Congenital Research Articles

Two complex coronary artery abnormalities discovered after an acute coronary syndrome : A case report

BackgroundComplex coronary artery abnormalities (CAA) are rare findings with no established guideline for their management in asymptomatic patients. Case summaryWe report the case of a 49-year-old male patient, with no medical history, who was incidentally diagnosed for two congenital complex CAA during for the management of an acute coronary syndrome without ST elevation.The coronary angiogram showed an acute atheromatous occlusion of the right coronary artery (RCA) that was treated by a drug-eluting stent.Transcatheter angiograms as well as the coronary computed tomography (CT) also revealed an ectopic RCA arising from the left cuspid with an inter-arterial course, and a second left anterior descending artery emerging from the RCA with a retro-pulmonary course.The present acute coronary syndrome was not in relation to his congenital disease but with an atheromatous disease. On 48 months of follow-up, the transthoracic echocardiography is normal and the patient remains asymptomatic despite the risk of sudden cardiac death and myocardial infarction. DiscussionThis case shows that CAA can be clinically silent for a long period of time without any correction. It highlights that ischemia in patients with CAA is not always due to the congenital disease. As patients seemed to remain at SCD risk despite surgical correction, not correcting the CAA might remain an alternative in asymptomatic adult patients.

Fetal Brain MRI Findings in Myotonic Dystrophy and Considerations for Prenatal Genetic Testing.

Congenital myotonic dystrophy type 1 (DM1) is a rare congenital neuromuscular disorder associated with high morbidity and potential early mortality requiring lifelong symptomatic management. Prenatal presentations of DM1 have been associated with nonspecific ultrasound findings such as clubbed foot, polyhydramnios, ventriculomegaly, and decreased fetal movement, but many cases of DM1 have no ultrasound anomalies. We sought to compare the clinical course and prenatal imaging findings in two cases of DM1 using retrospective chart review. This report demonstrates potential expansion of the prenatal phenotype of DM1 including fetal SVT and frontal bossing. Both cases shared unique prenatal imaging features of lateral ventricle dilation involving the anterior bodies and frontal horns on fetal MRI. Because congenital DM1 is most often maternally inherited, attention to maternal symptoms, physical examination, and family history can be helpful in recognizing cases. Molecular diagnosis of DM1 requires specialized testing of the 3' untranslated region of the DMPK gene, and DM1 will not be detected by current standard prenatal genetic testing with microarray, karyotype, or exome sequencing.

A likely pathogenic homozygous frameshift variant in BLOC1S6 associated with a rare form of congenital Hermansky-Pudlak syndrome 9

Hermansky-Pudlak syndrome (HPS) is a collection of autosomal recessive multisystemic disorders with at least 11 different types, categorized on the basis of involved genes. The disease is mostly characterized by tyrosinase-positive oculocutaneous albinism (OCA), platelet storage deficiency, absence of platelet dense bodies, and immune deficiency. Here we described a 2-month-old female infant with generalized hypotonia, recurrent infections, bilateral optic atrophy, nystagmus, cerebral atrophy, and elevated liver enzymes. Unlike her parents, she had chestnut colored hair, fair skin, and brown eyes. Parents had a consanguineous marriage, and their first child had died with similar symptoms at the age of 5 months. Whole exome sequencing (WES) was performed on DNA extracted from the patient's peripheral blood. Following the bioinformatics analysis, a likely pathogenic novel variant in the fifth exon of the BLOC1S6 gene (NM_001311255: c.506dupT: p. L169Ffs*33) was introduced by the Sadra Medical Genetic Laboratory. This variant was confirmed in the patient and segregated in both parents by Sanger sequencing.This report presented the first congenital case of HPS-9 worldwide that might have led to early neonatal death. Our current patient shows new considerable features related to the BLOC1S6 gene variant and HPS-9, which is a valuable source for future research, prediction, clinical management, genetic counseling, and prenatal diagnosing.

