A case of dilated cardiomyopathy caused by FHL2 gene variant and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical phenotype and genetic features of a child with dilated cardiomyopathy (DCM).@*METHODS@#Clinical data of the child who had presented at the Zhengzhou Children's Hospital on April 28, 2020 was collected. Trio-whole exome sequencing (trio-WES) was carried out for the child and her parents, and candidate variants were validated by Sanger sequencing. "FHL2" was taken as the key word to retrieve related literature from January 1, 1997 to October 31, 2021 in the PubMed database and was also searched in the ClinVar database as a supplement to analyze the correlation between genetic variants and clinical features.@*RESULTS@#The patient was a 5-month-old female infant presented with left ventricular enlargement and reduced systolic function. A heterozygous missense variant c.391C>T (p.Arg131Cys) in FHL2 gene was identified through trio-WES. The same variant was not detected in either of her parents. A total of 10 patients with FHL2 gene variants have been reported in the literature, 6 of them had presented with DCM, 2 with hypertrophic cardiomyopathy (HCM), and 2 with sudden unexplained death (SUD). Phenotypic analysis revealed that patients with variants in the LIM 3 domain presented hypertrophic cardiomyopathy and those with variants of the LIM 0~2 and LIM 4 domains had mainly presented DCM. The c.391C>T (p.Arg131Cys) has been identified in a child with DCM, though it has not been validated among the patient's family members. Based on the guidelines of the American College of Medical Genetics and Genomics, the c.391C>T(p.Arg131Cys) variant was re-classified as likely pathogenic (PS2+PM2_Supporting+PP3+PP5).@*CONCLUSION@#The heterozygous missense variant of c.391C>T (p.Arg131Cys) in the FHL2 gene probably predisposed to the DCM in this child, which has highlighted the importance of WES in the clinical diagnosis and genetic counseling.

Clinical and genetic analysis of eight children with Primary hypertrophic cardiomyopathy / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of eight children with Primary hypertrophic cardiomyopathy (HCM).@*METHODS@#Eight children with HCM admitted to the Department of Cardiology of Henan Children's Hospital from January 2018 to December 2021 were selected as the study subjects. Clinical data of the children were collected. Whole exome sequencing was carried out on two children, and trio whole exome sequencing was carried out on the remainder 6 children. Sanger sequencing was used to verify the candidate variants in the children and their parents, and the pathogenicity of the variants was evaluated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#The patients had included 5 males and 3 females, with their ages ranging from 5 to 13 years old. The average age of diagnosis was (7.87 ± 4.8) years old, and the cardiac phenotype showed non-obstructive HCM in all of the patients. WES has identified variants of the MYH7 gene in 4 children, including c.2155C>T (p.Arg719Trp), c.1208G>A (p.Arg403Gln), c.1358G>A (p.Arg453His), and c.1498G>A (p.Glu500Lys). Based on the guidelines from the ACMG, the first 3 variants were classified as pathogenic, while c.1498G>A (p.Glu500Lys) was classified as likely pathogenic (PM1+PM2_Supporting+PM6+PP3), which was also unreported previously. The remaining four children had all harbored maternal variants, including MYL2: c.173G>A (p.Arg58Gln; classified as pathogenic), TPM1: c.574G>A (p.Glu192Lys) and ACTC1: c.301G>A (p.Glu101Lys)(both were classified as likely pathogenic), and MYBPC3: c.146T>G (p.Ile49Ser; classified as variant of uncertain significance). Seven children were treated with 0.5 ~ 3 mg/(kg·d) propranolol, and their symptoms had improved significantly. They were followed up until September 30, 2022 without further cardiac event.@*CONCLUSION@#Genetic testing can clarify the molecular basis for unexplained cardiomyopathy and provide a basis for clinical diagnosis and genetic counseling. Discovery of the c.1498G>A (p.Glu500Lys) variant has also expanded the spectrum of MYH7 gene mutations underlying HCM.

Mental retardation autosomal dominant 35 caused by de novo missense variants in PPP2R5D gene: a case report and literature review / 中华神经科杂志

Objective:To enhance understanding of mental retardation autosomal dominant 35 (MRD35) by analyzing the clinical and genetic characteristics of the disease.Methods:Clinical and genetic data of 1 case of MRD35 in Beijing Children′s Hospital in July 2018 were reported, and literature review was conducted.Results:The male proband, 1 year and 3 months old, was admitted with the clinical manifestations including mental retardation, low-grade fever, a large forehead, flat nose, open mouth, and hypomyotonia. The brain magnetic resonance imaging showed enlarged lateral ventricles, cavum septum, cavum verge and cavum velum interpositum cyst. The whole exome sequencing test showed that the proband carried a missense mutation c.1258 G>A, (p.E420K) in the PPP2R5D gene, and the mutation was de novo confirmed by Sanger sequencing. There were ten literatures reported, including a total number of 31 cases. Counting on this case, totally 32 cases were included. Among the 32 patients, 32 cases (100.0%) had mental retardation, 26 cases (81.3%) with motor retardation, 26 cases (81.3%) with macrocephaly, 8 cases (25.0%) with epilepsy. Facial dysmorphic features, ocular abnormalities, skeletal abnormalities, and cardiac malformations were also reported. All reported individuals had missense mutations of PPP2R5D gene and were autosomal dominantly inherited. Conclusions:The main clinical manifestations of MRD35 include growth retardation/mental retardation, severe speech impairment, macrocephaly, hypomyotonia, seizures and dysmorphic facial features. A novel missense mutation in the PPP2R5D gene is the cause of MRD35.

