MYRF gene mutation leading to coronary artery anomaly combined with 46,XY sex development disorder, a case report and literature review

Abstract

Background

MYRF gene mutations can lead to the development of Cardio-Urogenital Syndrome (CUGS), characterized by congenital heart disease, abnormalities in the internal and external reproductive organs, and ocular anomalies. CUGS can manifest with various types of congenital heart diseases, such as Tetralogy of Fallot, Scimitar syndrome, Hypoplastic Left Heart Syndrome, Atrial Septal Defect, Ventricular Septal Defect, Dextrocardia, Aortic Arch Anomalies, and Pulmonary Vein Anomalies et al. Male patients (46,XY) may present with unilateral cryptorchidism, ambiguous genitalia, or even typical female genitalia. The most common ocular issues consistent with high myopia and nanophthalmos. To date, there have been reports of over 30 cases of MYRF gene mutations worldwide.

Case report

A 5-month-old female infant was admitted to Beijing Children’s Hospital affiliated with Capital Medical University due to “rapid breathing since birth.” No targeted therapy was administered prior to admission despite persistent tachypnea. Four months before admission, the infant was seen at a local hospital due to abnormalities in the external reproductive organs. Chromosomal analysis revealed 46, XY, and whole exome gene testing showed a MYRF gene mutation, identified heterozygosity for de novo mutations in the MYRF gene, splice site variant, respectively, that was not found in the gnomAD database, clinically presenting as Cardio-Urogenital Syndrome (GUGS; OMIM: 618280), inherited in an autosomal dominant (AD) manner. Family history was negative. The infant’s showed severely breathing progressively, leading to admission to our hospital. Electrocardiography showed pathological Q waves in leads I, avL, and V4-V6. Echocardiography revealed congenital heart disease of anomalous origin of the left coronary artery from the pulmonary artery, severe left ventricular enlargement (left ventricular end-diastolic diameter 35.2 mm), mild-to-moderate mitral regurgitation, and slightly reduced left ventricular systolic function (EF: 54%, which is just below the normal threshold 55%). Subsequent coronary angiography indicated the left coronary artery originating from the main pulmonary artery. The infant underwent further surgical treatment which confirmed the prior diagnosis and had a good postoperative recovery.

Conclusion

This case represents an exceptionally rare instance of MYRF-CUGS combined with coronary artery anomaly. This case report enriches the clinical phenotype spectrum of CUGS caused by MYRF gene mutations and improves recognition among clinicians.

Introduction

The myelin regulatory factor (MYRF) gene, located in the q12 region of chromosome 11, encodes a myelin phospholipid regulatory factor [1]. It is a key transcription factor involved in oligodendrocyte differentiation and central nervous system myelination. MYRF is primarily expressed at high levels in the central nervous system, with limited expression in the heart, lungs, diaphragm, and urogenital tract. In 2018, Kurahashi et al. [2]. first reported reversible vacuolization of myelin caused by MYRF gene mutations, leading to mild encephalitis/encephalopathy (OMIM#618113), an acute and reversible childhood brain disorder characterized by symptoms such as altered consciousness, delirium, and convulsions. Pinz et al. [3]. reported MYRF mutations in males with Scimitar syndrome and genitourinary anomalies. In 2019, Hamanaka et al. [4] reported MYRF gene mutations as a novel pathogenic factor in 46,XY and 46,XX sex development disorders. With the advancement and application of genetic testing technologies, MYRF gene mutations have been associated with AD ocular diseases such as nanophthalmos syndrome and high myopia after 2019 [5–9]. Based on previous reports, a syndrome related to MYRF gene mutations has been proposed: CUGS(OMIM#618280). CUGS is a rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by complex heart defects (including hypoplastic left heart, aortic valve atresia, mitral valve atresia, tubular hypoplasia of the ascending aorta, Scimitar syndrome), external urogenital abnormalities (including ambigous external genitalia, poorly defined urethral meatus, blind-ending vagina in females or bifid scrotum, penoscrotal hypospadias with micropenis and cryptorchidism in males). Congenital diaphragmatic hernia, pulmonary hypoplasia and intestinal malrotation are other major clinical features [10]. Individuals with 46,XY karyotype may exhibit a range of reproductive organ abnormalities, from isolated unilateral cryptorchidism to ambiguous genitalia and even typical female genitalia. Females may present with underdeveloped uterus, fallopian tubes, and ovaries, as well as congenital absence of the vagina. The majority of patients experience ocular issues such as high myopia and nanophthalmos (a form of microphthalmia characterized by short anterior-posterior segment, thickened choroid and sclera, and normal-sized lens). Other associated symptoms include diaphragmatic and pulmonary developmental anomalies. Research suggests that pulmonary and diaphragmatic development share common genetic controls [11]. Additionally, central nervous system developmental delays including speech delay, intellectual disability, motor delay, and autism spectrum disorders have been reported [12]. The prevalence of CUGS remains unquantified due to its rarity, and clinical identification primarily relies on symptom presentation, further confirmed by genetic testing.

