OBJECTIVE: To explore the clinical characteristics and genetic basis of two brothers featuring X-linked alpha thalassemia mental retardation (ATR-X) syndrome. METHODS: An infant who had presented at the Qilu Children's Hospital in 2020 for unstable upright head and inability to roll over and his family were selected as the study subjects. The clinical features of the child and one of his brothers were summarized, and their genomic DNA was subjected to targeted capture and next generation sequencing (NGS). RESULTS: The brothers had presented with mental retardation and facial dysmorphisms. NGS revealed that they had both harbored a hemizygous c.5275C>A variant of the ATRX gene located on the X chromosome, which was inherited from their mother. CONCLUSION The siblings were diagnosed with ATR-X syndrome. The discovery of the c.5275C>A variant has enriched the mutational spectrum of the ATRX gene.
Humans ; Infant ; Male ; alpha-Thalassemia/diagnosis* ; Ataxia Telangiectasia Mutated Proteins/genetics* ; East Asian People ; Intellectual Disability/genetics* ; Mental Retardation, X-Linked/diagnosis* ; Pedigree ; X-linked Nuclear Protein/genetics*

Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked intellectual disability. The main features of the patients include intellectual disability/global developmental delay, characteristic face, anomalies of fingers and toes, hypogonadism, linear skin hyperpigmentation, and tooth abnormalities in female patients, and obesity in male patients. A case of BFLS caused by a novel mutation of PHF6 gene who was treated in the Department of Pediatrics, Xiangya Hospital, Central South University was reported. The 11 months old girl presented the following symptons: Global developmental delay, characteristic face, sparse hair, ocular hypertelorism, flat nasal bridge, hairy anterior to the tragus, thin upper lip, dental anomalies, ankyloglossia, simian line, tapering fingers, camptodactylia, and linear skin hyperpigmentation. The gene results of the second-generation sequencing technology showed that there was a novel heterozygous mutation site c.346C>T (p.Arg116*) of the PHF6 (NM032458.3), variation rating as pathogenic variation. During the follow-up, the patient developed astigmatism, strabismus, awake bruxism, and stereotyped behavior, and the linear skin hyperpigmentation became gradually more evident. The disease is lack of effective therapy so far.
Humans ; Male ; Female ; Child ; Infant ; Intellectual Disability/genetics* ; Mental Retardation, X-Linked/pathology* ; Obesity/complications* ; Hypogonadism/pathology*

Humans ; Mental Retardation, X-Linked/genetics* ; Methyl-CpG-Binding Protein 2/genetics* ; Gene Duplication

OBJECTIVE: To analyze the clinical characteristics and genetic variant of a child featuring X-linked mental retardation. METHODS: Whole exome sequencing and Sanger sequencing were used for the detection of variant and pedigree validation, respectively. Clinical manifestation of patients with DDX3X gene variants were also reviewed. RESULTS: The child was found to harbor a heterozygous NM_001193416.3: c.1332_1333delCT (p.Leu445Serfs*19) variant of the DDX3X gene. The same variant was not found in either of her parents. CONCLUSION The child was diagnosed with X-linked mental retardation due to variant of the DDX3X gene. Above finding has enriched the spectrum of DDX3X gene variants and provided a basis for clinical diagnosis and prenatal diagnosis for this pedigrees.
Child ; DEAD-box RNA Helicases/genetics* ; Female ; Heterozygote ; Humans ; Intellectual Disability/genetics* ; Mental Retardation, X-Linked/genetics* ; Mutation ; Pedigree ; Pregnancy ; Exome Sequencing

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

OBJECTIVE: To analyze the clinical phenotype and genetic variants of a child with X-linked mental retardation caused by IQSEC2 gene mutation, and provide reference for the diagnosis of the disease. METHODS: The child was subjected to next generation sequencing (NGS), and the diagnosis was made by taking consideration of her clinical characteristics. RESULTS: The child has presented with global developmental delay, particularly in fine motor skill and language development, in addition with intellectual disability. Genetic testing revealed that she has harbored a heterozygous c.1861dup variant of the IQSEC2 gene, which was not detected in either parent. CONCLUSION The de novo c.186ldup variant of the IQSEC2 gene probably underlay the X-linked mental retardation in this child. Above finding has, expanded the spectrum of IQSEC2 gene mutations and provide a basis for the diagnosis of similar cases.
Female ; Guanine Nucleotide Exchange Factors/genetics* ; Heterozygote ; Humans ; Intellectual Disability/genetics* ; Mental Retardation, X-Linked/genetics* ; Mutation ; Phenotype

