Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.
Female ; Animals ; Mice ; Humans ; Child, Preschool ; Intellectual Disability/genetics* ; Heart Defects, Congenital/genetics* ; Facies ; Cleft Palate ; Muscle Hypotonia

OBJECTIVE: To explore the clinical features and genetic etiology of a child with Multiple congenital malformations-hypotonia-epilepsy syndrome type 3 (MCAHS3) and provide prenatal diagnosis for her parents. METHODS: A female child who had presented at Linyi People's Hospital on 27 July 2022 for recurrent convulsions for over 4 years was selected as the study subject. Clinical data of the child were collected. Peripheral blood samples were taken from the child and her parents and subjected for whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out on amniotic fluid sample at 18 weeks' gestation. Bioinformatic software was used to analyze the pathogenicity of the protein model for the variant loci. RESULTS: The child was a 4-year-old female with frequent seizures, peculiar facial appearance, hypotonia and severe developmental delay. Genetic analysis revealed that she has harbored compound heterozygous variants of the PIGT gene, namely c.1126del (p.H376Tfs*56) and c.1285G>C (p.E429Q), which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.1126del (p.H376Tfs*56) variant was predicted to be pathogenic (PVS1+PM2_Supporting+PM4), and c.1285G>C (p.E429Q) variant was predicted to be likely pathogenic (PM2_Supporting+PM3+PM4). Prenatal diagnosis suggested that the fetus also harbored the same compound heterozygous variants, and the pregnancy was terminated with induced labor. CONCLUSION The c.1126del (p.H376Tfs*56) and c.1285G>C (p.E429Q) compound heterozygous variants of the PIGT gene probably underlay the MCAHS3 in this patient, and prenatal diagnosis has prevented birth of further affected child in this family.
Humans ; Female ; Child ; Pregnancy ; Child, Preschool ; Muscle Hypotonia/genetics* ; Prenatal Diagnosis ; Computational Biology ; Epileptic Syndromes ; Facies

OBJECTIVE: To explore the clinical characteristics and genetic etiology for two children with Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (MEDHSIL). METHODS: Two children who had visited the Ningbo Women and Children's Hospital on October 15, 2021 were selected as the study subjects. Whole exome sequencing (WES) was carried out for both patients. Candidate variants were verified by Sanger sequencing of their family members. RESULTS: The two children were respectively found to harbor a heterozygous c.138delC (p.Ile47Serfs*42) variant and a c.833del (p.L278*) variant of the MEF2C gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS1+PS2+PM2_Supporting). CONCLUSION The c.138delC and c.833del variants of the MEF2C gene probably underlay the pathogenesis of MEDHSIL in the two children. Above findings have enriched the mutational spectrum of the MEF2C gene and enabled genetic counseling for their families.
Child ; Humans ; Family ; Genetic Counseling ; Language ; MEF2 Transcription Factors/genetics* ; Muscle Hypotonia/genetics* ; Neurodevelopmental Disorders

