Fetal Presentation of MYRF-Related Cardiac Urogenital Syndrome: An Emerging and Challenging Prenatal Diagnosis

Abstract

Purpose: MYRF-related cardiac-urogenital syndrome (MYRF-CUGS) is a rare condition associated with heterozygous MYRF variants. The description of MYRF-CUGS phenotype is mostly based on postnatal cases and 36 affected individuals have been published so far. We aim now to delineate the prenatal phenotype of MYRF-CUGS by reporting clinical data from fetuses and neonates with a pathogenic MYRF variant.

Methods: Detailed radiographic, pathological, clinical, and molecular data from 12 prenatal cases were collected through an international collaborative study. Adding the five fetuses previously published, we were able to study a cohort of 17 cases.

Results: Main ultrasound-accessible manifestations of MYRF-CUGS include congenital heart defects (13/17, 76%), congenital diaphragmatic hernia (10/17, 59%) and disorders of sexual differentiation in 46, XY fetuses (7/14; 50%). Postnatal examination and/or autopsy data highlighted additional birth defects and neurological findings with a large spectrum of severity. Molecular results revealed ten previously unpublished variants, one missense and nine predicted truncating variants (three frameshift, three nonsense and three splice site variants).

Conclusion: We report the first prenatal cohort of MYRF-CUGS, allowing us to further characterize the variable expressivity of this rare disorder in fetuses. Severe congenital anomalies with a poor prognosis are more frequent than previously described in postnatal cases. Our data suggest that MYRF-CUGS is characterized by a recurrent recognizable malformative association, accessible to prenatal diagnosis, with a significant intrafamilial phenotypic variability making genetic counseling challenging.

FIGURE 1

Photographs of individuals with MYRF‐CUGS. (A) Facies without specific dysmorphic features (CF.1, CF.2, CF.8, CF.9). (B) External genitalia. CF.1: ambigous genitalia, double blind‐ending vagina, no uterus, no fallopian tubes, no ovaries, cryptorchidism; CF.2: micropenis and hypospadias; CF.8: cryptorchidism, scrotum hypoplasia, micropenis, hypospadias; CF.9: micropenis, peno‐scrotal hypospadias, prepuce in sapper apron, cryoptorchidism. (C) Congenital diaphragmatic hernia (asterisk) and hypoplasic left heart syndrome (arrow) in fetuses CF.1 and CF.2.

FIGURE 2

MRI and US images of the right eye and left eye revealed an always normal morphology of the globe and small eyes with a short axial length for fetuses CF.3 and CF.9 matching with a nanophtalmos phenotype. (A) Sagittal, coronal and axial virtopsy MRI scans after TOP at 26 + 4 WG, eyes antero‐posterior diameter was 14.2mm (5–50th percentile) and transverse diameter was 13.4mm (50–95th percentile). (B) Coronal prenatal MRI scan of both CF.3 eyes at 32 WG. Eye axial length was 13.44mm (< 5th percentile) and anteroposterior diameter was 13.08mm (< 5th percentile). (C) Axial prenatal US image of both CF.5 eyes at 23 WG. Left eye axial length was 11.6 mm (5th percentile) and right eye axial length was 12 mm (5–50th percentile). (D) Axial prenatal MRI scan of both CF.9 eyes at 32 WG. Eyes anteroposterior and transverse diameters were 13 × 13.5 mm (< 5th percentile).

FIGURE 3

Graphical representation of monogenic disease‐associated MYRF variants identified in the litterature and in our study (IBS1.0.3). Variants described in this study in association with CUGS phenotype and nanophtalmos phenotype (top line). Variants described as pathogenic or likely pathogenic in the litterature associated with CUGS, nanophtalmos and MERS phenotype (bottom line). Variants in red points are nonsense/frameshift, variants in blue squares represent missense, and variants in green arrows are splice sites. Pro, Proline Rich Domain. DBD, DNA‐Binding Domain. ICA, Intramolecular Chaperone Auto‐processing domain. C‐Term, C‐Terminal Conserve Domain.