A Systematic Review of the Association of Elastosis Perforans Serpiginosa and Congenital Disorders

Background: Elastosis perforans serpiginosa (EPS) is a skin condition marked by transepidermal elimination of abnormal elastic fibers, with a classical presentation of papules or plaques arranged in serpiginous, annular, or arcuate patterns on the neck, face, arms, or other flexural regions. A previous review of the literature reported that approximately 1/4 of EPS cases are associated with congenital disorders, including Down syndrome, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. To the knowledge of these authors, no review examining the association of EPS and congenital disorders has been performed since 1968. Objective: The primary objective of this paper is to perform an updated review of the literature focused on the associations between EPS and congenital disorders. Methods: We searched electronic databases (Medline, Web of Science, PubMed) for literature pertaining to EPS and Down syndrome, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. Results: Evidence for the association of EPS and congenital disorders is 57 cases from 48 published papers. Conclusions: Our results suggest an association between EPS and congenital disorders. However, current evidence is limited to case reports, underscoring the need for future research investigating the relationship between EPS and congenital disorders.

Unveiling the Significance of the Androgen Receptor Gene in Disorders of Sex Development

Abstract Disorders of sex development (DSD) encompass a range of congenital conditions where the development of chromosomal, gonadal or anatomical sex is atypical. There are many genes associated with DSD, and one of them is the androgen receptor (AR) gene, which plays a pivotal role in normal sex development. Studies reported numerous genetic variations in the AR gene that lead to 46, XY DSD, including androgen insensitivity syndrome and hypospadias. Identifying and understanding the genetic causes of DSD will aid the healthcare providers design a tailored-made management for DSD patients and optimise patients’ quality of life. This narrative review will explore the significance of the AR gene in DSD while discussing DSD in general.

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

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. 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. 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). 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.

Bart syndrome with musculoskeletal deformity: a rare case report

Introduction: Bart syndrome is a rare genetic disorder characterized by epidermolysis bullosa (EB), aplasia cutis congenita i.e., congenital local absence of skin, and nail abnormalities. Case Presentation: We herein present a case of a 14-year old boy with Bart Syndrome. The syndrome was diagnosed clinically. On examination, multiple generalized blisters were present and absence of nails in toes of both feet and middle finger of left hand which was associated with musculoskeletal deformity. Discussion: Bart Syndrome, an inherited autosomal dominant disorder, is an exceedingly rare disorder. Musculoskeletal deformity is an uncommon presentation of this syndrome. It is mostly associated with Dystrophic type of EB. It is mostly a clinical diagnosis however, histopathological study, direct immunofluorescence, and genetic testing helps in diagnosing the type of EB. Conclusion: The absence of skin in a localized area at birth is a crucial indicator for diagnosing Bart Syndrome at birth which later heals and can obscure the diagnosis. Early diagnosis and conservative management prevent the disease progression and complications.

Clinical Characteristics and Mortality Risk Factors of Hospitalized COVID-19 in Children: An Experience of Two Years Pandemic in Regional Referral Hospital

Coronavirus disease 2019 (COVID-19) has spread worldwide rapidly. COVID-19 in children is relatively mild compared to adults. However, several studies showed high mortality rates in children with underlying diseases. This study aimed to describe the clinical characteristics and outcomes of pediatric COVID-19 cases in regional referral hospital. This study was retrospective observational study using data from Medical Record Dr. Moewardi General Hospital between October 1st, 2020 and October 30th, 2022. The epidemiological and clinical data were extracted from the database and were compared with outcomes of patients. All statistical analyses were performed by SPSS software version 27. This study enrolled 371 (19,9%) children with confirmed RT-PCR SARS CoV-2 from 1856 hospitalized suspected children whereas 55% were males, and 63% aged under 5 years old. Moderate-severe patients accounted for 18% of the cases. Cough (74,4%), fever (66,6%) and shortness of breath (22,6) are the most common symptoms while 99 (26,7%) patients who had chronic diseases with the most common diseases being congenital heart disease, hematological malignancy and neurological disorders. Patient outcomes were significantly related to age, degree of severity and chronic disease with p=0.004, p< 0.001, and p< 0.001 respectively. After performing multivariate regression analysis, degree of severity [p<0.001; adjusted OR = 28.03, 95% CI (10.73–73.21)] was found to be significant predictors for mortality. The clinical and epidemiological data revealed that the majority symptom were cough, fever and shortness of breath. Mortality rate during hospitalization was higher in children with moderate-to-severe COVID-19.