Objective: To summarize the genetic and clinical phenotypic characteristics of patients with early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) caused by multiple epidermal growth factor 10 (MEGF10) gene defect. Methods: The clinical data of 3 infants in 1 family with EMARDD caused by MEGF10 gene defect diagnosed in the Department of Neonatology, Xiamen Children's Hospital in April 2022 were analyzed retrospectively. Using "multiple epidermal growth factor 10" "myopathy" or "MEGF10" "myopathy" as the key words, and searching the relevant literature reports of CNKI, Wanfang Database and PubMed Database from the establishment of the database to September 2022. Combined with this family, the main clinical information and genotype characteristics of EMARDD patients caused by MEGF10 gene defect were summarized. Results: The proband, male, first infant of monozygotic twins, was admitted to hospital 7 days after birth "due to intermittent cyanosis with weak sucking". The infant had dysphagia accompanied with cyanosis of lips during feeding and crying after birth. Physical examination on admission revealed reduced muscle tone of the extremities, flexion of the second to fifth fingers of both hands with limited passive extension of proximal interphalangeal joints, and limited abduction of both hips. He was diagnosed as dysphagia of newborn, congenital dactyly. After admission, he was given limb and oral rehabilitation training, breathing gradually became stable and oral feeding fully allowed, and discharged along with improvement. The younger brother of the proband was admitted to the hospital at the same time, and his clinical manifestations, diagnosis and treatment process were the same as those of the proband. The elder brother of the proband died at the age of 8 months due to the delayed growth and development, severe malnutrition, hypotonia, single palmoclal crease and weak crying. A whole exon sequencing of the family was done, and found that the 3 children were all compound heterozygous variations at the same site of MEGF10 gene, with 2 splicing variants (c.218+1G>A, c.2362+1G>A), which came from the father and mother respectively, and the new variation was consistent with the autosomal recessive inheritance model. Three children were finally diagnosed as EMARDD caused by MEGF10 gene defect. There are 0 Chinese literature and 18 English literature that met the search conditions. Totally 17 families including 28 patients were reported. There were 31 EMARDD patients including 3 infants from this family. Among them, there were 13 males and 18 females. The reported age of onset ranged from 0 to 61 years. Except for 5 patients with incomplete clinical data, 26 patients were included in the analysis of phenotypic and genotypic characteristics. The clinical features were mainly dyspnea (25 cases), scoliosis (22 cases), feeding difficulties (21 cases), myasthenia (20 cases), and other features including areflexia (16 cases) and cleft palate or high palatal arch(15 cases). Muscle biopsy showed non-specific changes, with histological characteristics ranging from slight muscle fiber size variation to minicores change which was seen in all 5 patients with at least 1 missense mutation of allele. In addition, the adult onset was found in patients with at least 1 missense variant of MEGF10 gene. Conclusions: MEGF10 gene defect related EMARDD can occur in the neonatal period, and the main clinical features are muscle weakness, breathing and feeding difficulties. Patients with myopathy who have at least 1 missense mutation and muscle biopsy indicating minicores change may be relatively mild.
Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Young Adult ; Cyanosis ; Deglutition Disorders ; EGF Family of Proteins ; Muscle Hypotonia ; Muscle Weakness ; Muscular Diseases/genetics* ; Retrospective Studies

OBJECTIVE: To analyze the clinical features of 3M syndrome and effect of growth hormone therapy. METHODS: Clinical data of four children diagnosed with 3M syndrome by whole exome sequencing at Hunan Children's Hospital from January 2014 to February 2022 were retrospectively analyzed, which included clinical manifestation, results of genetic testing and recombinant human growth hormone (rhGH) therapy. A literature review was also carried our for Chinese patients with 3M syndrome. RESULTS: The clinical manifestations of the 4 patients included severe growth retardation, facial dysmorphism and skeletal malformations. Two patients were found to harbor homozygous variants of CUL7 gene, namely c.4717C>T (p.R1573*) and c.967_993delinsCAGCTGG (p.S323Qfs*33). Two patients were found to harbor 3 heterozygous variants of the OBSL1 gene including c.1118G>A (p.W373*), c.458dupG (p.L154Pfs*1002) and c.690dupC (p.E231Rfs*23), among which c.967_993delinsCAGCTGG and c.1118G>A were unreported previously. Eighteen Chinese patients with 3M syndrome were identified through the literature review, including 11 cases (11/18, 61.1%) carrying CUL7 gene variants and 7 cases (7/18, 38.9%) carrying OBSL1 gene variants. The main clinical manifestations were in keeping with previously reported. Four patients were treated with growth hormone, 3 showed obvious growth acceleration, and no adverse reaction was noted. CONCLUSION 3M syndrome has a typical appearance and obvious short stature. To attain accurate diagnosis, genetic testing should be recommended for children with a stature of less than -3 SD and facial dysmorphism. The long-term efficacy of growth hormone therapy for patients with 3M syndrome remains to be observed.
Humans ; Child ; Retrospective Studies ; Dwarfism/genetics* ; Muscle Hypotonia/genetics* ; Growth Hormone/therapeutic use* ; Cytoskeletal Proteins/genetics*

