Objective: To explore the genetic basis of a child with chronic kidney disease featuring renal shrinkage and creatinine increase. Methods: Peripheral venous blood samples were taken from the child, his brother and two parents and subjected to whole exome sequencing. Suspected mutations were verified by Sanger sequencing. Bioinformatic analysis was carried out to predict the influence of mutations on the structure and function of the protein product. Results: High-throughput and Sanger sequencing revealed that the child has carried compound heterozygous mutations of the COL4A4 gene, namely c. 4550T>G in exon 47 (inherited from his mother) and c. 199C>T in exon 5 (inherited from his father). Neither mutation was reported previously. Bioinformatic analysis showed that both mutations have located in highly conserved regions. The same mutations were not found in his brother. Conclusion The compound heterozygous c. 4550T>G and c. 199C>T mutations probably underlie the disease in this child. The findings have enriched the mutation spectrum of the COL4A4 gene.

OBJECTIVE: To detect variants of NF1 gene among thirteen patients with neurofibromatosis type 1. METHODS: Genomic DNA was extracted from peripheral blood samples of the patients. High-throughput sequencing was employed to detect potential variants of the NF1 and NF2 genes. RESULTS: Thirteen pathogenic variants were identified among the patients, which included one NF1 deletion, three missense variants, three nonsense variants and six frameshifting variants. Among these, 10 variants have been associated with neurofibromatosis type 1. c.4180A>T (p.Asn1394Tyr), c.4217dupT (p.Leu1406fs) and c.1753dupT(p.Leu585Phefs*3) were unreported previously. Based on the guidelines of the American College of Medical Genetics and Genomics, c.4180A>T (p.Asn1394Tyr) was predicted to be likely pathogenic (PS2+PM1+PM2+PP2), while c.4217dupT (p.Leu1406fs) and c.1753dupT (p.Leu585Phefs*3) were predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION Variants of the NF1 gene probably underlay the disease among these children. Above findings have enriched the the spectrum of NF1 gene variants.
Child ; Genes, Neurofibromatosis 1 ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Mutation ; Neurofibromatosis 1/genetics*

OBJECTIVE: To explore the genetic basis of a pedigree affected with peroneal muscular atrophy. METHODS: Neuroelectrophysiological examination and whole exome sequencing were carried out for the proband, a six-year-and-ten-month-old boy. Suspected variant was verified in his family members through Sanger sequencing. Bioinformatic analysis was carried to predict the conservation of amino acid sequence and impact of the variant on the protein structure and function. RESULTS: Electrophysiological examination showed demyelination and axonal changes of motor and sensory nerve fibers. A heterozygous missense c.1066A>G (p. Thr356Ala) variant was found in exon 11 of the MFN2 gene in the proband and his mother, but not in his sister and father. Bioinformatic analysis using PolyPhen-2 and Mutation Taster software predicted the variant to be pathogenic, and that the sequence of variation site was highly conserved among various species. Based no the American College of Medical Genetics and Genomics standards and guidelines, the c.1066A>G (p. Thr356Ala) variant of MFN2 gene was predicted to be likely pathogenic (PS1+ PM2+ PP3+ PP4). CONCLUSION The heterozygous missense c.1066A>G (p.Thr356Ala) variant of the MFN2 gene probably underlay the disease in the proband, and the results have enabled genetic counseling and prenatal diagnosis for this family.
Charcot-Marie-Tooth Disease/genetics* ; Child ; China ; Drosophila Proteins/genetics* ; Exons ; Female ; Heterozygote ; Humans ; Male ; Membrane Proteins/genetics* ; Mutation ; Pedigree ; Pregnancy ; Whole Exome Sequencing