The Diagnosis and Treatment of Rare Diseases in Children: Now and Future / 罕见病研究

Rare diseases refer to a group of diseases having very low incident rates in the population without unified definition up till now. Approximately 50% to 75% of rare diseases occur at birth or in childhood, incurring huge psychological and economic burden to families and society. With the rapid development of diagnostic technology and the continuous progress in treatment and the introduction of relevant policies, China has made great progress in the prevention and treatment of rare diseases. This article summarizes the latest progress in the diagnosis, clinical management, and research of pediatric rare diseases; and explores the prospects in the future.

Long-term prognosis of allergic bronchopulmonary aspergillosis in children with cystic fibrosis / 中华实用儿科临床杂志

Objective:To analyze the long-term prognosis and prognostic factors of allergic bronchopulmonary aspergillosis(ABPA) in children suffering from cystic fibrosis (CF).Methods:An observational study was performed.All children who were admitted to the Department of Respiratory, Beijing Children′s Hospital, Capital Medical University from August 2014 to June 2018, with more than 2 years of followed up for the diagnosis of CF accompanied by ABPA were involved.Results:Three children met the inclusion criteria, with 2 boys and 1 girl, and their diagnostic age were 14, 8 and 9 years old, respectively.The follow-up duration ranged from 2 to 6 years.All the 3 cases were treated with systemic corticosteroids and antifungal agent.In case 1, the initial dose of prednisone was 0.75 mg/(kg·d), and the course of treatment was more than 5 years.The corticosteroid-dependent patient suffered from expectoration and chest pain, and radiographic findings indicated exacerbation, while his lung function was normal.Treating with initial dose of prednisone 2 mg/(kg·d) for 9 months, case 2 had normal serum immunoglobulin E(IgE) concentration, but his pulmonary artery was infiltrated by lesions, thus leasing to lobectomy.In case 3, the initial dose of prednisone was 0.6 mg/(kg·d), and the course of treatment was 18 months.And she developed persistent hypoxemia, and decreased pulmonary function, so lung transplantation was necessary 2 years after diagnosis.Conclusions:Systemic glucocorticoid combined with antifungal therapy is the main treatment for CF with ABPA, but there are individual differences in the efficacy.The level of serum total IgE is not always consistent with lung function and chest images.The overall prognosis is poor, and it is infeasible to evaluate the prognosis by single factor.

Identification of variants in TNNI3 gene in two children with restrictive cardiomyopathy / 中华医学遗传学杂志

OBJECTIVE@#To identify the pathogenesis in two patients of restrictive cardiomyopathy (RCM) using high-throughput sequencing.@*METHODS@#Peripheral blood samples from the two patients and their parents were collected and genomic DNAs were extracted to conduct targeted next generation sequencing or whole exome sequencing. Bioinformation analysis was performed to identify the pathogenic variants in genes associated with cardiomyopathy, which were further validated by Sanger sequencing.@*RESULTS@#By high throughput sequencing, we detected a de novo heterozygous variant c.549+1G>T in TNNI3 gene in patient 1. The variant has not been reported previously and was predicted to be pathogenic in line with American College of Medical Genetics and Genomics (ACMG) guidelines (PVS1+PS2+PM2). Another heterozygous variant c.433C>T (p.Arg145Trp) in TNNI3 gene was identified in patient 2 and his father. The variant had been reported as pathogenic variant in Clinvar and HGMD databases; based on ACMG guidelines, the variant was predicted to be likely pathogenic (PS3+PM1+PP3).@*CONCLUSION@#TNNI3 variants may be the causative gene responsible for restrictive cardiomyopathy in the two patients. High throughput sequencing results provide bases for the diagnosis of restrictive cardiomyopathy.

Analysis of SMARCA2 gene mutation in a child with Nicolaides-Baraitser syndrome / 中华医学遗传学杂志

Objective@#To explore the molecular basisfor a child featuring short stature, abnormal facial features and developmental delay.@*Methods@#Genomic DNA was extracted from peripheral blood samples from the child and his family members. Next-generation sequencing was carried out to screen the whole exomes of the core family. Detected variants were filtered and analyzed according to the standards and guidelines for the interpretation of sequence variants recommended by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.@*Results@#Trio-based sequencing has identified a de novo variant c. 3593T>G (p.Val1198Gly) in the SMARCA2gene in the patient. The variant was located in the Helicase C-terminal domain and was classified as pathogenic based on the guidelines.@*Conclusion@#The patient was diagnosed with Nicolaides-Baraitser syndrome caused by SMARCA2 gene mutation.

Analysis of SMARCA2 gene mutation in a child with Nicolaides-Baraitser syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the molecular basisfor a child featuring short stature, abnormal facial features and developmental delay.@*METHODS@#Genomic DNA was extracted from peripheral blood samples from the child and his family members. Next-generation sequencing was carried out to screen the whole exomes of the core family. Detected variants were filtered and analyzed according to the standards and guidelines for the interpretation of sequence variants recommended by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.@*RESULTS@#Trio-based sequencing has identified a de novo variant c.3593T>G (p.Val1198Gly) in the SMARCA2 gene in the patient. The variant was located in the Helicase C-terminal domain and was classified as pathogenic based on the guidelines.@*CONCLUSION@#The patient was diagnosed with Nicolaides-Baraitser syndrome caused by SMARCA2 gene mutation.