Noonan Syndrome: Relation of Genotype to Cardiovascular Phenotype—A Multi-Center Retrospective Study

Background: Noonan syndrome (NS) is a congenital genetic disorder with a prevalence of 1 in 1000 to 2500 live births, and is characterized by distinctive facial features, short stature, chest deformities, and congenital heart disease. This study aims to evaluate the prevalence of specific genetic mutations and their impact on cardiovascular and other outcomes in NS. Methods: We conducted a retrospective clinical study of 25 pediatric patients diagnosed with NS at two institutions: The Mother and Child Health Care Institute of Serbia and the Clinic for Children Diseases, University Clinical Center of the Republic of Srpska. Patients underwent whole-exome sequencing (WES) to identify genetic mutations. Clinical data, including cardiovascular manifestations, psychomotor development, and stature, were analyzed in relation to mutation types. Results: The cohort comprised 60% male and 40% female patients, with a median age at diagnosis of 7.2 years. Cardiovascular abnormalities were present in 88% of patients. Mutations in PTPN11 were most commonly associated with pulmonary valve stenosis (PVS), while RAF1 mutations were prevalent in patients with hypertrophic cardiomyopathy (HCM). No significant association was found between cardiac disease and delayed psychomotor development (p = 0.755), even though the likelihood ratio showed significance in that regard (p = 0.018). Short stature was observed in 48% of patients but was not significantly correlated with genetic type of disease, presence of cardiac disease, or developmental delay. Conclusions: The study confirms the high prevalence of cardiovascular manifestations in NS and highlights genotype–phenotype correlations. While cardiac abnormalities are common, their impact on psychomotor development and stature is less clear. Further research is needed to explore genetic interactions influencing these outcomes and refine clinical management strategies.

THE CONNECTION OF LOCAL RETINAL DETACHMENT IN THE MACULAR AREA WITH THE FOSSA OF THE OPTIC DISC. DIFFERENTIAL DIAGNOSIS (CLINICAL CASE)

Relevance. The optic nerve pit is a congenital disease manifested by a depression in the disc of the optic nerve, which affects about 0.9% of the population. Complications occur in 25–75% of patients and may include retinal detachment. The causes of detachment remain unclear, but two theories of the occurrence of this complication have been put forward. Fluorescence angiography and optical coherence tomography are used for diagnosis. The treatment of retinal detachment in ONDP is not standardized and includes laser treatment, vitrectomy and other methods for fluid drainage. It is important to differentiate ONDP from other causes of central retinal detachment.Objective. Based on a clinical case, to demonstrate an approach to the diagnosis and treatment of local retinal detachment in the macular area associated with the fossa of the optic disc.Materials and methods. This article presents a clinical case of retinal detachment in the macular area associated with the fossa of the optic disc. Results and discussions. When comparing two clinical cases, the similarity of the ophthalmoscopic picture and the differences in the OCT and FAG images were revealed.Conclusions. The accumulation of fluid under the neuroepithelium is not a pathognomic sign, therefore it is important to carry out differential diagnosis in central serous retinal detachment associated with the fossa of the optic disc.