Case report

A 5-month-old infant (46,XY) with female external genitalia weighing 5.1 kg, presented with tachypnea from birth, which here parents initially did not recognize. The infant had not undergone any heart surgery. At one month of age, the infant showed signs of male genital development and was examined at a local hospital, where chromosomal analysis revealed 46,XY karyotype. Due to progressive worsening of rapid breathing, the infant was admitted to our hospital. Electrocardiography revealed sinus rhythm, right axis deviation, complete right bundle branch block, and pathological Q waves in leads I, avL, and V4-V6 (Fig. 1).

Fig. 1.

Sinus rhythm, right axis deviation, with complete right bundle branch block, raised the pathological Q waves observable in leads I, avL, and V4-V6, and ST-T changes

Echocardiography indicated congenital heart disease: high likelihood of anomalous origin of the left coronary artery (Fig. 2), severe left ventricular enlargement (left ventricular end-diastolic diameter 35.2 mm), mild-to-moderate mitral regurgitation, and slightly reduced left ventricular systolic function (EF: 54%, which is just below the normal threshold 55%). LVEF was measured using the M-mode ultrasound method. This slightly decrease in EF (54%) reflects the extensive collateral network: right coronary artery flow retrogradely perfuses the anomalous left coronary artery. Pelvic ultrasound revealed no definite uterine or ovarian tissue. Testicular ultrasound showed a hypoechoic nodule in the left iliac fossa, suggestive of left testicular tissue, and heterogeneous nodules in the lower abdomen of the right kidney, indicating right testicular tissue with microlithiasis.

Fig. 2.

The echocardiogram indicates that the left coronary artery originates from the pulmonary artery

After informed consent, genetic testing was conducted on the patient and his parents. After variant filtering and prioritizing, whole exome sequencing indicated heterozygosity for a splice site mutation located in intron 9 of the MYRF gene (c.1389-2delA), leading to Cardio-urogenital syndrome (OMIM: 618280) / AD (Table 1). Trio-based sequencing confirmed this variant as de novo—present in the proband but absent in both parents (Figs. 3 and 4). Moreover, this novel mutation is absent from all major population databases, including ESP6500, 1000 Genomes Project, ExAC, or gnomAD databases. In silico analysis predicts a deleterious splicing effect for the variant, with PhyloP scores indicate high evolutionary conservation across vertebrates and neutrality among placental mammals (Table 2). Upon admission, the Physical Examination(PE)revealed normal blood pressure, absence of dysmorphic facial features, and intact mental status. Tachypnea is noted with a respiratory rate of 50 breaths per minute with visible inspiratory retractions. Not cardiac murmurs were heard over the precordium, and without dry or wet rales in the lungs. The liver was palpable 2.0 cm below the right costal margin, the spleen was not palpable below the costal margin, and no testes were palpable in the bilateral inguinal regions. The penis measured approximately 2 cm in length, with the urethra located behind the penis, presenting as a urogenital sinus (Fig. 5). Further examination of the airways revealed no significant abnormalities, while coronary angiography (aortic root angiography) indicated no opening of the left coronary artery and a well-displayed right coronary artery originating from the right coronary sinus, with visible collateral circulation flowing into the left coronary artery and draining into the posterior wall of the pulmonary artery (Fig. 6). Following a cardiac surgery consultation, the patient underwent corrective surgery for the anomalous origin of the coronary artery from the pulmonary artery at the age of five months. The patient is currently recovering well postoperatively. The family provided positive feedback regarding the diagnostic and therapeutic outcomes.

Table 1.

The Whole Exome Sequencing of MYRF gene Relevant Fingdings Interpretationand Sanger sequencing validation results in the pedigree

PS: The WES result report that: MYRF; NM_001127392.1: c.1389-2delA variant, not reported in patient with CUGS in the published literature. Acording to the ACMG, we interpret this as a Pathogenic, PVS1 + PS2 + PM2_supporting + pp4, the supplement provides evidence to support the classification of the variant

Fig. 3.

Whole exome sequencing identifiying the MYRF mutation (c.1389-2delA) and validated by Sanger sequencing in the pedigree

Fig. 4.

Pedigree analysis showing the de novo c.1389-2delA variant identified in the proband (shaded square) but absent in both parents. The father (white square) and mother (white circle) are wild type (−/−)

Table 2.

Pathogenicity prediction

SpliceAI	PhyloP Vertebrates	PhyloP Placetal Mammals
D	H	N

About the Table 2, D-deleterious; H-high; N-neutral

Fig. 5.