OBJECTIVE: To explore the clinical features and genetic basis of a child with Galactosemia. METHODS: A child who had presented at the Children's Hospital Affiliated to Zhengzhou University on November 20, 2019 was selected as the study subject. Clinical data of the child was collected. Whole exome sequencing was carried out for the child. Candidate variants were validated by Sanger sequencing. RESULTS: Clinical manifestations of the child have included anemia, feeding difficulty, jaundice, hypomyotonia, abnormal liver function and coagulation abnormality. Tandem mass spectrometry showed increased citrulline, methionine, ornithine and tyrosine. Urine organic acid analysis showed increased phenyllactic acid, 4-hydroxyphenylacetic acid, 4-hydroxyphenyllactic acid, 4-hydroxyphenylpyruvate and N-acetyltyrosine. Genetic testing revealed that the child has harbored compound heterozygous variants of the GALT gene, namely c.627T>A (p.Y209*) and c.370G>C (p.G124R), which were respectively inherited from her healthy parents. Among these, c.627T>A (p.Y209*) was known as a likely pathogenic variant, while c.370G>C (p. G124R) was unreported previously and also predicted as a likely pathogenic variant(PM1+PM2_Supporting+PP3_Moderate+PPR). CONCLUSION Above discovery has expanded the spectrum of the GALT gene variants underlying Galactosemia. Patients with thrombocytopenia, feeding difficulties, jaundice, abnormal liver function and coagulation abnormality without obvious causes should be analyzed by screening of metabolic diseases in combination with genetic testing.
Child ; Female ; Humans ; Galactosemias/genetics* ; Genetic Testing ; Health Status ; Methionine ; Muscle Hypotonia ; Mutation

OBJECTIVE: To explore the genetic etiology of a child with D bifunctional protein deficiency (DBPD) born to a consanguineous pedigree. METHODS: A child with DBPD who was admitted to the First Affiliated Hospital of Hainan Medical College on January 6, 2022 due to hypotonia and global developmental delay was selected as the study subject. Clinical data of her pedigree members were collected. Peripheral blood samples of the child, her parents and elder sisters were collected and subjected to whole exome sequencing. Candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 2-year-and-9-month-old female, had featured hypotonia, growth retardation, unstable head lift, and sensorineural deafness. Serum long-chain fatty acids were elevated, and auditory brainstem evoked potentials had failed to elicit V waves in both ears with 90 dBnHL stimulation. Brain MRI revealed thinning of corpus callosum and white matter hypoplasia. The child's parents were secondary cousins. Their elder daughter had a normal phenotype and no clinical symptoms related to DBPD. Elder son had frequent convulsions, hypotonia and feeding difficulties after birth, and had died one and a half month later. Genetic testing revealed that the child had harbored homozygous c.483G>T (p.Gln161His) variants of the HSD17B4 gene, for which both of her parents and elder sisters were carriers. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.483G>T (p.Gln161His) was rated as a pathogenic variant (PM1+PM2_Supporting+PP1+PP3+PP4). CONCLUSION The homozygous c.483G>T (p.Gln161His) variants of the HSD17B4 gene caused by the consanguineous marriage probably underlay the DBPD in this child.
Female ; Humans ; Pedigree ; Muscle Hypotonia ; Hearing Loss, Sensorineural ; Protein Deficiency ; Mutation

OBJECTIVES: To study the clinical and genetic features of Joubert syndrome (JS) in children. METHODS: A retrospective analysis was performed on the clinical data, genetic data, and follow-up data of 20 children who were diagnosed with JS in the Department of Children's Rehabilitation, the Third Affiliated Hospital of Zhengzhou University, from January 2017 to July 2022. RESULTS: Among the 20 children with JS, there were 11 boys and 9 girls. The common clinical manifestations were developmental delay (20 children, 100%), abnormal eye movement (19 children, 95%), and hypotonia (16 children, 80%), followed by abnormal respiratory rhythm in 5 children (25%) and unusual facies (including prominent forehead, low-set ears, and triangular mouth) in 3 children (15%), and no limb deformity was observed. All 20 children (100%) had the typical "molar tooth sign" and "midline cleft syndrome" on head images, and 6 children (30%) had abnormal eye examination results. Genetic testing was performed on 7 children and revealed 6 pathogenic genes, i.e., the CPLANE1, RPGRIP1L, MKS1, CC2D2A, CEP120, and AHI1 genes. CONCLUSIONS For children with developmental delay, especially those with abnormal eye movement and hypotonia, it is recommended to perform a head imaging examination to determine the presence or absence of "molar tooth sign" and "midline cleft syndrome", so as to screen for JS to avoid missed diagnosis and misdiagnosis. There are many pathogenic genes for JS, and whole-exome sequencing can assist in the diagnosis of JS.
Male ; Female ; Humans ; Child ; Cerebellum ; Abnormalities, Multiple/genetics* ; Kidney Diseases, Cystic/genetics* ; Eye Abnormalities/genetics* ; Retina ; Retrospective Studies ; Muscle Hypotonia/genetics*