The efficacy of high pressure liquid chromatography (HPLC) in detecting congenital glycosylation disorders (CDG)

Abstract Objectives Congenital disorders of glycosylation (CDG) are a family of rare inherited metabolic disorders. This study aimed to examine the carbohydrate-deficient transferrin (CDT) screening results of 1,328 patients with suspected CDG by using transferrin- high pressure liquid chromatography (Tf- HPLC) method and to evaluate the performance of the method as a reference diagnostic tool. Methods Relative CDT levels (CDT concentrations expressed as percent of total transferrin) were determined in serum samples by HPLC. The method sensitivity, specificity and positive predictive value (PPV) were further calculated. Results Abnormal transferrin isoform profile consistent with CDG Type-I and CDG Type-II were determined in 50 cases; in 44 cases asiolo-Tf (7.63 ± 5.44 %) and disialo-Tf (36.29 ± 9.04 %), in six cases monosialo-Tf (3.95 ± 0.95 %) and trisialo-Tf (25.05 ± 4.46 %) were determined and decreased tetrasialo-Tf (49.75 ± 11.59 %) was identified in all cases. Two cases having abnormal CDT pattern were molecularly diagnosed with hereditary fructose intolerance and galactosemia and 11 cases diagnosed with CDG based on clinical and molecular analysis showed a normal pattern. The sensitivity, specificity and positive predictive values of Tf-HPLC method were 81.96 %, 99% and 96 %, respectively. Conclusions Tf-HPLC is a useful, highly sensitive, cost-advantageous and reliable method for the detection and preliminary diagnosis of CDG for laboratories working with large sample series.

A Stillborn Baby with Tetra-amelia Syndrome in Jember: A Case Report

Tetra-amelia syndrome is a rare congenital disorder characterized by the absence of all four extremities. This extremity disorder occurs in 1 in 1,300 to 2,000 births. This condition is caused by genetic mutations in the WNT3 and RSPO2 genes. Specific risk factors for tetra-amelia syndrome remain unclear. This is also due to the lack of studies that discuss specific risk factors for tetra-amelia syndrome. In this case report, we discuss a stillborn baby with tetra-amelia syndrome to a mother with various pregnancy risk factors in Jember. This case report aims to examine the presence of several risk factors in the mother and their relationship with congenital disorders, especially tetra-amelia syndrome.

Psychological well-being of women with uterine infertility before considering uterus transplantation as a treatment option.

While uterus transplantation offers a promising treatment option for women with uterine factor infertility (UFI), the potential for graft failure and lack of organ availability could have subsequent psychological repercussions for women. Exploring baseline psychological well-being for women with UFI who could become uterine transplant recipients is essential to identify specific psychological challenges to be considered prior to transplantation. UFI can be congenital uterine absence, namely Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), or acquired uterine absence (hysterectomy). To analyse baseline psychological well-being among women with UFI. A survey including demographic data and two internationally validated psychological questionnaires, Depression, Anxiety and Stress Scale (DASS-21),13 and Fertility Quality of Life (FertiQoL), was disseminated to women with UFI. Data from these instruments was compared between groups and then to data that uses these tools in the general infertility population. The study included 39 women (mean age 29.54 years). Higher scores for moderate symptoms of depression, anxiety, and stress were reported for the entire UFI cohort. More women with congenital UFI showed 'severe' symptoms for depression/anxiety, compared to women with acquired UFI. Women with acquired UFI showed poorer FertiQoL scores compared to both women with congenital UFI and to the general infertility population scores in previously published data. Clinicians should consider accessing increased psychological support for women with UFI when discussing fertility options including uterine transplant, and they may need to tailor this support depending on whether the patient has congenital or acquired UFI.

Expert Opinion for Defining a Severe Bleeding Phenotype to Guide Prophylaxis in Patients with Nonsevere Hemophilia.

Prophylaxis is the standard of care for patients with severe hemophilia, patients with moderate hemophilia, or those with another congenital bleeding disorder that is associated with a severe bleeding phenotype and/or a high risk of spontaneous life-threatening bleeding. Patients with nonsevere hemophilia (factor VIII [FVIII] ≥ 1%) may also have a bleeding phenotype that requires prophylaxis. To date, however, there are no clear criteria as to when prophylaxis is indicated in these patients. Also, the term "severe bleeding phenotype (SBPT)" is neither included in the definitions of the International Society on Thrombosis and Haemostasis (ISTH) nor specified in the World Federation of Hemophilia (WFH) guidelines. Based on our personal experience and available evidence, we propose the criteria we use to define an SBPT and when we consider offering prophylaxis in patients with nonsevere hemophilia. Our proposals can be the basis for discussions in the community about the assessment of SBPT and the initiation of prophylaxis in patients with nonsevere hemophilia without inhibitors.

