A 7-year-old girl was admitted to the hospital with rapidly progressive vision loss. Since 1 year of age, she had exhibited developmental delay accompanied by visual impairment and neutropenia. Combined with genetic testing and molecular pathogenicity analysis, she was diagnosed with Cohen syndrome (CS) caused by compound heterozygous variants in VPS13B (c.6940+1G>T and c.2911C>T). The c.6940+1G>T variant resulted in exon 38 skipping, leading to a frameshift and premature termination. Reverse transcription quantitative polymerase chain reaction revealed significantly reduced VPS13B gene expression (P<0.05). Bioinformatic analysis suggested that both variants likely produce truncated proteins. This case highlights that integrating clinical features with molecular pathogenicity assessment (DNA, RNA, and protein analysis) can improve early diagnostic accuracy for CS.
Humans ; Female ; Child ; Vesicular Transport Proteins/genetics* ; Developmental Disabilities/etiology* ; Muscle Hypotonia/etiology* ; Myopia/etiology* ; Heterozygote ; Intellectual Disability/etiology* ; Microcephaly/etiology* ; Obesity/genetics* ; Growth Disorders/etiology* ; Retinal Degeneration/genetics* ; Psychomotor Disorders/genetics* ; Fingers/abnormalities*

Global developmental delay (GDD) and intellectual disability (ID) refer to deficits in cognitive and adaptive functioning that arise during the developmental period. GDD/ID is often accompanied by complex developmental abnormalities, with congenital craniofacial malformations being among the most common, such as craniosynostosis, cleft lip and palate, and congenital tooth agenesis. However, the underlying mechanisms of GDD/ID associated with congenital craniofacial malformations remain unclear. With the increasing number of reported genetic syndromes, genetic factors are emerging as key contributors to the concurrent abnormalities in brain and craniofacial development. Studies have identified Wnt, SHH, FGF, and BMP as classical regulatory molecules in craniofacial development, and their roles have also been closely linked to various stages of brain development. This review focuses on the regulatory roles of Wnt, SHH, FGF, and BMP signaling pathways in brain and craniofacial development, as well as the pathogenic mechanisms underlying their association with GDD/ID and craniofacial malformations. The aim is to provide new insights into the etiology of GDD/ID combined with congenital craniofacial malformations.
Humans ; Craniofacial Abnormalities/complications* ; Signal Transduction ; Developmental Disabilities/metabolism* ; Intellectual Disability/complications* ; Animals ; Hedgehog Proteins/genetics* ; Fibroblast Growth Factors/genetics*

OBJECTIVE: To explore the clinical features and management of a child with Chitayat syndrome. METHODS: A child presented at the Fengqing People's Hospital on August 8 2019 was selected as the study subject. Clinical data of the child were retrospectively analyzed. Peripheral blood samples were collected from the child and his father and sister. Whole-exome sequencing (WES) was carried out. Candidate variant was verified by Sanger sequencing. Genome Browser, AlphaFold, and PolyPhen-2 were employed for protein structure simulation and amino acid sequence conservation analysis. Pathogenicity of the variant was rated based on guidelines from the American College of Medical Genetics and Genomics (ACMG). Literature was retrieved from databases including CNKI, Wanfang, and PubMed using the keyword "Chitayat syndrome". The clinical characteristics and prognosis of patients with Chitayat syndrome were reviewed and analyzed. This study was approved by the Ethics Committee the Seventh Affiliated Hospital of Sun Yat-sen University (Ethics No.: KY-2024-086-01). RESULTS: The child was born at full term and had special facial features, skeletal abnormalities, recurrent respiratory tract infections and global developmental delay. WES and Sanger sequencing revealed that he has harbored a heterozygous c.266A>G p.(Tyr89Cys) variant of the ERF gene. Protein structure modeling suggested that the mutant protein has increased spatial distance between the side chain group and DNA, which may reduce its binding affinity to DNA. Amino acid sequence analysis indicated that the p.Tyr89 residue is highly conserved across multiple species. The variant was therefore classified as pathogenic (PM1+PM2_Supporting+PM6+PS1+PP3). The patient was diagnosed with "Chitayat syndrome". Nutritional support and rehabilitation training were recommended, though the child had died of severe pneumonia at 13 months old. Literature retrieval has collected 7 relevant articles, which involved 14 cases of Chitayat syndrome confirmed by genetic testing. Together with our case, all patients had facial dysmorphisms and skeletal deformities. Fourteen patients (93.3%) had respiratory distress. Seven of them (46.7%) had recurrent respiratory infections and 7 (46.7%) were confirmed with respiratory tract malacia. Eight (53.3%) patients had neuropsychological retardation, while 8 (53.3%) had growth delay. The main interventions for Chitayat syndrome include respiratory and nutritional support, and rehabilitation training for developmental delays. CONCLUSION Chitayat syndrome is rarely seen and its clinical manifestations may vary. Airway management and early intervention of developmental delay are important for improving the prognosis.
Humans ; Male ; Exome Sequencing ; Female ; Mutation ; Child, Preschool ; Infant ; Developmental Disabilities/genetics*

