Expanding the Prenatal Phenotype of MYRF-Related Cardiac-Urogenital Syndrome
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction:
Cardiac-urogenital syndrome (CUGS) is an emerging, multisystemic disorder characterized by congenital heart defects, urogenital, and ocular abnormalities attributed to heterozygous MYRF variants. Diaphragmatic anomalies, primary pulmonary hypoplasia, intestinal malrotation, and intellectual/developmental disabilities are also associated. To date, over 50 individuals with MYRF-CUGS have been identified, of which the prenatal presentation was detailed in a limited number of cases. Here we describe the features of 5 fetuses with MYRF-CUGS, further delineating the prenatal spectrum of disease.
Methods:
Retrospective review of all molecularly confirmed cases of MYRF-CUGS evaluated at a single fetal center. Data were collected for prenatal imaging (ultrasound, echocardiogram, MRI), pregnancy outcome, postnatal course, fetal autopsy, and genetic testing. Descriptive statistics were employed.
Results:
5 fetuses were confirmed to harbor a de novo pathogenic/likely pathogenic MYRF variant (c.803_831del29, c.789dup, c.789del, c.46+5G>A, and c.2246A>G) via exome/genome sequencing (ES/GS). The first diagnosis was made in 2019, while the latter 4 were identified from April-July 2024. 4 male and 1 female fetus were confirmed by normal cytogenetics. 3 pregnancies were ongoing and 2 elected interruption of pregnancy. For the completed pregnancies, 1 neonate expired on DOL 1 after planned palliative delivery, and 2 resulted in a liveborn.
Cardiac and genitourinary anomalies were identified prenatally in all 5 fetuses. Cardiac anomalies included 3 cases of hypoplastic aortic arch, 2 cases of suspected Scimitar syndrome, and 1 case each of hypoplastic left heart syndrome, dilated/thickened pulmonary veins, hypoplastic right pulmonary artery, coarctation of the aorta, heterotaxy, dextrocardia, mesocardia, atrial septal defect, ventricular septal defect, ipsilateral pulmonary veins, and dilated cardiac structure. In the 46,XY fetuses, genitourinary anomalies seen prenatally ranged from hypospadias (3/4) to bifid scrotum (2/4) to ambiguous genitalia with no identifiable phallus (1/4). On postnatal examination/pelvic ultrasound, the latter fetus had female appearing external genitalia, an ovoid structure between the bladder and rectum (potentially representing a uterus), and no clear identification of testicles or ovaries. In the 46,XX fetus, prenatal ultrasound identified urinary tract dilation with mildly dilated renal pelves and slightly echogenic renal parenchyma; fetal autopsy was unremarkable for genitourinary anomalies.
Diaphragmatic anomalies were confirmed in 2/5 cases and suspected in 1 terminated case with no fetal autopsy. In the first confirmed case, prenatal ultrasound identified left-sided congenital diaphragmatic hernia (CDH), while fetal body MRI raised concern for bilateral CDH versus left-sided CDH with right-sided eventration. Ultimately, fetal autopsy confirmed bilateral CDH. In the second confirmed case, a right-sided CDH was not found until postnatal CTA. Primary pulmonary hypoplasia was present prenatally in 2/5 cases. In the 2 living neonates, ophthalmology evaluation identified bilateral congenital cataracts in 1 and was unremarkable on DOL 1 in the other. Intestinal malrotation was seen in 1 case on fetal autopsy.
Additional common prenatal features included increased nuchal translucency/cystic hygroma (3/5), pericardial effusion (3/5), and vertebral body segmentation anomalies (2/5). Polyhydramnios, right choroid plexus cysts, clinodactyly, and two-vessel cord were each seen in 1 case. Additionally, bronchopulmonary sequestration was postnatally identified in 1 case.
Conclusion:
This represents the largest cohort of prenatally diagnosed MYRF-CUGS reported to date. Despite the paucity of prior reports, our single fetal center identified this diagnosis in 5 fetuses, 4 of which occurred over a four-month span. This suggests that MYRF-CUGS may be an underrecognized cause of birth defects and should be considered in the differential diagnosis when multisystemic involvement is seen prenatally. Increased identification of MYRF variants may be due to the increased availability of prenatal sequencing. Importantly, 1 fetus was found to harbor an intronic variant (c.46+5G>A), underscoring the value of GS. This case series includes the first reported instances of heterotaxy, bronchopulmonary sequestration, and congenital cataracts as part of the phenotypic spectrum.
