OBJECTIVE: To explore the genetic basis for a EAST/SeSAME syndrome child featuring epilepsy, ataxia, sensorineural deafness and intellectual disability. METHODS: A child with EAST/SeSAME syndrome who had presented at the Third Affiliated Hospital of Zhengzhou University in January 2021 was selected as the study object. Peripheral blood samples of the child and her parents were collected and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: Genetic testing revealed that the child has harbored compound heterozygous variants of the KCNJ10 gene, namely c.557T>C (p.Val186Ala) and c.386T>A (p.Ile129Asn), which were inherited from her mother and father, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted as likely pathogenic (PM1+PM2_Supporting+PP3+PP4; PM1+PM2_Supporting+PM3+PP3+PP4). CONCLUSION The patient was diagnosed with EAST/SeSAME syndrome due to the compound heterozygous variants of the KCNJ10 gene.
Humans ; Child ; Female ; Intellectual Disability/genetics* ; Hearing Loss, Sensorineural/genetics* ; Ataxia ; Genetic Diseases, X-Linked ; Mutation

OBJECTIVE: To explore the genetic basis for a child affected with cerebral creatine deficiency syndrome 1 (CCDS1). METHODS: High-throughput sequencing was carried out to screen pathogenic variant associated with the clinical phenotype of the proband. The candidate variant was verified by Sanger sequencing. RESULTS: High-throughput sequencing revealed that the proband has carried heterozygous c.327delG variant of the SLC6A8 gene, which was verified by Sanger sequencing.Neither parent was found to carry the same variant. CONCLUSION The de novo heterozygous c.327delG variant of the SLC6A8 gene probably underlay the CCDS1 in this child.
Brain Diseases, Metabolic, Inborn/genetics* ; Creatine ; Genetic Testing ; Heterozygote ; Humans ; Mental Retardation, X-Linked ; Mutation

Arrhythmias, Cardiac ; Genetic Diseases, X-Linked/genetics* ; Gigantism/genetics* ; Heart Defects, Congenital/genetics* ; Humans ; Intellectual Disability/genetics* ; Male ; Neuroblastoma

OBJECTIVE: To report on the clinical features and result of genetic testing for a child featuring immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. METHODS: Clinical records, genetic testing, laboratory investigation and treatment of the child were summarized in addition with a comprehensive review of the literature. RESULTS: The 3-year-old boy was administered due to intractable diarrhea, recurrent infections, liver dysfunction and failure to thrive, though no diabetes or skin disorder was observed. Laboratory testing showed elevated liver enzymes and total IgE, decreased albumin and electrolyte imbalance. Gastrointestinal endoscopy revealed erosion and granules in the duodenum, and edema in the terminal ileum and colon. Biopsies showed villous atrophy in the duodenum and terminal ileum. Genetic testing revealed that the patient has carried a missense c.1087A>G (p.I363V) variant in the exon 10 of the FOXP3 gene. He was treated with enteral and parenteral nutrition, anti infection and Sirolimus, and was waiting for hemopoietic stem cell transplantation. CONCLUSION Although IPEX syndrome usually occur during infancy, it should not be ruled out solely based on the age, and its presentation can be variable. For male children with refractory diarrhea, autoimmune disorder and growth retardation, the diagnosis should be suspected and confirmed by genetic testing.
Child, Preschool ; Diabetes Mellitus, Type 1/genetics* ; Diarrhea/genetics* ; Forkhead Transcription Factors/genetics* ; Genetic Diseases, X-Linked/genetics* ; Genetic Testing ; Humans ; Immune System Diseases/genetics* ; Male ; Mutation ; Polyendocrinopathies, Autoimmune/genetics*

