Objective:To analyze the clinical characteristics and genotypic changes of six children with RARS2 gene variants. Methods:The clinical data of 6 children with RARS2 gene variants diagnosed at the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2024 were collected. Genetic variants were detected using trio-whole exome sequencing. Genomic DNA was extracted from samples and subjected to high-throughput sequencing. Variants were detected and analyzed using relevant databases and software. Pathogenic variants were validated by Sanger sequencing. The protein structure encoded by a previously unreported variant was predicted using a SWISS-MODEL online server. This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethics No.: 2024-373-01). Results:Among the six children, four were males and two were females, with the most recent follow-up age ranging from 1-year-and-1-month to 7 years old. The age of onset was under 1 year in all cases. All six children exhibited seizures, including infantile spasms in three, spasms and tonic spasms in one, and focal seizures in two. One child became seizure-free for 4 ~ 5 years following Valproic acid combined with topiramate and adrenocorticotropic hormone (ACTH) pulse therapy, but subsequently experienced a relapse. Another child has remained seizure-free for nearly one year with oral sodium valproate, levetiracetam, and a " cocktail" therapy. Seizures were not controlled in the remaining four children. Pontocerebellar hypoplasia was observed on neuroimaging in two children. All six patients exhibited severe psychomotor retardation. A total of 10 RARS2 gene variants were identified, three of which were previously unreported. Conclusion:The predominant clinical features of Pontocerebellar hypoplasia associated with RARS2 gene variants include infantile onset, severe psychomotor retardation or regression, drug-resistant epilepsy, and feeding difficulties. The characteristic neuroimaging finding is pontocerebellar hypoplasia. However, its appearance may vary widely with time. The majority of affected children have a poor prognosis.

Objective:To explore the clinical and genetic characteristics of two children diagnosed with two rare genetic diseases simultaneously.Methods:Two children with comorbidity of two genetic diseases due to dual genetic mutations diagnosed at the Third Affiliated Hospital of Zhengzhou University respectively in May 2022 and March 2023 were selected as the study subjects. Clinical and genetic data of the two children were retrospectively analyzed. This study has been approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-062-01).Results:Child 1 was a 2-year-and-4-month-old boy whose clinical manifestations included facial dysmorphism, developmental delay, short stature, microcephaly, cleft palate, cryptorchidism, hypospadias, recurrent infections and immunological abnormalities. Whole exome sequencing revealed that he had harbored a heterozygous c.6595delT (p.Y2199Ifs*65) variant of the KMT2D gene and a heterozygous c. 1892G>A (p.R631Q) variant of the PIK3R1 gene. This has led to a dual genetic diagnosis of Kabuki syndrome and PI3Kδ-related immunodeficiency type 36. Child 2 was a 15-year-old girl whose clinical manifestations included epilepsy, Albright′s hereditary osteodystrophy, long body trunk, short limbs, hypocalcemia, hyperphosphatemia and hyperparathyroidism. The child also had a family history of short stature. Whole exome sequencing revealed that she had harbored a heterozygous c. 2T>C (p.Met1? ) variant of the GNAS gene and deletion of exons 2 to 6 of the SHOX gene. The two variants have led to dual diagnose of pseudohypoparathyroidism and X-linked idiopathic short stature. Conclusion:When the clinical phenotype of a genetic disease is complex and cannot be fully explained with a single genetic variant, multiple pathogenic variants should be considered, and this may lead to the diagnosis of co-morbid genetic diseases. To adopt or supplement corresponding genetic testing in time and re-analyze the genetic data may facilitate accurate diagnosis of comorbid genetic diseases.