Abstract 4119744: Evaluation of Neuropsychological development and Factors Affecting it in Children With Cyanotic and Acyanotic Congenital Cardiac Disease After Surgical Treatment

Objective: To evaluate neuropsychological development in children with cyanotic and acyanotic congenital heart diseases (CHDs) after surgical treatment and analyze the risk factors. Methods: 89 children who received follow-up in Fuwai Hospital after surgical treatment of CHDs were recruited in this study and 90 normal children were recruited as the control group. The children with CHDs were divided into cyanotic CHDs group and acyanotic CHDs group. Neuropsychological development was assessed according to Pediatric-psychological mental test scale and statistical analysis was employed. Results: The acyanotic CHDs group achieved better distribution of development quotient than cyanotic CHDs group (p < 0.05) but worse than the normal control group (p = 0.004). The proportion in cyanotic CHDs group with developmental quotient below the moderate level was higher than that of the normal control group (p < 0.001), but there was no significant difference between the cyanotic CHDs group and acyanotic CHDs group (p = 0.055). Multivariate regression analysis indicated that for cyanotic CHDs group, younger age at cardiac surgery, lower body mass, lower preoperative blood glucose level, lower BIS level, and prolonged duration of tracheal intubation after surgery were linked with lower scores in the test scale (p < 0.05); for acyanotic CHDs group, younger age at cardiac surgery, lower body mass, lower temperature during surgery and prolonged duration of tracheal intubation after surgery were linked with lower scores in the test scale(p < 0.05). Conclusion: Distinct neuropsychological impairment could be present in children with cyanotic CHDs. Younger age at cardiac surgery, body mass, preoperative blood glucose level, BIS level during surgery, temperature during surgery and duration of tracheal intubation after surgery were perioperative factors that could influence long-time neuropsychological development in children with CHDs.

Cerebrotendinous Xanthomatosis (CTX) Disease Prevalance in Patients with Autism Spectrum Disorder (ASD): A Prospective Observational Study

Background: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive congenital metabolic disorder which is characterized by the impairment of the enzymatic activity of sterol 27-hydroxylase. CTX, a rare neurodegenerative disease of sterol metabolism, can affect multiple systems, including the nervous system.It has been demonstrated that many congenital metabolic diseases like CTX are associated with Autism Spectrum Disorder (ASD). The aim of this study is to identify the prevalence of CTX disease in patients with ASD. Method: The clinical conditions of all patients were evaluated using the Mignarri Scoring Index. A socio-demographic form and Gilliam Autism Rating Scale-2 were applied to all participants. Results: In total, 101 children and adolescents with ASD were analyzed for genes. Following genetic analyses, four patients with mutations in the CYP27A1 gene, two homozygous variants and two different heterozygous mutations were identified. Most common symptom was diarrhea. 67.3% of all patients and 3 in 4 cases with CYP27A1 gene mutation had gone through psychiatric evaluation. A family history of a psychiatric disorder was present in 19.8% of all cases and in 75% of cases with mutations.Moreover, all mutant cases had comorbid Oppositional Defiant Disorder (ODD). 81.2% of all patients and all mutant patients were diagnosed with a behavioral disorder. Conclusion: psychiatric manifestations ranging from personality changes to behavioral disorders might accompany CTX. Better understanding and knowledge of the CTX disease by distinguishing specific psychiatric and systemic symptoms might help prevent missed diagnoses, progressive neurological deterioration and permanent disability through early initiation of chenodeoxycholic acid treatment.