The penis measured approximately 2 cm in length, with the urethra located behind the penis, presenting as a urogenital sinus

Fig. 6.

Aortic root angiography demonstrating absent of left coronary artery ostium (arrow), right coronary artery originating from the right coronary (a and b), collateral vessels demonstrating retrograde filling into the left coronary artery system, coursing along the posterior wall of the pulmonary artery (c and d)

Discussion

The article reports a case of coronary artery anomaly combined with 46,XY sex development disorder caused by a variant in the MYRF gene. This case expands the phenotypic spectrum of MYRF-related CUGS to include coronary artery anomalies.

The MYRF gene is located on human chromosome 11q12→q13.1 and encodes a product of 1111 amino acids. It is a membrane-bound transcription factor located in the endoplasmic reticulum, containing PRO, a DNA-binding domain similar to the yeast transcription factor Ndt80 (Ndt80 DBD), an intramolecular chaperone auto-processing domain (ICA), a transmembrane domain (TM), and a functionally unknown C-terminal conserved domain [13–17]. Pathogenic variants in the DBD, ICD, and TM domains correlate with sex development and cardiovascular defects. CUGS caused by MYRF gene mutations (OMIM: 618280) is a rare, clinically diverse, autosomal dominant genetic disease resulting from pathogenic variations leading to loss of protein function within the MYRF gene. The MYRF gene encodes a membrane-associated homotrimeric protein, a myelin regulatory factor, containing several crucial domains including the DNA binding domain (DBD), the intramolecular chaperone domain (ICD) [18], an N-terminal proline-rich region with a nuclear localization sequence, and a transmembrane domain. The MYRF protein exerts transcription factor activity through the formation of a homotrimer [18–20]. Structural modeling predictions by Qi et al. [11] suggest that missense variations within the ICD can destabilize the trimeric structure of the MYRF protein, thereby affecting its transcriptional activity. Fan et al. [21] found in mice that missense variations in the DBD domain of the MYRF gene can affect protein function through mechanisms such as protein insufficiency and dominant negative effects. Additionally, high expression of the MYRF protein in the embryonic heart, lungs, and diaphragm in mice suggests its crucial role in the normal development of these organsv [11, 22]. CUGS involves multiple organ and systemic anomalies, with abnormalities in the internal and external reproductive organs, congenital heart disease, ocular anomalies, and congenital diaphragmatic hernia being relatively common. Early severe congenital heart disease, diaphragmatic hernia, and pulmonary hypoplasia contribute to decreased survival rates in affected children [3].

Congenital heart structural anomalies are the most common manifestation in patients with MYRF defects, found in over 90% of cases [23, 24]. The most common and most fatal condition is hypoplastic left heart, followed by Scimitar syndrome, with anomalous origin of the coronary artery being newly discovered. Genitourinary structural defects are the second most common presentation. In affected 46,XY individuals, ambiguous (hypospadias, cryptorchidism, and small penis) to fully female genitalia can be observed [24], while females may exhibit underdeveloped uterus, fallopian tubes, and ovaries, as well as congenital absence of the vagina. Some patients also present with ocular issues (including high myopia and nanophthalmos), diaphragmatic anomalies, pulmonary developmental anomalies, and developmental delays.

In summary, we report a 5-month-old patient whose clinical presentation and genetic testing are fully consistent with MYRF-CUGS. Coronary angiography ultimately confirmed the left coronary artery originating from the pulmonary artery, which was essential for clinical decision-making and treatment. We propose that all MYRF mutation carriers, especially those presenting with heart failure, ventricular enlargement, or even a borderline reduction in LVEF, should undergo periodic ECG and coronary-focused echocardiography to detect early signs of anomalous coronary origins. If screening reveals any indication of coronary artery origin abnormality, timely coronary angiography should be performed to confirm the diagnosis and assess hemodynamics. To our knowledge, this report describes one of the very few documented cases of a MYRF-associated coronary artery anomaly and expands the clinical spectrum by identifying a previously unreported variant. Future functional studies of MYRF variants are needed to elucidate how haploinsufficiency disrupts coronary vessel development. This case report enriches the clinical phenotype spectrum of CUGS caused by MYRF gene variations and enhances the understanding of this condition among specialized healthcare professionals.

Author contributions

Jianhua Ding and Zhen Zhen conducted the literature review and contributed to the manuscript’s writing; Yong Gai and Zhenyu Lv contributed to the acquisition and analysis of clinical data; Yanyan Xiao was responsible for the revision of the manuscript. All authors have read and approved the final version of the manuscript.

Funding

This study has not been supported by any fund.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Beijing Children’s Hospital, Capital Medical University. Written informed consent was obtained from the guardian.

Consent for publication

Written informed consent for the publication of this case report and accompanying images was obtained from the patient’s guardian.

Competing interests

The authors declare no competing interests.