De novo variants in Myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies

Abstract

Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated with the control of the expression of myelin-related genes. However, it is highly expressed in human tissues and mouse embryonic tissues outside the nervous system such as the stomach, lung, and small intestine. It has not previously been reported as a cause of any Mendelian disease. We report here two males with Scimitar syndrome [MIM 106700], and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis. Gross neurologic functioning appears to be within normal limits. In both individuals a de novo variant in MYRF was identified using exome sequencing. Neither variant is found in gnomAD. Heterozygous variants in MYRF should be considered in patients with variants of Scimitar syndrome and urogenital anomalies.

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. ()

“…On autopsy, the fetus had ambiguous external genitalia ( Figure 1a This report provides a more complete understanding of the anatomy associated with this novel disorder, and provides additional support to link de novo variants in MYRF with a recognizable syndrome of cardiac and urogenital anomalies. We agree with Pinz et al (2018)…”

Functional mechanism and pathogenic potential of MYRF ICA domain mutations implicated in birth defects

“…We now know that MYRF is also expressed in other tissues such as stomach, lung, heart, ovary, eye, and developing gonads [12][13][14][15] . Consistently, MYRF coding variants have been implicated in both myelin and non-myelin diseases [13][14][15][16][17][18][19] , and whole-body Myrf knockout led to embryonic lethality in mouse independent of OL development 1 . In keeping with myelin-independent functions of Myrf, Myrf orthologs are found and play an important role in organisms without myelin 2,3,6,7 .Myrf is generated as a type-II membrane protein in the endoplasmic reticulum (ER) 4-6 .…”

“…If deleterious mutations hit the ICA domain, its auto-cleavage function may be impaired, potentially abolishing the transcription factor function of Myrf. Several MYRF coding variants have been implicated in birth defects [13][14][15][16][17][18][19] . These anomalies commonly involve defects in heart, lung, and urogenital tract and are thought to constitute a novel syndrome.…”

The clinical overlap between cardiac‐urogenital syndrome, Meacham syndrome, and PAGOD syndrome. Report of a new patient with cardiac‐urogenital syndrome

“…Motor skills were achieved fairly within the normal range. Brain Brain MRI was normal in the first patient and not reported in the latter (Pinz et al, 2018;Qi et al, 2018).…”

“…(Kurahashi et al, 2018). There have been clinical reports of several patients with heterozygous loss of function variants in MYRF presenting structural anomalies in different organs, mainly the heart, lung, diaphragm, and sexual organs (Chitayat et al, 2018;Homsy et al, 2015;Jin et al, 2017;Pinz et al, 2018;Qi et al, 2018;Rossetti et al, 2019). Truncating variants in MYRF were described in patients with genital anomalies (Hamanaka et al, 2019).…”