OBJECTIVE: To explore the clinical and genetic characteristics of two children diagnosed with two rare genetic diseases simultaneously. METHODS: Two children with comorbidity of two genetic diseases due to dual genetic mutations diagnosed at the Third Affiliated Hospital of Zhengzhou University respectively in May 2022 and March 2023 were selected as the study subjects. Clinical and genetic data of the two children were retrospectively analyzed. This study has been approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-062-01). RESULTS: Child 1 was a 2-year-and-4-month-old boy whose clinical manifestations included facial dysmorphism, developmental delay, short stature, microcephaly, cleft palate, cryptorchidism, hypospadias, recurrent infections and immunological abnormalities. Whole exome sequencing revealed that he had harbored a heterozygous c.6595delT (p.Y2199Ifs*65) variant of the KMT2D gene and a heterozygous c.1892G>A (p.R631Q) variant of the PIK3R1 gene. This has led to a dual genetic diagnosis of Kabuki syndrome and PI3Kδ-related immunodeficiency type 36. Child 2 was a 15-year-old girl whose clinical manifestations included epilepsy, Albright's hereditary osteodystrophy, long body trunk, short limbs, hypocalcemia, hyperphosphatemia and hyperparathyroidism. The child also had a family history of short stature. Whole exome sequencing revealed that she had harbored a heterozygous c.2T>C (p.Met1?) variant of the GNAS gene and deletion of exons 2 to 6 of the SHOX gene. The two variants have led to dual diagnose of pseudohypoparathyroidism and X-linked idiopathic short stature. CONCLUSION When the clinical phenotype of a genetic disease is complex and cannot be fully explained with a single genetic variant, multiple pathogenic variants should be considered, and this may lead to the diagnosis of co-morbid genetic diseases. To adopt or supplement corresponding genetic testing in time and re-analyze the genetic data may facilitate accurate diagnosis of co-morbid genetic diseases.
Child, Preschool ; Female ; Humans ; Male ; Class Ia Phosphatidylinositol 3-Kinase/genetics* ; Comorbidity ; Exome Sequencing ; Mutation ; Rare Diseases/genetics* ; Retrospective Studies ; Adolescent

OBJECTIVE: To analyze the clinical characteristics and genotypic changes of six children with RARS2 gene variants. METHODS: The clinical data of 6 children with RARS2 gene variants diagnosed at the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2024 were collected. Genetic variants were detected using trio-whole exome sequencing. Genomic DNA was extracted from samples and subjected to high-throughput sequencing. Variants were detected and analyzed using relevant databases and software. Pathogenic variants were validated by Sanger sequencing. The protein structure encoded by a previously unreported variant was predicted using a SWISS-MODEL online server. This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethics No.: 2024-373-01). RESULTS: Among the six children, four were males and two were females, with the most recent follow-up age ranging from 1-year-and-1-month to 7 years old. The age of onset was under 1 year in all cases. All six children exhibited seizures, including infantile spasms in three, spasms and tonic spasms in one, and focal seizures in two. One child became seizure-free for 4 ~ 5 years following Valproic acid combined with topiramate and adrenocorticotropic hormone (ACTH) pulse therapy, but subsequently experienced a relapse. Another child has remained seizure-free for nearly one year with oral sodium valproate, levetiracetam, and a "cocktail" therapy. Seizures were not controlled in the remaining four children. Pontocerebellar hypoplasia was observed on neuroimaging in two children. All six patients exhibited severe psychomotor retardation. A total of 10 RARS2 gene variants were identified, three of which were previously unreported. CONCLUSION The predominant clinical features of Pontocerebellar hypoplasia associated with RARS2 gene variants include infantile onset, severe psychomotor retardation or regression, drug-resistant epilepsy, and feeding difficulties. The characteristic neuroimaging finding is pontocerebellar hypoplasia. However, its appearance may vary widely with time. The majority of affected children have a poor prognosis.
Humans ; Male ; Female ; Child, Preschool ; Infant ; Child ; Olivopontocerebellar Atrophies/genetics* ; Arginine-tRNA Ligase/genetics* ; Mutation ; Cerebellar Diseases