OBJECTIVE: To explore the genetic basis of a child with chronic kidney disease featuring renal shrinkage and creatinine increase. METHODS: Peripheral venous blood samples were taken from the child, his brother and two parents and subjected to whole exome sequencing. Suspected mutations were verified by Sanger sequencing. Bioinformatic analysis was carried out to predict the influence of mutations on the structure and function of the protein product. RESULTS: High-throughput and Sanger sequencing revealed that the child has carried compound heterozygous mutations of the COL4A4 gene, namely c.4550T>G in exon 47 (inherited from his mother) and c.199C>T in exon 5 (inherited from his father). Neither mutation was reported previously. Bioinformatic analysis showed that both mutations have located in highly conserved regions. The same mutations were not found in his brother. CONCLUSION The compound heterozygous c.4550T>G and c.199C>T mutations probably underlie the disease in this child. The findings have enriched the mutation spectrum of the COL4A4 gene.
Child ; Collagen Type IV ; genetics ; Exons ; Female ; Humans ; Male ; Mutation ; Nephritis, Hereditary ; diagnosis ; genetics ; Pedigree ; Whole Exome Sequencing

OBJECTIVE: To explore the clinical characteristics and genetic variants in a child with tyrosine hydroxylase-deficient infantile Parkinsonism with motor delay. METHODS: Clinical feature of the patient was summarized. Genomic DNA was extracted from peripheral blood samples taken from the child and her family members. All exons of GCH1, TH and SPR genes were subjected to targeted capture and next-generation sequencing. Suspected variants were verified by Sanger sequencing. RESULTS: The child could not sit alone at 7 month and 11 days. Physical examination suggested motor retardation and hypotonia, limb stiffness, head nodding, slight torticollis, and language and intellectual developmental delays. She developed involuntary shaking of limbs at 3 month old, which lasted approximately 10 seconds and aggregated with excitement and before sleeping. Cranial MRI revealed widening of subarachnoid space on the temporomandibular and particularly temporal sides. Genetic testing revealed that she has carried a nonsense c.457C>T (p.R153X) variant, which was known to be pathogenic, and a novel missense c.720C>G (p.I240M) variant of the TH gene. The two variants were derived from her father and mother, respectively. CONCLUSION The child was diagnosed as tyrosine hydroxylase-deficient infantile Parkinsonism with motor delay due to compound heterozygous variants of the TH gene. Above finding has enriched the spectrum of TH gene variants.
Brain ; diagnostic imaging ; Codon, Nonsense ; Dystonic Disorders ; congenital ; genetics ; Female ; Genetic Testing ; High-Throughput Nucleotide Sequencing ; Humans ; Infant ; Magnetic Resonance Imaging ; Mutation ; Parkinsonian Disorders ; genetics ; Tyrosine 3-Monooxygenase ; genetics

Objective: To explore the clinical and genetic characteristics of primary coenzyme Q10 deficiency caused by coenzyme Q4 (COQ4) variants. Methods: Clinical data were collected, while COQ4 gene was sequenced. Results: Here were reported a boy of 3 months old who came to our hospital presented with feeding difficulties, repeated respiratory infections, convulsions for 3 months. He was subsequently diagnosed as cerebral atrophy, and growth retardation. All exons were sequenced.c.211G>A(p.A71T, maternal), c. 436T>A(p.F146I, paternal) were detected. After treatment with coenzyme Q10, the convulsive symptoms improved significantly. Literature review revealed that totally 14 cases with primary coenzyme Q10 deficiency caused by COQ4 gene mutation were reported. The onset age varies from neonatal to 18 years old, and the clinical manifestations are heterogeneous, including cardiomyopathy, epilepsy, ataxia, cerebellar atrophy, respiratory insufficiency, and growth retardation. Conclusion For cases with atypical clinical manifestations of primary coenzyme Q10 deficiency, gene detection is helpful for an early diagnosis and treatment.