Cardiac-urogenital syndrome (CUGS) is an emerging, multisystemic disorder characterized by congenital heart defects, urogenital, and ocular abnormalities attributed to heterozygous MYRF variants. Diaphragmatic anomalies, primary pulmonary hypoplasia, intestinal malrotation, and intellectual/developmental disabilities are also associated. To date, over 50 individuals with MYRF-CUGS have been identified, of which the prenatal presentation was detailed in a limited number of cases. Here we describe the features of 5 fetuses with MYRF-CUGS, further delineating the prenatal spectrum of disease.
Methods:
Retrospective review of all molecularly confirmed cases of MYRF-CUGS evaluated at a single fetal center. Data were collected for prenatal imaging (ultrasound, echocardiogram, MRI), pregnancy outcome, postnatal course, fetal autopsy, and genetic testing. Descriptive statistics were employed.
Results:
5 fetuses were confirmed to harbor a de novo pathogenic/likely pathogenic MYRF variant (c.803_831del29, c.789dup, c.789del, c.46+5G>A, and c.2246A>G) via exome/genome sequencing (ES/GS). The first diagnosis was made in 2019, while the latter 4 were identified from April-July 2024. 4 male and 1 female fetus were confirmed by normal cytogenetics. 3 pregnancies were ongoing and 2 elected interruption of pregnancy. For the completed pregnancies, 1 neonate expired on DOL 1 after planned palliative delivery, and 2 resulted in a liveborn.
Cardiac and genitourinary anomalies were identified prenatally in all 5 fetuses. Cardiac anomalies included 3 cases of hypoplastic aortic arch, 2 cases of suspected Scimitar syndrome, and 1 case each of hypoplastic left heart syndrome, dilated/thickened pulmonary veins, hypoplastic right pulmonary artery, coarctation of the aorta, heterotaxy, dextrocardia, mesocardia, atrial septal defect, ventricular septal defect, ipsilateral pulmonary veins, and dilated cardiac structure. In the 46,XY fetuses, genitourinary anomalies seen prenatally ranged from hypospadias (3/4) to bifid scrotum (2/4) to ambiguous genitalia with no identifiable phallus (1/4). On postnatal examination/pelvic ultrasound, the latter fetus had female appearing external genitalia, an ovoid structure between the bladder and rectum (potentially representing a uterus), and no clear identification of testicles or ovaries. In the 46,XX fetus, prenatal ultrasound identified urinary tract dilation with mildly dilated renal pelves and slightly echogenic renal parenchyma; fetal autopsy was unremarkable for genitourinary anomalies.
Diaphragmatic anomalies were confirmed in 2/5 cases and suspected in 1 terminated case with no fetal autopsy. In the first confirmed case, prenatal ultrasound identified left-sided congenital diaphragmatic hernia (CDH), while fetal body MRI raised concern for bilateral CDH versus left-sided CDH with right-sided eventration. Ultimately, fetal autopsy confirmed bilateral CDH. In the second confirmed case, a right-sided CDH was not found until postnatal CTA. Primary pulmonary hypoplasia was present prenatally in 2/5 cases. In the 2 living neonates, ophthalmology evaluation identified bilateral congenital cataracts in 1 and was unremarkable on DOL 1 in the other. Intestinal malrotation was seen in 1 case on fetal autopsy.
Additional common prenatal features included increased nuchal translucency/cystic hygroma (3/5), pericardial effusion (3/5), and vertebral body segmentation anomalies (2/5). Polyhydramnios, right choroid plexus cysts, clinodactyly, and two-vessel cord were each seen in 1 case. Additionally, bronchopulmonary sequestration was postnatally identified in 1 case.
Conclusion:
This represents the largest cohort of prenatally diagnosed MYRF-CUGS reported to date. Despite the paucity of prior reports, our single fetal center identified this diagnosis in 5 fetuses, 4 of which occurred over a four-month span. This suggests that MYRF-CUGS may be an underrecognized cause of birth defects and should be considered in the differential diagnosis when multisystemic involvement is seen prenatally. Increased identification of MYRF variants may be due to the increased availability of prenatal sequencing. Importantly, 1 fetus was found to harbor an intronic variant (c.46+5G>A), underscoring the value of GS. This case series includes the first reported instances of heterotaxy, bronchopulmonary sequestration, and congenital cataracts as part of the phenotypic spectrum.
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