R. , Svaren, J. , Willingham, M. , Barres, B. A. , & Emery, B. (2013). MYRF is a membrane‐associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS Biology, 11(8), e1001625. 10.1371/journal.pbio.1001625 PubMed DOI PMC

Chitayat, D. , Shannon, P. , Uster, T. , Nezarati, M. M. , Schnur, R. E. , & Bhoj, E. J. (2018). An additional individual with a De novo variant in myelin regulatory factor (MYRF) with cardiac and urogenital anomalies: Further proof of causality: Comments on the article by Pinz et al. (2018). American Journal of Medical Genetics Part A, 176(9), 2041–2043. 10.1002/ajmg.a.40360 PubMed DOI

Drut, R. M. , Quijano, G. , Drut, R. , & Las, H. J. (1988). Rhabdomyomatous dysplasia of the lung. Pediatric Pathology, 8(4), 385–390. 10.3109/15513818809041572 PubMed DOI

Dupuis, C. , Charaf, L. A. , Brevière, G. M. , & Abou, P. (1993). “Infantile” form of the scimitar syndrome with pulmonary hypertension. The American Journal of Cardiology, 71(15), 1326–1330. 10.1016/0002-9149(93)90549-r PubMed DOI

Emery, B. , Agalliu, D. , Cahoy, J. D. , Watkins, T. A. , Dugas, J. C. , Mulinyawe, S. B. , Ibrahim, A. , Ligon, K. L. , Rowitch, D. H. , & Barres, B. A. (2009). Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell, 138(1), 172–185. 10.1016/j.cell.2009.04.031 PubMed DOI PMC

Fan, C. , An, H. , Sharif, M. , Kim, D. , & Park, Y. (2021). Functional mechanisms of MYRF DNA‐binding domain mutations implicated in birth defects. The Journal of Biological Chemistry, 296, 100612. 10.1016/j.jbc.2021.100612 PubMed DOI PMC

Gupta, N. , Endrakanti, M. , Gupta, N. , Dadhwal, V. , Naini, K. , Manchanda, S. , Khan, R. , & Jana, M. (2022). Diverse clinical manifestations and intrafamilial variability due to an inherited recurrent MYRF variant. American Journal of Medical Genetics. Part A, 188(7), 2187–2191. 10.1002/ajmg.a.62744 PubMed DOI

Huang, H. , Zhou, F. , Zhou, S. , & Qiu, M. (2021). MYRF: A mysterious membrane‐bound transcription factor involved in myelin development and human diseases. Neuroscience Bulletin, 37(6), 881–884. 10.1007/s12264-021-00678-9 PubMed DOI PMC

Kim, D. , An, H. , Fan, C. , & Park, Y. (2021). Identifying oligodendrocyte enhancers governing Plp1 expression. Human Molecular Genetics, 30(23), 2225–2239. 10.1093/hmg/ddab184 PubMed DOI PMC

Kurahashi, H. , Azuma, Y. , Masuda, A. , Okuno, T. , Nakahara, E. , Imamura, T. , Saitoh, M. , Mizuguchi, M. , Shimizu, T. , Ohno, K. , & Okumura, A. (2018). MYRF is associated with encephalopathy with reversible myelin vacuolization. Annals of Neurology, 83(1), 98–106. 10.1002/ana.25125 PubMed DOI

Lienicke, U. , Hammer, H. , Schneider, M. , Heling, K. , Wauer, R. R. , Mau, H. , & Vogel, M. (2002). Rhabdomyomatous dysplasia of the newborn lung associated with multiple congenital malformations of the heart and great vessels. Pediatric Pulmonology, 34(3), 222–225. 10.1002/ppul.10114 PubMed DOI

Pinz, H. , Pyle, L. C. , Li, D. , Izumi, K. , Skraban, C. , Tarpinian, J. , Braddock, S. R. , Telegrafi, A. , Monaghan, K. G. , Zackai, E. , & Bhoj, E. J. (2018). De novo variants in myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies. American Journal of Medical Genetics Part A, 176(4), 969–972. 10.1002/ajmg.a.38620 PubMed DOI PMC

Qi, H. , Yu, L. , Zhou, X. , Wynn, J. , Zhao, H. , Guo, Y. , Zhu, N. , Kitaygorodsky, A. , Hernan, R. , Aspelund, G. , Lim, F. Y. , Crombleholme, T. , Cusick, R. , Azarow, K. , Danko, M. E. , Chung, D. , Warner, B. W. , Mychaliska, G. B. , Potoka, D. , … Shen, Y. (2018). De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. PLoS Genetics, 14(12), e1007822. 10.1371/journal.pgen.1007822 PubMed DOI PMC

Reese, M. G. , Eeckman, F. H. , Kulp, D. , & Haussler, D. (1997). Improved splice site detection in genie. Journal of Computational Biology, 4, 311–323. 10.1089/cmb.1997.4.311 PubMed DOI

Rossetti, L. Z. , Glinton, K. , Yuan, B. , Liu, P. , Pillai, N. , Mizerik, E. , Magoulas, P. , Rosenfeld, J. A. , Karaviti, L. , Sutton, V. R. , Lalani, S. R. , & Scott, D. A. (2019). Review of the phenotypic spectrum associated with haploinsufficiency of MYRF. American Journal of Medical Genetics Part A, 179(7), 1376–1382. 10.1002/ajmg.a.61182 PubMed DOI PMC

Shapiro, M. B. , & Senapathy, P. (1987). RNA splice junctions of different classes of eukaryotes: Sequence statistics and functional implications in gene expression. Nucleic Acids Research, 15, 7155–7174. 10.1093/nar/15.17.7155 PubMed DOI PMC

Wang, H. , Kalfa, D. , Rosenbaum, M. S. , Ginns, J. N. , Lewis, M. J. , Glickstein, J. S. , Bacha, E. A. , & Chai, P. J. (2018). Scimitar syndrome in children and adults: Natural history, outcomes, and risk analysis. The Annals of Thoracic Surgery, 105(2), 592–598. 10.1016/j.athoracsur.2017.06.061 PubMed DOI

Yeo, G. , & Burge, C. B. (2004). Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. Journal of Computational Biology, 11, 377–394. 10.1089/1066527041410418 PubMed DOI

Diagnostic efficacy and clinical utility of whole-exome sequencing in Czech pediatric patients with rare and undiagnosed diseases