OBJECTIVE: To detect pathogenic variant of the FGD1 gene in a boy with Aarskog-Scott syndrome. METHODS: Genetic variant was detected by high-throughput sequencing. Suspected variant was verified by Sanger sequencing. The nature and impact of the candidate variant were predicted by bioinformatic analysis. RESULTS: The child was found to harbor a novel c.1906C>T hemizygous variant of the FGD1 gene, which has led to conversion of Arginine to Tryptophane at codon 636(p.Arg636Trp). The same variant was found in his mother but not father. Based on the American College of Medical Genetics and Genomics guidelines, the c.1906C>T variant of FGD1 gene was predicted to be likely pathogenic(PM1+PM2+PM5+PP2+PP3+PP4). CONCLUSION The novel c.1906C>T variant of the FGD1 gene may underlay the Aarskog-Scott syndrome in this child. Above finding has enabled diagnosis for the boy.
Child ; Dwarfism ; Face/abnormalities* ; Genetic Diseases, X-Linked ; Genitalia, Male/abnormalities* ; Guanine Nucleotide Exchange Factors/genetics* ; Hand Deformities, Congenital/genetics* ; Heart Defects, Congenital ; Humans ; Male ; Mutation

OBJECTIVE: To explore the genetic basis for a pedigree affected with Nance-Horan syndrome. METHODS: Clinical manifestation of the patients was analyzed. Genomic DNA was extracted from peripheral blood samples of the pedigree members and 100 unrelated healthy controls. A panel of genes for congenital cataract was subjected to next-generation sequencing (NGS), and candidate variant was verified by Sanger sequencing and bioinformatic analysis based on guidelines of American College of Medical Genetics and Genomics (ACMG). mRNA expression was determined by reverse transcriptase-PCR (RT-PCR). Linkage analysis based on short tandem repeats was carried out to confirm the consanguinity. RESULTS: A small insertional variant c.766dupC (p.Leu256Profs*21) of the NHS gene was identified in the proband and his affected mother, but not among unaffected members and the 100 healthy controls. The variant was unreported in Human Gene Mutation Database (HGMD) and other databases. Based on the ACMG guideline, the variant is predicted to be pathogenic (PVS1+PM2+PM6+PP4). CONCLUSION The novel variant c.766dupC of the NHS gene probably underlay the X-linked dominant Nance-Horan syndrome in this pedigree.
Cataract/genetics* ; Genetic Diseases, X-Linked ; Humans ; Mutation ; Pedigree ; State Medicine ; Tooth Abnormalities

OBJECTIVE: To explore the genetic pathogenesis of X-linked agammaglobulinemia in two patients for clinical diagnosis and family counseling. METHODS: Data was collected from the patients' family including clinical information, blood immunoglobulin level, as well as classification and subgrouping of B lymphocytes. Gene mutations were screened by whole exome sequencing (WES) through next-generation sequencing (NGS), the result was verified with Sanger sequencing. RESULTS: A BTK c.1627T>C (p.Ser543Pro) variant was found in the pedigree. The phenotype and variant have co-segregated in the pedigree. The variant was not found in population database. The variant has affected in the kinase domain which contained no benign variants and is harmful as predicted through bioinformatic analysis. CONCLUSION BTK c.1627T>C (p.Ser543Pro) is a pathogenic variant contributing to X-linked agammaglobulinemia in this pedigree. Above finding has provided reproduction guidance for this family.
Agammaglobulinaemia Tyrosine Kinase/genetics* ; Agammaglobulinemia/genetics* ; DNA Mutational Analysis ; Genetic Diseases, X-Linked ; Humans ; Mutation ; Pedigree