Evaluation of pitolisant, sodium oxybate, solriamfetol, and modafinil for the management of narcolepsy: a retrospective analysis of the FAERS database

ObjectiveNarcolepsy, a rare neurological disorder believed to have an autoimmune etiology, necessitates lifelong management. This study aimed to provide evidence supporting the safety of pharmacological treatment for narcolepsy.MethodsFive-year data on pitolisant, sodium oxybate, solriamfetol, and modafinil were extracted from the FDA Adverse Event Reporting System (FAERS) self-reporting database for the period spanning from 2019 to 2023. Various statistical methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network analysis (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to quantify the signals. Finally, a comparative analysis was conducted between demographic data, outcomes, and inherent associations among the medications and the signals.ResultsAfter data analysis, we obtained 50 signals (a cumulative count of 762 cases) for pitolisant, 640 signals (corresponding to 46,962 cases) for sodium oxybate, 40 signals (equivalent to 1,228 cases) for solriamfetol, and finally, 72 signals (representing 632 cases) for modafinil. The majority of these patients were female. Psychiatric and nervous system disorders were identified as the predominant adverse drug events (ADEs). For sodium oxybate, it is crucial to consider psychiatric disorders (such as suicidal ideation), respiratory disorders (including sleep apnea syndrome and respiratory depression), and signs of pregnancy and congenital familial diseases. For solriamfetol, noteworthy new ADEs include drug inefficacy, suicidal ideation, restless legs syndrome, and somnambulism. Furthermore, a relationship has been observed between modafinil use and restricted fetal growth, spontaneous abortion, cognitive disorders, and drug inefficacy and abuse.ConclusionThe majority of observed adverse reactions in this study were consistent with those listed in the product instructions. However, potential novel or notable ADE signals were identified through real-world pharmacovigilance analysis. It is anticipated that this paper will offer additional information regarding safe and rational medication for narcolepsy.

Manic Fringe promotes endothelial-to-mesenchymal transition mediated by the Notch signalling pathway during heart valve development.

A fundamental event in the formation of heart valves involves the transformation of endocardial cells within the outflow tract (OFT) and atrioventricular canal (AVC) cushions through a process known as endothelial-to-mesenchymal transition (EndMT). Aberrant EndMT is a primary cause of congenital valvular malformations. Manic Fringe (MFNG) has been previously associated with cardiovascular development, although its role in heart valve development remains underexplored. In this study, we seek to enhance our understanding of MFNG's involvement in valve formation and its association with EndMT. Staining results of histological section revealed the expression of MFNG in the AVC and OFT from embryonic day 9.5 to 10.5 (E9.5-E10.5), when EndMT takes place. Cellular data demonstrated that MFNG exerts a positive regulatory influence on the EndMT process, promoting endothelial cell (EC) migration by enhancing the activity of the Notch signalling pathway. MFNG knockdown mediated by antisense morpholino oligonucleotides (MO) injection caused abnormal development of the heart and valves in zebrafish. Furthermore, through whole-exome sequencing (WES), we identified a heterozygous MFNG mutation in patients diagnosed with tetralogy of Fallot-pulmonary valve stenosis (TOF-PS). Cellular and molecular assays confirmed that this deleterious mutation reduced MFNG expression and hindered the EndMT process. In summary, our study verifies that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway during the heart and valve development. The MFNG deleterious variant induces MFNG loss of function, potentially elucidating the underlying molecular mechanisms of MFNG's involvement in the pathogenesis of congenital heart valve defects. These observations contribute to our current genetic understanding of congenital heart valve disease and may provide a potential target for prenatal diagnosis and treatment. KEY MESSAGES: Our examination revealed, for the first time, that MFNG exhibited high expression levels during EndMT of heart valve development in mice. Our findings provide compelling evidence that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway. Our results identified, for the first time, a deleterious MFNG p. T77M variant that inhibited the EndMT process by downregulating the activity of the Notch signalling pathway, thereby preventing the normal valve formation. MFNG may serve as an early diagnostic marker and an effective therapeutic target for the clinical treatment of congenital heart valve defects.