OBJECTIVE: To analyze the clinical manifestations and genotype of a child with You-Hoover-Fong syndrome (YHFS) to enhance clinical understanding of this disease. METHODS: Clinical data of a child who visited the Department of Pediatric Neurorehabilitation of the Women's and Children's Hospital Affiliated to Xiamen University in March 2025 for global developmental delay was collected. Peripheral blood samples of the child and his parents were collected for chromosomal microarray analysis and whole exome sequencing (WES). Sanger sequencing was performed for parental validation, and candidate variant was assessed for pathogenicity. Clinical and genetic analyses were conducted based on the child's phenotype. A literature review was performed by retrieving previously reported cases of YHFS due to TELO2 gene variants. This study was approved by the Medical Ethics Committee of the Women's and Children's Hospital Affiliated to Xiamen University (Ethics No.: KY-2023-044-K02). RESULTS: The child was a 1-year-and-2-month-old male presenting with global developmental delay, encephalodysplasia, congenital heart disease and distinctive facial features. WES revealed that the child has harbored compound heterozygous variants of the TELO2 gene, namely c.1826G>A (p.Arg609His) and c.1514_1515delAG (p.Glu505Alafs21). Sanger sequencing confirmed that his mother carried a heterozygous c.1826G>A variant and his father carried a heterozygous c.1514_1515delAG variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as likely pathogenic (PM2_Supproting+PM3_Strong+PP1+PP3; PVS1+PM2_Supproting). Literature review has identified 9 articles reporting 31 cases of YHFS due to TELO2 gene variants, with primary clinical manifestations including developmental delay, intellectual disability, distinctive facial features, and congenital heart disease. CONCLUSION The c.1826G>A (p.Arg609His) and c.1514_1515delAG (p.Glu505Alafs*21) compound heterozygous variants of the TELO2 gene probably underlay the pathogenesis of this child. Above finding has provided a basis for the clinical and genetic diagnosis of the child, which also enriched the mutational spectrum of the TELO2 gene, and improved understanding of YHFS.
Humans ; Male ; Infant ; Heterozygote ; Developmental Disabilities/genetics* ; Female ; Exome Sequencing ; Mutation ; Phenotype ; Abnormalities, Multiple/genetics* ; Child, Preschool