OBJECTIVE: To analyze the clinical phenotype and pathogenic variant in a child diagnosed with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH). METHODS: Clinical phenotype of the child was reviewed. Whole exome sequencing was carried out for the child. Candidate variant was verified by Sanger sequencing of the family member. RESULTS: The proband manifested dyskinesia, development delay, cerebellar hypoplasia and bilateral hearing impairment. WES results revealed that the proband has carried a pathogenic c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene, which was verified by Sanger sequencing to be a de novo variant. CONCLUSION The c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene probably underlay the MICPCH in the proband. Above finding has provided a basis for genetic counseling. WES should be considered for the diagnosis of neurological dysplasia.
Cerebellum/abnormalities* ; Child ; Developmental Disabilities ; Family ; Humans ; Mental Retardation, X-Linked ; Microcephaly/genetics* ; Nervous System Malformations

OBJECTIVE: To analyze the clinical symptom and parental origin of patients with MECP2 duplication syndrome in order to provide a basis for genetic counseling and prenatal diagnosis. METHODS: Clinical symptoms of four patients who were diagnosed with MECP2 duplication syndrome by copy number variation sequencing (CNV-Seq) were reviewed. The maternal origin of the duplications were verified. RESULTS: All patients were males, and CNV-Seq revealed that they have all harbored a duplication in the Xq28 region spanning 0.32 ~ 0.86 Mb, which were derived from asymptomatic mothers. The clinical symptoms of three patients with three copies included delayed speech, intellectual disability, and muscular hypotonia, while the patient with four copies had died at 6 months after birth, with clinical symptoms including recurrent infections, seizures, and spasticity. CONCLUSION The four cases of MECP2 duplication syndrome have shown complete penetrance and have all derived from asymptomatic mothers. As a stable and reliable method, CNV-Seq can accurately detect the MECP2 duplication syndrome.
Chromosomes, Human, X ; DNA Copy Number Variations ; Gene Duplication ; Humans ; Male ; Mental Retardation, X-Linked ; Methyl-CpG-Binding Protein 2/genetics* ; Phenotype

OBJECTIVE: To explore the genetic basis for a pedigree affected with X-linked recessive mental retardation Claes-Jensen type. METHODS: Genomic DNA was extracted from peripheral blood samples of the patient, his parents (phenotypically normal) and two elder brothers with similar clinical manifestations. Whole exome sequencing was carried out for the proband, and the result was verified by Sanger sequencing. RESULTS: The proband was found to harbor a hemizygous c.1565C>T missense variant in exon 11 of the KDM5C gene. The transition has resulted in replacement of serine by phenylalanine at position 522 (p.Ser522Phe). Sanger sequencing showed that the patient's two elder brothers and mother carried the same variant, which was predicted to be probably damaging by SIFT, PolyPhen2 and Mutation_Taster. The three affected brothers presented with similar clinical phenotypes characterized by mental retardation, speech delay, behavioral problem, self-limited epilepsy responsible to medication, short stature and microcephaly. The mother only had mild cognitive impairment and learning disability. The same variant was not found in their father and was unreported previously. CONCLUSION The c.1565C>T (p.Ser522Phe) of the KDM5C gene probably underlay the X-linked recessive mental retardation Claes-Jensen type in this pedigree.
Aged ; Female ; Histone Demethylases/genetics* ; Humans ; Male ; Mental Retardation, X-Linked/pathology* ; Mutation, Missense/genetics* ; Pedigree ; Phenotype ; Whole Exome Sequencing

OBJECTIVE: To explore the genetic basis for a family affected with mental retardation combined with autism. METHODS: For the family featuring X-linked recessive inheritance of mental retardation combined with autism, clinical data and peripheral blood samples were collected. Potential mutations of genes associated with intellectual impairment were sequenced with an Ion PGM platform. Suspected mutations were verified with a PCR-Sanger sequencing method. RESULTS: The patient with mental retardation had mild abnormal electroencephalograph(EEG), while brain MRI and CT scans showed no obvious abnormality. Two ABC (autism behavior checklist) testing scores were 73 and 66 when he was 7- and 13-year-old, respectively. A novel hemizygous mutation, c.64C>T (p.L22F), was detected in the GRIA3 gene in the patient, for which his mother was a heterozygous carrier. The mutation site was predicted to be possibly damaging and disease causing by PolyPhen_2 and MutationTaster. CONCLUSION The novel hemizygous c.64C>T (p.L22F) mutation of the GRIA3 gene probably underlies the phenotypes of mental retardation combined with autism in this family. Considering the variable clinical manifestation of mental retardation and genetic heterogeneity of autism, genetic testing is essential for making the correct diagnosis.
Adolescent ; Autistic Disorder ; genetics ; Child ; Humans ; Intellectual Disability ; genetics ; Male ; Mental Retardation, X-Linked ; genetics ; Mutation ; Receptors, AMPA ; genetics