A prediction model of echocardiographic variables to screen for potentially correctable shunts in adult ASD-PAH patients.

Atrial septal defect (ASD) is a prevalent congenital heart condition in adults that leads to pulmonary hypertension (PAH) and right heart failure if left untreated. During a routine follow-up of adult ASD-PAH patients, the suitability of shunt closure depends on the invasive right heart catheterization (RHC).Nevertheless, performing RHC at every follow-up is impractical and may be harmful. The present retrospective cross-sectional study was designed to investigate which echocardiographic variables are related to pulmonary vascular resistance (PVR) in adult ASD-PAH patients and proposed a model using these variables to screen for patients with a correctable shunt. A total of 530 adult ASD-PAH patients with pulmonary arterial systolic pressure (PASP) of ≥60 mmHg measured using transthoracic echocardiogram (TTE) were included in the study. All RHCs were performed within 3 months after TTE. The correctable shunt was defined as PVR ≤3 wood units (WU). Multivariate regressions were performed utilizing echocardiographic variables. A scoring system was constructed based on the predictors of PVR ≤3 WU using multivariate logistic regression analysis. The scoring system was then examined using a receiver operating characteristic (ROC) analysis. In addition, clinical utility of the model was determined based on decision curve analysis and a calibration curve was used to evaluate model conformity. Estimated pulmonary arterial systolic pressure, velocity through the pulmonary valve, tricuspid annulus early diastolic velocity, and maximum defect dimension were identified as independent predictors. The area under the ROC curve of the predictive value in the model was 0.905 [95% confidence interval (CI): 0.878-0.931, sensitivity: 84.3%, specificity: 83.6%]. The net benefit of the model was notable in terms of a wide-range probability threshold in decision curve analysis, indicating that the prediction model had good clinical applicability. The model's calibration curve was close to an ideal diagonal line, showing good predictive accuracy between the actual and predictive probabilities. The study model was demonstrated to be valuable in predicting adult ASD-PAH patients with a correctable shunt, which may help clinicians to make appropriate treatment decision for follow-up patients.

Clinical features and genetic analysis of a child with Congenital disorder of glycosylation due to novel variants of COG6 gene

To analyze the clinical characteristics of a child with Congenital disorder of glycosylation due to compound heterozygous variants of COG6 gene (COG6-CDG). A child who was admitted to Xi'an Children's Hospital on January 10, 2023 was selected as the study subject. Clinical data were collected. Pathogenic variants were analyzed by whole exome sequencing, and candidate variants were verified by Sanger sequencing, in vitro experiments and bioinformatic analysis. This study was approved by the Medical Ethics Committee of Xi'an Children's Hospital (Ethics No. 20230101). The child, a 1-month-8-day-old male, was admitted for diarrhea and weight loss for one month. He had presented with cholestasis, diarrhea, facial dysmorphism, poor response, bilateral Simian crease, and brain atrophy. After discharge, he had continued to have high fever, feeding difficulty, and deceased finally. Whole exome sequencing results showed that he had harbored compound heterozygous variants of the COG6 gene, namely c.807delT (p.F269Lfs*37) and c.1746+1G>C (p.Gly565_Met582del). Sanger sequencing verified that the variants were inherited from his father and mother, respectively. In vitro experiments verified that the c.1746+1G>C variant could affect the mRNA splicing and produce a truncated protein, whilst the c.807delT variant could significantly reduce gene expression at both mRNA and protein levels. Based on the guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP), the variants were classified as pathogenic (PVS1+PM3+PM2_Supporting) and likely pathogenic (PVS1+PM2_Supporting), respectively. The c.807delT (p.F269Lfs*37) and c.1746+1G>C (p.Gly565_Met582del) compound heterozygous variants of the COG6 gene probably underlay the pathogenesis of this child. Above finding has enriched the mutational spectrum of COG6-CDG and provided a basis for the genetic counseling for this family.