OBJECTIVE: To carry out Sanger sequencing for MMACHC gene variants among 65 Chinese pedigrees affected with combined methylmalonic aciduria and homocysteinemia, and summarize their genetic and clinical characteristics and prognosis. METHODS: Clinical characteristics of the 65 children identified with Methylmalonic acidemia and homocysteinemia at the Children's Hospital Affiliated to Zhengzhou University (Zhengzhou Children's Hospital) from April 2017 to April 2022 were selected as the study subjects. Potential variants of the MMACHC gene were detected by direct sequencing of the PCR products. RESULTS: The median age of the 65 children was 3 months (14 days to 17 years old). These included 28 cases (43.08%) from neonatal screening, 11 cases (16.92%) with a history of jaundice, and 9 cases (13.85%) with various degrees of anemia. The main clinical symptoms included development delay, slow growth, epilepsy, hydrocephalus, lethargy, feeding difficulty, regression or decline in motor ability, recurrent respiratory infections, anemia, jaundice, respiratory and heart failures, hydrocephalus, limb weakness, and hypertension. Blood and urine tandem mass spectrometry screening has revealed increase of methylmalonic acid, propionyl carnitine, propionyl carnitine/acetylcarnitine ratio, and propionyl carnitine/free carnitine ratio to various extents, and blood homocysteine was increased in all patients. The detection rate of genetic variants was 98.46% (128/130), and in total 22 types of MMACHC gene variants were detected. The most common ones have included c.609G>A (W203X) (58/128), c.658-660del (K220del) (19/128), and c.80A>G (Q27A) (16/128). Two novel variants have been identified, namely c.565C>T (p.R189C) and c.624_ 625delTG (p.A208Afs), which were respectively predicted as likely pathogenic (PM2_Supporting+PM3+PP2+PP3) and pathogenic (PVS1+PM2_Supporting+PM3+PP2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Exon 4 had the highest frequency for the detection. CONCLUSION Identification of MMACHC gene variants has confirmed the diagnosis in the children, among which the c.609G>A variant has the highest frequency. Discovery of the new variants has enriched the mutational spectrum of the MMACHC gene.
Humans ; Amino Acid Metabolism, Inborn Errors/genetics* ; Hydrocephalus ; Oxidoreductases

Objective:To investigate the clinical phenotype and gene variation conditions in neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), so as to provide a basis for genetic counseling and clinical diagnosis and treatment of the family.Methods:11 cases of neonatal intrahepatic cholestasis who visited the Children's Hospital Affiliated to Zhengzhou University between February 2019 and March 2021 were selected as the study subjects. High-throughput sequencing technology was used to detect the gene variation condition in 11 neonatal patients and 100 normal control neonates. The suspicious loci and family members were verified by Sanger sequencing and QPCR technology.Results:All 11 children with NICCD had different degrees of jaundice and liver damage symptoms, combined with coagulation dysfunction and anemia ( n = 7), cardiac malformation ( n = 2), elevated myocardial enzymes ( n = 4), hyperlipidemia ( n = 1), hyperkalemia ( n = 1), persistent diarrhea ( n = 3), developmental delay ( n = 1). A total of 10 different types of SLC25A13 gene mutations were detected in 11 cases, including three frameshift mutations, two splicing changes, two missense mutations, one intron insertion, one nonsense mutation, and one heterozygous deletion. After reviewing literature and databases, c.1878delG(p.I627Sfs*73) and exon11 deletion were novel mutations that had not been reported at home or abroad. Conclusion:The clinical features of NICCD are non-specific, and genetic testing aids in the early and accurate diagnosis of the disease, providing an important basis for clinical treatment and genetic counseling for family members. In addition, the detection of novel mutation sites has enriched the SLC25A13 gene variation spectrum.