OBJECTIVE: To explore the genetic basis for a boy affected with Cohen syndrome. METHODS: A boy admitted to Children's Hospital of Nanjing Medical University in January 2021 was selected as the study subject. Genome DNA was extracted from peripheral blood samples from the child and his parents. Whole exome sequencing (WES) was carried out. And candidate variants were verified by Sanger sequencing. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 202106060-1). RESULTS: WES revealed that the child has harbored compound heterozygous variants of the VPS13B gene, namely c.1563+1G>A and c.3007insC (p.A1003Afs*13), which were inherited from his mother and father, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rates as pathogenic. The c.3007insC (p.A1003Afs*13) was unreported previously. CONCLUSION The compound heterozygous variants c.1563+1G>A and c.3007insC (p.A1003Afs*13) of the VPS13B gene probably underlay the pathogenesis of Cohen syndrome in this child. Above finding has enriched the mutational spectrum of VPS13B gene.
Humans ; Male ; Vesicular Transport Proteins/genetics* ; Intellectual Disability/genetics* ; Muscle Hypotonia/genetics* ; Microcephaly/genetics* ; Fingers/abnormalities* ; Myopia/genetics* ; Obesity/genetics* ; Developmental Disabilities/genetics* ; Mutation ; Exome Sequencing ; Child ; Heterozygote ; Retinal Degeneration

The patient is a 10-month and 21-day-old girl who began to show developmental delays at 3 months of age, with severe language developmental disorders, stereotyped movements, and easily provoked laughter. Physical examination revealed fair skin and a flattened occiput. At 10 months of age, a video electroencephalogram suggested atypical absence seizures, with migrating slow-wave activity observed during the interictal period. Whole exome sequencing of three family members indicated a novel mutation in the AP2M1 gene, c.508C>T (p.R170W), in the patient. A total of six cases of autosomal dominant intellectual developmental disorder 60 with seizures associated with mutations in the AP2M1 gene have been reported both domestically and internationally (including this study). The main clinical features included developmental delays (6 cases), language developmental disorders (5 cases), stereotyped movements (3 cases), a tendency to smile (1 case), and atypical absence seizures (4 cases). Interictal electroencephalograms showed widespread spike waves and spike-slow wave discharges (5 cases), and migrating slow-wave activity (1 case). The c.508C>T (p.R170W) mutation may be a hotspot for mutations in the AP2M1 gene, and its clinical features are similar to those of Angelman syndrome.
Humans ; Female ; Seizures/genetics* ; Infant ; Mutation ; Intellectual Disability/genetics* ; Electroencephalography ; Developmental Disabilities/genetics*

OBJECTIVE: To explore the clinical features and genetic etiology of two children with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH). METHODS: Two children with MICPCH who were presented at the Henan Provincial People's Hospital between April 2019 and December 2021 were selected as the study subjects. Clinical data of the two children were collected, along with peripheral venous blood samples of them and their parents, and amniotic fluid sample of the mother of child 1. Whole exome sequencing (WES), array-comparative genomic hybridization (aCGH) and real-time quantitative PCR (qPCR) were carried out for the children, their parents and the fetus. The pathogenicity of candidate variants were evaluated. RESULTS: Child 1 was a 6-year-old girl featuring motor and language delay, whilst child 2 was a 4.5-year-old girl mainly featuring microcephaly and mental retardation. WES revealed that child 2 has harbored a 158.7 kb duplication in Xp11.4 (chrX: 41446160_41604854), which has encompassed exons 4~14 of the CASK gene. The same duplication was not found in either of her parents. aCGH revealed that child 1 has harbored a 29 kb deletion at Xp11.4 (chrX: 41637892_41666665), which encompassed exon 3 of the CASK gene. The same deletion was not found in either of her parents and the fetus. The above results were confirmed by qPCR assay. Above deletion and duplication were not found in the ExAC, 1000 Genomes and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PS2+PM2_Supporting). CONCLUSION The deletion of exon 3 and duplication of exons 4~14 of the CASK gene probably underlay the pathogenesis of MICPCH in these two children, respectively.
Humans ; Child ; Female ; Child, Preschool ; Microcephaly/genetics* ; Developmental Disabilities/genetics* ; Intellectual Disability/complications* ; Comparative Genomic Hybridization ; Mutation