OBJECTIVE: To explore the clinical and genetic characteristics of a child with intellectual development disorder and seizures due to a variant of AP2M1 gene. METHODS: Clinical data of a child with intellectual development disorder and epilepsy who was admitted to the Department of Pediatric Neurology of the Third Affiliated Hospital of Zhengzhou University in January 2021 were retrospectively analyzed. Peripheral blood samples of the child and his parents were collected for whole exome sequencing. Candidate variant was verified by Sanger sequencing and pathogenicity analysis. The three-dimensional structure of the AP2M1 protein was visualized using Chimera v1.10.1 software. Pathogenicity of candidate variant was classified according to the Standards and Guidelines for the Interpretation of Sequence Variants from the American College of Medical Genetics and Genomics American College of Medical Genetics (ACMG). With "AP2M1 gene" "epilepsy" "intellectual disability" as the keywords, relevant cases were searched from CNKI, Wanfang Data knowledge service platform and PubMed databases with the search time spanning from the establishment of the database to September 2024. This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethics No.: 2020-57). RESULTS: The child was a 8-years-and-6-months-old boy, who could raise his head at 3 months and sit alone at 8 months old. He could not walk alone at 1 year old and underwent 2 months' rehabilitation treatment, and could walk alone and call his parents at 1-and-a-half-years-old. At 4-years-and-10-months-old, he started to have frequent seizures, manifesting as low level of consciousness, body shaking, accompanied by blinking, lasting about a few seconds several times a day and could be relieved. With the treatment of sodium valproate combined with lamotrigine, the convulsions were controlled, but his movement and cognition were lagged behind. DNA sequencing revealed that he has harbored a novel variant of the AP2M1 gene (NM_004068.3) c.508C>T (p.Arg170Trp). Sanger sequencing confirmed that both of his parents were of the wild-type. According to the guidelines from the American College for Medical Genetics and Genomics (ACMG), the variant was rated as pathogenic (PS2+PS4+PM1+PM2+PP2+PP3). The difference between the wild-type and mutant AP2M1 proteins can be clearly viewed through its three-dimensional structure. Two previous reports have included 5 cases due to the same variant. Common manifestations have included seizures (100%, 5/5), motor retardation (100%, 5/5), intellectual impairment (100%, 5/5), autism spectrum disorder (60%, 3/5), ataxia (100%, 5/5), and special facial features (20%, 1/5). CONCLUSION The c.508C>T (p.Arg170Trp) variant of the AP2M1 gene may underlie the intellectual retardation and seizure in this child.
Humans ; Male ; Child ; Intellectual Disability/genetics* ; Seizures/genetics* ; Exome Sequencing ; Mutation

Objective:To explore the clinical and genetic characteristics of two children diagnosed with two rare genetic diseases simultaneously.Methods:Two children with comorbidity of two genetic diseases due to dual genetic mutations diagnosed at the Third Affiliated Hospital of Zhengzhou University respectively in May 2022 and March 2023 were selected as the study subjects. Clinical and genetic data of the two children were retrospectively analyzed. This study has been approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-062-01).Results:Child 1 was a 2-year-and-4-month-old boy whose clinical manifestations included facial dysmorphism, developmental delay, short stature, microcephaly, cleft palate, cryptorchidism, hypospadias, recurrent infections and immunological abnormalities. Whole exome sequencing revealed that he had harbored a heterozygous c.6595delT (p.Y2199Ifs*65) variant of the KMT2D gene and a heterozygous c. 1892G>A (p.R631Q) variant of the PIK3R1 gene. This has led to a dual genetic diagnosis of Kabuki syndrome and PI3Kδ-related immunodeficiency type 36. Child 2 was a 15-year-old girl whose clinical manifestations included epilepsy, Albright′s hereditary osteodystrophy, long body trunk, short limbs, hypocalcemia, hyperphosphatemia and hyperparathyroidism. The child also had a family history of short stature. Whole exome sequencing revealed that she had harbored a heterozygous c. 2T>C (p.Met1? ) variant of the GNAS gene and deletion of exons 2 to 6 of the SHOX gene. The two variants have led to dual diagnose of pseudohypoparathyroidism and X-linked idiopathic short stature. Conclusion:When the clinical phenotype of a genetic disease is complex and cannot be fully explained with a single genetic variant, multiple pathogenic variants should be considered, and this may lead to the diagnosis of co-morbid genetic diseases. To adopt or supplement corresponding genetic testing in time and re-analyze the genetic data may facilitate accurate diagnosis of comorbid genetic diseases.