Objective:To explore the clinical phenotype and genetic etiology for seven children with CHARGE syndrome (CS).Methods:Clinical data of 7 children with CS diagnosed between March 2020 and December 2022 at the Children′s Hospital Affiliated to Zhengzhou University were analyzed. Genomic DNA was extracted from peripheral blood samples from the children and their parents, and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing and pathogenicity analysis. This study was approved by the Medical Ethics Committee of the Children′s Hospital Affiliatedto Zhengzhou University (Ethics No. 2024-K-023).Results:The ages of the children had ranged from 1 day after birth to 12 years old, and all of them had shown growth retardation. The reasons for their admission had included postnatal breathing, swallowing and feeding difficulties in five cases. One child was found to have abnormal external genitalia in conjunct with hearing impairment, whilst another child had shown no secondary sexual characteristics during puberty. All of the children were found to harbor CHD7 gene variants, which included 3 nonsense variants, 2 frameshifting variants and 2 missense variants, i. e., c. 6292C>T (p.R2098*), c.2754G>A (p.W918*), c. 469C>T (p.R157*), c. 3308T>A (p.V1103D), c. 7111delC (p.Q2371Kfs), c. 6023delA (p.D2008Vfs) and c. 3565C>T (p.R1189C). All of the variants were de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 3308T>A (p.V1103D) and c. 3565C>T (p.R1189C) variants were rated as likely pathogenic (PS2+ PM2_Supporting+ PP3), whilst the remainders were rated as pathogenic (PVS1+ PS2+ PM2_Supporting). Conclusion:There is strong clinical and genetic heterogeneity in CS. Early genetic testing may facilitate accurate diagnosis. The detection of novel variants has expanded the phenotypic spectrum of CS and the mutational spectrum of the CHD7 gene.

Objective:To investigate the clinical and genetic features of patients with spastic paraplegia and psychomotor retardation with or without seizures (SPPRS) caused by HACE1 gene mutation. Methods:Clinical data, auxiliary examination and genetic test results of a child with SPPRS caused by HACE1 gene mutation who was admitted to Henan Children′s Hospital in April 2019 were collected. The clinical and genotypic characteristics of children with SPPRS were summarized by searching the relevant literature up to June 2024, retrieved from CNKI, Wanfang and PubMed databases with the terms of " HACE1" "SPPRS" "seizures" "spastic paraplegia". Results:The patient was a 11 months and 20 days old male, with a clinical phenotype including global developmental delay, leg spastic tremor, frequent epileptic seizures, obesity, and concurrent urethral malformation. Brain magnetic resonance imaging (MRI) showed enlarged bilateral ventricles, hypoplastic corpus callosum, delayed myelination. Genetic test results revealed compound heterozygous variants c.994C>T (p.R332 *) and c.1679-2A>G in the HACE1 gene (according to the transcript NM_020771), respectively inherited from his mother and father, with c.1679-2A>G being a newly reported variant. A total of 6 English literatures reported 21 SPPRS patients in 11 families, and HACE1 gene mutations were mainly characterized by nonsense mutations. The main clinical manifestations included global developmental delay (21 cases), movement disorders (21 cases), intellectual disabilities (18 cases), seizures (13 cases), obesity (13 cases), skeletal abnormalities (11 cases), microcephaly (9 cases), ocular abnormalities (9 cases), distinctive facial features (5 cases), sensorineural hearing loss (5 cases), and short stature (3 cases). MRI predominantly showed hypoplasia of the corpus callosum, ventricular dilation, paucity of white matter and cerebral atrophy. There were no clear genotype-phenotype correlations. A total of 13 HACE1 gene mutations were reported, including 9 nonsense mutations, 2 frameshift mutations, 1 in-frame mutation, and 1 missense mutation. Among the 11 families, only 2 families with 5 patients were caused by compound heterozygous mutations, c.1852_1853del (p.L832del) and c.454C>T (p.Q152 *), c.2242C>T (p.R748 *) and c.2019_2020insTTTAGGTATTTTTAGGTATT (p.P674fs). The other 16 patients in 9 families were caused by homozygous mutations of the remaining 9 mutations. Conclusions:SPPRS is rare and usually occurs in infancy. The main clinical manifestations include comprehensive developmental delay, movement disorders, epilepsy, etc. Currently, no clear genotype-phenotype correlation has been found. The c.1679-2A>G variant of the HACE1 gene is an unreported variant and enriches the mutation spectrum of the HACE1 gene.