OBJECTIVE: To explore the clinical and genetic characteristics of two children with developmental delay. METHODS: Two children who had presented at the Children's Hospital Affiliated to Shandong University on August 18, 2021 were enrolled as the study subjects. Clinical and laboratory examination, chromosomal karyotyping and high-throughput sequencing were carried out for both children. RESULTS: Both children had a 46,XX karyotype. High-throughput sequencing showed that they have respectively carried a c.489delG (p.Q165Rfs*14) and a c.1157_1158delAT (p.Y386Cfs*22) frameshifting variant of the CTCF gene, both had a de novo origin and were unreported previously. CONCLUSION The CTCF gene variants probably underlay the development delay in the two children. Above discovery has enriched the mutational spectrum of the CTCF gene and has important implications for revealing the genotype-phenotype correlation for similar patients.
Child ; Humans ; Developmental Disabilities/genetics* ; High-Throughput Nucleotide Sequencing ; Intellectual Disability/genetics* ; Karyotyping ; Mutation

OBJECTIVE: To explore the genetic basis for a child with congenital heart disease (CHD) and global developmental delay (GDD). METHODS: A child who was hospitalized at the Department of Cardiac Surgery of Fujian Children's Hospital on April 27, 2022 was selected as the study subject. Clinical data of the child was collected. Umbilical cord blood sample of the child and peripheral blood samples of his parents were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 3-year-and-3-month-old boy, had manifested cardiac abnormalities and developmental delay. WES revealed that he had harbored a nonsense variant of c.457C>T (p.Arg153*) in the NONO gene. Sanger sequencing showed that neither of his parents has carried the same variant. The variant has been recorded by the OMIM, ClinVar and HGMD databases, but not in the normal population databases of 1000 Genomes, dbSNP and gnomAD. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), it was rated as a pathogenic variant. CONCLUSION The c.457C>T (p.Arg153*) variant of the NONO gene probably underlay the CHD and GDD in this child. Above finding has expanded the phenotypic spectrum of the NONO gene and provided a reference for the clinical diagnosis and genetic counseling for this family.
Humans ; Male ; Computational Biology ; DNA-Binding Proteins ; Genetic Counseling ; Genomics ; Heart Defects, Congenital/genetics* ; Mutation ; Parents ; RNA-Binding Proteins ; Child, Preschool ; Developmental Disabilities/genetics*

OBJECTIVE: To explore the genetic etiology of two patients with developmental delay and intellectual disability. METHODS: Two children who were respectively admitted to Henan Provincial People's Hospital on August 29, 2021 and August 5, 2019 were selected as the study subjects. Clinical data were collected, and array comparative genomic hybridization (aCGH) was carried out on the children and their parents for the detection of chromosomal microduplication/microdeletions. RESULTS: Patient 1 was a 2-year-and-10-month female and patient 2 was a 3-year-old female. Both children had featured developmental delay, intellectual disability, and abnormal findings on cranial MRI. aCGH revealed that patient 1 has harbored arr[hg19] 6q14.2q15(84621837_90815662)×1, a 6.19 Mb deletion at 6q14.2q15, which encompassed ZNF292, the pathogenic gene for Autosomal dominant intellectual developmental disorder 64. Patient 2 has harbored arr[hg19] 22q13.31q13.33(46294326_51178264)×1, a 4.88 Mb deletion at 22q13.31q13.33 encompassing the SHANK3 gene, haploinsufficiency of which can lead to Phelan-McDermid syndrome. Both deletions were classified as pathogenic CNVs based on the guidelines of American College of Medical Genetics and Genomics (ACMG) and were not found in their parents. CONCLUSION The 6q14.2q15 deletion and 22q13-31q13.33 deletion probably underlay the developmental delay and intellectual disability in the two children, respectively. Haploinsufficiency of the ZNF292 gene may account for the key clinical features of the 6q14.2q15 deletion.
Humans ; Child ; Female ; Child, Preschool ; Intellectual Disability/genetics* ; Comparative Genomic Hybridization ; Chromosome Disorders/genetics* ; Chromosome Deletion ; Magnetic Resonance Imaging ; Chromosomes, Human, Pair 22 ; Developmental Disabilities/genetics* ; Carrier Proteins/genetics* ; Nerve Tissue Proteins/genetics*