Objective:To analyze the clinical characteristics and genotypic changes of six children with RARS2 gene variants. Methods:The clinical data of 6 children with RARS2 gene variants diagnosed at the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2024 were collected. Genetic variants were detected using trio-whole exome sequencing. Genomic DNA was extracted from samples and subjected to high-throughput sequencing. Variants were detected and analyzed using relevant databases and software. Pathogenic variants were validated by Sanger sequencing. The protein structure encoded by a previously unreported variant was predicted using a SWISS-MODEL online server. This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethics No.: 2024-373-01). Results:Among the six children, four were males and two were females, with the most recent follow-up age ranging from 1-year-and-1-month to 7 years old. The age of onset was under 1 year in all cases. All six children exhibited seizures, including infantile spasms in three, spasms and tonic spasms in one, and focal seizures in two. One child became seizure-free for 4 ~ 5 years following Valproic acid combined with topiramate and adrenocorticotropic hormone (ACTH) pulse therapy, but subsequently experienced a relapse. Another child has remained seizure-free for nearly one year with oral sodium valproate, levetiracetam, and a " cocktail" therapy. Seizures were not controlled in the remaining four children. Pontocerebellar hypoplasia was observed on neuroimaging in two children. All six patients exhibited severe psychomotor retardation. A total of 10 RARS2 gene variants were identified, three of which were previously unreported. Conclusion:The predominant clinical features of Pontocerebellar hypoplasia associated with RARS2 gene variants include infantile onset, severe psychomotor retardation or regression, drug-resistant epilepsy, and feeding difficulties. The characteristic neuroimaging finding is pontocerebellar hypoplasia. However, its appearance may vary widely with time. The majority of affected children have a poor prognosis.

Objective:To summarize the clinical characteristics of patients with epilepsy caused by focal cortical dysplasia (FCD), and identify the influencing factors for postoperative seizure controls.Methods:Fifty-seven patients with epilepsy caused by FCD admitted to Department of Neurosurgery, Third Affiliated Hospital of Zhengzhou University from July 2019 to November 2023 were chosen; standard preoperative evaluation, surgery, postoperative management and follow-up were performed. A retrospective study of clinical data, imaging and video electroencephalogram (VEEG) data, surgical approaches, pathological findings, and follow-up data was performed; influencing factors for postoperative seizure controls were analyzed.Results:In these 57 patients with epilepsy caused by FCD, 29 were males (50.88%) and 28 were females (49.12%). Onset age was 30.00 (8.00, 74.50) months, and surgery age was 95.00 (50.00, 138.50) months. Focal to bilateral tonic-clonic seizures (42/57; 73.68%) and epileptic spasms (13/57; 22.81%) were common seizure types. Cranial MRI was positive in 34 patients (59.65%), mainly manifested as abnormal cortical gyri/sulci morphology (17/57; 29.82%). In 43 patients accepted PET-CT, hypometabolic sites were detected in 40 (93.02%), and complete agreement between PET/MRI fusion results and actual lesion sites was noted in 40 (93.02%). FCD type I was noted in 16 patients (28.07%), type II in 39 (68.42%), and type III in 2 (3.51%). By December 2023, 44 (77.19%) had Engel grading I, 4 (7.02%) had grading II, 4 (7.02%) had grading III, and 5 (8.77%) had grading IV. Children with good prognosis (Engel grading I+II) and those with poor prognosis (Engel grading III+IV) showed significant differences in terms of time from first seizure to surgery, positive/negative MRI, and regularity of postoperative ASMs ( P<0.05). Conclusions:Focal to bilateral tonic-clonic seizure is the most common seizure type in patients with epilepsy caused by FCD, and abnormal cortical gyri/sulci morphology is the most common MRI manifestation; PET/MRI fusion imaging is superior to PET-CT or MRI in identifying epileptogenic foci. Poor seizure control can be noted in patients with long onset time to surgery, with negative cranial MRI results, or with irregular postoperative ASMs.