Objective: To explore the clinical and genetic characteristics of children with dopa-responsive dystonia (DRD) caused by tyrosine hydroxylase (TH) gene variations. Methods: Clinical data of 9 children with DRD caused by TH gene variations diagnosed in the Department of Children Rehabilitation, the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2022 were retrospectively collected and analyzed, including the general conditions, clinical manifestations, laboratory tests, gene variations and follow-up data. Results: Of the 9 children with DRD caused by TH gene variations, 3 were males and 6 were females. The age at diagnosis was 12.0 (8.0, 15.0) months. The initial symptoms of the 8 severe patients were motor delay or degression. Clinical symptoms of the severe patients included motor delay (8 cases), truncal hypotonia (8 cases), limb muscle hypotonia (7 cases), hypokinesia (6 cases), decreased facial expression (4 cases), tremor (3 cases), limb dystonia (3 cases), diurnal fluctuation (2 cases), ptosis (2 cases), limb muscle hypertonia (1 case) and drooling (1 case). The initial symptom of the very severe patient was motor delay. Clinical symptoms of the very severe patient included motor delay, truncal hypotonia, oculogyric crises, status dystonicus, hypokinesia, decreased facial expression, and decreased sleep. Eleven TH gene variants were found, including 5 missense variants, 3 splice site variants, 2 nonsense variants, and 1 insertion variant, as well as 2 novel variants (c.941C>A (p.T314K), c.316_317insCGT (p.F106delinsSF)). Nine patients were followed up for 40 (29, 43) months, and no one was lost to follow-up. Seven of the 8 severe patients were treated by levodopa and benserazide hydrochloride tablets and 1 severe patient was treated by levodopa tablets. All the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets. Although the weight of the patients increased and the drug dosage was not increased, the curative effect remained stable and there was no obvious adverse reaction. One severe patient developed dyskinesia in the early stage of treatment with levodopa and benserazide hydrochloride tablets and it disappeared after oral administration of benzhexol hydrochloride tablets. Until the last follow-up, motor development of 7 severe patients returned to normal and 1 severe patient still had motor delay due to receiving levodopa and benserazide hydrochloride tablets for only 2 months. The very severe patient was extremely sensitive to levodopa and benserazide hydrochloride tablets and no improvement was observed in this patient. Conclusions: Most of the DRD caused by TH gene variations are severe form. The clinical manifestations are varied and easily misdiagnosed. Patients of the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets, and it takes a long time before full effects of treatment become established. Long-term effect is stable without increasing the drug dosage, and no obvious side effect is observed.
Female ; Humans ; Infant ; Male ; Benserazide/therapeutic use* ; Dystonia/genetics* ; Hypokinesia/drug therapy* ; Levodopa/pharmacology* ; Muscle Hypotonia ; Retrospective Studies ; Tyrosine 3-Monooxygenase/genetics*

OBJECTIVE: To analyze the clinical and genetic characteristics of a child featuring Xia-Gibbs syndrome. METHODS: Whole exome sequencing was carried out for the child. RESULTS: The patient has presented with developmental delay, hypotonia, strabismus and snoring. Cranial MRI revealed hypomyelination, while the EEGs were normal. Genetic testing revealed a de novo variant of the AHDC1 gene, namely c.730delA (p.Ile244Serfs*16), which was classified as pathogenic (PVS1+PS2+PM2). Together with 60 cases from the literature, individuals harboring a AHDC1 variant commonly have delayed motor milestones, speech delay, facial dysmorphism and hypotonia. Dysgenesis of corpus callosum is also common. In total 47 AHDC1 variants have been reported, among which truncating variants were the most common type. CONCLUSION The c.730delA (p.Ile244Serfs*16) variant of the AHDC1 gene probably underlay the Xia-Gibbs syndrome in this patient. Above finding has provided a basis for the clinical diagnosis.
Abnormalities, Multiple/genetics* ; Child ; DNA-Binding Proteins/genetics* ; Humans ; Intellectual Disability/genetics* ; Muscle Hypotonia ; Mutation ; Whole Exome Sequencing