Diverse clinical manifestations and intrafamilial variability due to an inherited recurrent MYRF variant

Abstract

MYRF monoallelic variants have been described in syndromic forms characterized by cardiac‐urogenital syndrome and isolated nanophthalmos with/without minor systemic manifestations. We describe a large family with a paternally inherited pathogenic variant in MYRF that manifested as congenital diaphragmatic hernia (CDH), cardiac and urogenital abnormalities, and/or nanophthalmos with significant intrafamilial variability.

Case Report: De novo variant in myelin regulatory factor in a Chinese child with 46,XY disorder/difference of sex development, cardiac and urogenital anomalies, and short stature

“…Compared with the variants presenting severe syndromic forms, the variants that manifested nanophthalmos occurred in the final six exons of MYRF or their associated splice sites (after exon 22), except for the variants c.789delC (p.S264Afs*8) and c.789dupC (p.S264Qfs*74). The c.789dupC (p.S264Qfs*74) had been observed in variable phenotypic manifestations (10,12,17), while c.789delC (p.S264Afs*8) had only been described in the milder clinical presentation of DSDs and isolated nanophthalmos in previous reports (11,17), although they had the same position of de novo mutations. Therefore, we agree that severe syndromic manifestations are relevant to MYRF haploinsufficiency, while isolated nanophthalmos may sometimes affect MYRF homotrimerization, autoproteolysis, or transcriptional activity (19).…”

“…The clinical characteristics and MYRF gene variants of twenty patients (male: 16, female: 4) with CUGS who carried MYRF gene variants, as documented in these studies, are summarized in Table 1. The most common clinical presentation of syndromic MYRF is as follows: CHD (18/20, 90.0%), (10,13,17), nanophthalmos with mitral valve prolapse, unilateral cryptorchidism and micropenis (n = 1, c.789dupC/p.S264Qfs*74) (12), nanophthalmos with unilateral cryptorchidism and ASD (n = 1, c.789dupC/ p.S264Qfs*74) (10), nanophthalmos with posterior fossa cyst (n = 1, c.1553C > T/p.T518M) (18), and 2 large nanophthalmos families with or without dextrocardia or CDH (c.789dupC/ p.S264Qfs*74, c.3376-1G > A, and c.3361delC/p.R1121Gfs*36) (12,19), their clinical characteristics and MYRF gene variants are summarized in Table 3.…”

“…In addition to the central nervous system, MYRF is also expressed in the heart, lungs, diaphragm, and genitourinary tract. A series of de novo heterozygous mutations in MYRF were identified in patients with CUGS (6)(7)(8)(9)(10). The symptoms of CUGS included partial anomalous pulmonary venous return associated with tracheal anomalies, pulmonary hypoplasia, congenital diaphragmatic hernia (CDH), thyroid fibrosis, thymic involution, cleft spleen, penoscrotal hypospadias, and cryptorchidism (6).…”

MYRF: A unique transmembrane transcription factor‐ from proteolytic self‐processing to its multifaceted roles in animal development

“…[7,[34][35][36]41,42] Additionally, it presents with a wide spectrum of developmental delay and intellectual disability, pulmonary abnormalities, diaphragmatic issues, and intestinal malrotation. [41,[43][44][45][46][47][48] Many aspects of these developmental processes remain incompletely understood, and the causes of abnormal development are not well-established. A pathogenic variant of MYRF is also associated with neurological conditions characterized by extensive myelin vacuolization, reflecting similar findings observed in mice where Myrf plays a crucial role in regulating myelination.…”

Two sisters with cardiac‐urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism?

“…However, clinical manifestations can be highly variable with varying degrees of severity. To date, more than 30 cases of MYRF deficiency have been described in the literature, but many more patients with similar phenotypic manifestations, including clinically fully expressed cardiac‐urogenital syndrome, have been presented without an established diagnosis by MYRF genetic testing (Gupta et al, 2022; Pinz et al, 2018; Qi et al, 2018; Rossetti et al, 2019). So far, no case of familial occurrence associated with gonadal mosaicism has been described.…”