Objective:To explore the clinical and genetic characteristics of three children with Hyperekplexia.Methods:Three children who were diagnosed with Hyperekplexia at the Third Affiliated Hospital of Zhengzhou University between June 2018 and March 2020 were selected as the study subjects. Clinical data of the three children were collected. All children were subjected to whole exome sequencing. Pathogenicity of candidate variants were verified by Sanger sequencing and bioinformatic analysis.Results:The three children were all males, and had presented exaggerated startle reflexes and generalized stiffness in response to unexpected auditory or tactile stimulation, or had frequent traumatic falls following exaggerated startle. All children had shown positive nose-tapping reflex, though EEG and cranial MRI exams were all negative. Whole exome sequencing revealed that two children had harbored homozygous variants of the GLRB gene, of which the c. 1017_c.1018insAG (p.G340Rfs*14) was unreported previously. The third child had harbored compound heterozygous variants of the GLRA1 gene, among which the c.1262T>A (p.IIe421Asn) variant showed an unreported autosomal recessive inheritance. All children had responded well to clonazepam treatment. Conclusion:Patients with Hyperekplexia have typical clinical manifestations. Early clinical identification and genetic analysis can facilitate their diagnosis.

Objective:To explore the clinical and genetic characteristics of two children with Neurodevelopmental disorders (NDDs) due to variants of TANC2 gene. Methods:Clinical data of two children who were admitted to the Third Affiliated Hospital of Zhengzhou University respectively in April 2020 and April 2021 were retrospectively analyzed. Peripheral blood samples of the children and their parents were collected and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. By using " TANC2 gene", "Neurodevelopmental disorders", "Nervous system development disorders", " TANC2" as the key words, similar cases were searched from the CNKI, Wanfang database platform and PubMed database, with the search time set as from the establishment of the database to December 2023. This study was approved by Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethics No. 2020-57). Results:Case 1 was a 1-year-and-3-month-old girl who had developed convulsions at 1 year old and had three episodes of seizures. Her epilepsy had resolved with the treatment of oxcarbazepine, which was stopped at the age of 2-year-and-7-month. Her language, movement and intelligence development were all normal. Case 2 was a 1-year-and-10-month-old boy, who had developed convulsions at 1 year old. His seizure type was myoclonus, and the frequency was dozens of times a day. His epilepsy had resolved with the treatment of sodium valproate. His language, movement and intelligence development was delayed for about half a year. Genetic analysis showed that both children had harbored novel variants of the TANC2 gene (NM_025185.4), including c. 3398G>A (p.Gly1133Glu) and c.2829+ 1G>A, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the former was rated as likely pathogenic (PS2+ PM2_Supporting+ PP3) and the latter was rated as pathogenic (PVS1+ PS2+ PM2_Supporting). Two previous reports were retrieved, which had involved 17 cases and 16 variants. Common features had included autism spectrum disorder (70.6%, 12/17), intellectual disability (94.1%, 16/17), language and motor retardation (88.2%, 15/17; 58.8%, 10/17), facial dysmorphism, epilepsy, ataxia, and thoracic and spinal deformities. Conclusion:Variants of the TANC2 gene probably underlay the epilepsy and development delay in these children with NDDs.