OBJECTIVE: To investigate the gene mutation of patients with WAS gene defect and its correlation with clinical manifestations. METHODS: Thirty-one patients consulted in Children's Hospital of Soochow University from January 2013 to February 2018 were enrolled in this study. The hot pot mutations of WAS gene in 31 patients were detected and related clinical phenotypes were analyzed retrospectively. RESULTS: All patients were male. The median onset age was 1 month (range, 0-83 months). Nine mutants were reported as novel mutations among 25 mutants detected in 31 patients, including c.1234_1235dupCC, c.1093-1097delG, c.28-30dupC, c.436G>T, c.273 + 10_273 + 11dupCC, c.995_996insG, c.1010T>A, c.332_333delCC and c.683C>T mutations. There were 25 cases of classic WAS which mutations included missense mutation, deletion mutation, insertion mutation, splicing mutation and nonsense mutation, 2 cases of X-linked thrombocytopenia (XLT) were induced by missense mutation, 1 case of intermittent X-linked thrombocytopenia (IXLT) was induced by splicing mutation, 2 cases of X-linked pancytopenia were induced by missense mutation. Intravenous immunoglobulin (IVIG) and glucocorticoid therapy in IXLT patient was effective, and remission could be sustained, platelets could be increased in the short-term in treated XLT patients, but only a small part of classic WAS patients(8.0%) showed transient response to it, the IVIG and glucocorticoid therapy did not improve the status of platelet in XLP patients. Immune laboratory examination showed that CD3 was decreased in 60.0% patients, CD19 was decreased in 12.0% patients, and CD56CD16 in 4 patients was decreased, accounting for 16.0%. Out of 24 patients, 22 patients were alive after treated with hematopoietic stem cell transplantation (HSCT), 4 patients who were not given HSCT died of brain bleeding and severe infection, 1 patient diagnosed as IXLT got remission and survived. CONCLUSION WAS gene defect is an important basis for the diagnosis of WAS and related diseases. IVIG plus glucocorticoid therapy is less effective for fewer patients, the HSCT is an effective treatment for WAS.
Genetic Diseases, X-Linked ; Humans ; Male ; Mutation ; Phenotype ; Retrospective Studies ; Thrombocytopenia ; Wiskott-Aldrich Syndrome Protein ; genetics

OBJECTIVE: To study the clinical features and gene mutation spectrum of children with sideroblastic anemia (SA) and the clinical value of targeted next-generation sequencing in the molecular diagnosis of children with SA. METHODS: Clinical data were collected from 36 children with SA. Targeted next-generation sequencing was used to detect mutations in SA-related pathogenic genes and genes associated with heme synthesis and mitochondrial iron metabolism. The association between genotype and clinical phenotype was analyzed. RESULTS: Of the 36 patients, 32 had congenital sideroblastic anemia (CSA) and 4 had myelodysplastic syndrome with ring sideroblasts (MDS-RS). Mutations in CSA-related genes were detected in 19 children (19/36, 53%), among whom 9 (47%) had ALAS2 mutation, 4 (21%) had SLC25A38 mutation, and 6 (32%) had mitochondrial fragment deletion. No pathogenic gene mutation was detected in 4 children with MDS-RS. Among the 19 mutations, 89% (17/19) were known mutations and 11% (2/19) were novel mutations. The novel mutation of the ALAS2 gene c.1153A>T(p.I385F) was rated as "possibly pathogenic" and the novel mutation of the SLC25A38 gene c.175C>T(p.Q59X) was rated as "pathogenic". CONCLUSIONS ALAS2 and SLC25A38 gene mutations are commonly seen in children with CSA, but mitochondrial gene fragment deletion also accounts for a relatively high proportion. For children with hypoplastic anemia occurring in infancy, mitochondrial disease should be considered.
5-Aminolevulinate Synthetase ; Anemia, Sideroblastic ; genetics ; Child ; Genetic Diseases, X-Linked ; Humans ; Mitochondrial Membrane Transport Proteins ; Mutation ; Myelodysplastic Syndromes ; Phenotype

OBJECTIVE: To explore the genetic basis for a case of recurrent fetal congenital hydrocephalus. METHODS: Next-generation sequencing was carried out for the fetus, the gravida and two of her sisters. RESULTS: The fetus was found to harbor a c.1765T>C (p.Tyr589His) mutation in exon 14 of the L1CAM gene, which was derived from the gravida. CONCLUSION Male fetuses with recurrent hydrocephalus should be subjected to testing of the L1CAM gene to facilitate genetic counseling and prenatal diagnosis.
DNA Mutational Analysis ; Female ; Fetus ; Genetic Diseases, X-Linked ; diagnosis ; genetics ; Humans ; Hydrocephalus ; diagnosis ; genetics ; Male ; Mutation ; Neural Cell Adhesion Molecule L1 ; genetics ; Pedigree ; Pregnancy