The fragile X syndrome is a common X-linked mental retardation and autism, affecting females as well as males. The fragile site X chromosomes were studied in a series of 153 mentally retarded boys of unknown etiology to determine the frequency of fragile X syndrome, and to assess the feasibility of making a clinical diagnosis of the fragile X syndrome in young boys before cytogenetic results were known. The 10 boys (6.4%) were positive for fra (X) (q27). The phenotype of fra (X) (q27) positive patients were typical except one who also had sex chromosomal mosaicism. There were three pairs of siblings among the fra (X) (q27) positive patients. Frequency of expression of the fragile site was in 10 to 47 per cent of cells. In addition, 19 boys showed a previously unsuspected chromosomal abnormality. The frequency of the fragile X syndrome in the present study is not significantly different from those in Caucasians and Japanese population. The fragile X syndrome can be recognized by noting key aspects of family history as well as the clinical features in mentally retarded boys.
Child ; Child, Preschool ; Fragile X Syndrome/diagnosis/epidemiology/*genetics ; Humans ; Intellectual Disability/*genetics ; Karyotyping ; Male

Intellectual disability, occurring in 1%-3% of the general population, is a common disease of the nervous system in children. Since diverse genetic and environmental factors contribute to its pathogenesis, the etiological diagnosis of intellectual disability is challenging with respect to the selection of diagnostic tests. It is important to determine the etiology of intellectual disability for the assessment of prognosis, treatment and the family plan. This paper summarizes the research progress in etiology and diagnosis for intellectual disability and introduces the recommended clinical genetics diagnostic approach from the American Academy of Pediatrics.
Chromosome Banding ; High-Throughput Nucleotide Sequencing ; Humans ; Intellectual Disability ; diagnosis ; etiology ; genetics ; Microarray Analysis

OBJECTIVE: To explore the genetic etiology for a child featuring mental retardation, language delay and autism. METHODS: G-banding chromosomal karyotyping and single nucleotide polymorphism array (SNP-array) were carried out for the child and her parents. RESULTS: The child was found to have a 46,XX,dup(8p?) karyotype, for which both of her parents were normal. SNP-array revealed that the child has harbored a 6.8 Mb deletion in 8p23.3p23.1 and a 21.8 Mb duplication in 8p23.1p12, both of which were verified as de novo pathogenic copy number variants. CONCLUSION The clinical features of the child may be attributed to the 8p deletion and duplication. SNP-array can facilitate genetic diagnosis for children featuring mental retardation in conjunct with other developmental anomalies.
Humans ; Child ; Pregnancy ; Female ; Intellectual Disability/genetics* ; Prenatal Diagnosis ; Karyotyping ; Chromosome Banding ; Chromosome Deletion

OBJECTIVE: To analyze the (CGG)n repeats of FMR1 gene among patients with unexplained mental retardation. METHODS: For 201 patients with unexplained mental retardation, the (CGG)n repeats of the FMR1 gene were analyzed by PCR and FragilEase RESULTS: For the 201 patients with unexplained mental retardation, 15 were identified with full mutations of the FMR1 gene. The prevalence of fragile X syndrome (FXS) in patients with unexplained mental retardation was determined as 7.5% (15/201). Prenatal diagnosis was provided for 6 pregnant women with pre- or full mutations. Analysis revealed that women with mental retardation and full FMR1 mutations exhibited a skewed XCI pattern with primary expression of the X chromosome carrying the mutant allele. CONCLUSION FXS has a high incidence among patients with unexplained mental retardation. Analysis of FMR1 gene (CGG)n repeats in patients with unexplained mental retardation can facilitate genetic counseling and prenatal diagnosis for their families. FMR1 gene (CGG)n repeats screening should be recommended for patients with unexplained mental retardation.
Female ; Fragile X Mental Retardation Protein/genetics* ; Fragile X Syndrome/genetics* ; Humans ; Intellectual Disability/genetics* ; Mutation ; Pregnancy ; Prenatal Diagnosis

OBJECTIVES: To summarize the clinical phenotype and genetic characteristics of children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations. METHODS: A retrospective analysis was performed on the medical data of 8 children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations who were diagnosed and treated in the Department of Pediatrics, Xiangya Hospital of Central South University. RESULTS: The mean age of onset was 9 months for the 8 children. All children had moderate-to-severe developmental delay (especially delayed language development), among whom 7 children also had seizures. Among these 8 children, 7 had novel heterozygous mutations (3 with frameshift mutations, 2 with nonsense mutations, and 2 with missense mutations) and 1 had 6p21.3 microdeletion. According to the literature review, there were 48 Chinese children with mental retardation caused by SYNGAP1 gene mutations (including the children in this study), among whom 40 had seizures, and the mean age of onset of seizures was 31.4 months. Frameshift mutations (15/48, 31%) and nonsense mutations (19/48, 40%) were relatively common in these children. In terms of treatment, among the 33 children with a history of epileptic medication, 28 (28/33, 85%) showed response to valproic acid antiepileptic treatment and 16 (16/33, 48%) achieved complete seizure control after valproic acid monotherapy or combined therapy. CONCLUSIONS Children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations tend to have an early age of onset, and most of them are accompanied by seizures. These children mainly have frameshift and nonsense mutations. Valproic acid is effective for the treatment of seizures in most children.
Child ; Humans ; Intellectual Disability/diagnosis* ; Codon, Nonsense ; Retrospective Studies ; Valproic Acid ; ras GTPase-Activating Proteins/genetics* ; Mutation ; Seizures/genetics*

OBJECTIVETo explore the clinical feature and genetic diagnosis for Smith-Magenis syndrome (SMS).

METHODThe clinical data, including craniofacial anomalies, physical and mental status were analyzed. Routine and high resolution G-banding was performed to analyze the karyotype of the patient and her parents, and array comparative genomic hybridization (array CGH) was used to detect small chromosome anomaly.

RESULTA-two-year old girl was sent to our clinic for mental retardation and cardiac malformation. Some sleep problems were reported by parents, including difficulties falling asleep, shortened sleep cycles. She also had some neurobehavioral symptoms including hyperactivity and self-injurious behaviors head-banging. She had distinctive craniofacial features including low hairline, frontal bossing, a broad face, broad nasal bridge, a tented upper lip, prognathism, low-set ears and high-vaulted arch. She had moderate mental retardation. Cardiac findings included ventricular septal defect, atrial septal defect, overriding aorta and pulmonary hypertension. Primary ventriculomegaly was seen in magnetic resonance imaging (MRI). Routine karyotype analysis showed a karyotype of 46, XX. However, high resolution karyotype analysis showed a suspected partial deletion of the short arm of chromosome 17. Array comparative genomic hybridization (array CGH) finely mapped the deletion to a 3.8 Mb region on 17p11.2. The molecular karyotype was then ascertained as 46, XX.arr17p11.2(16543655-20374751)×1dn. The parents had normal karyotypes.

CONCLUSIONSmith-Magenis syndrome is a multisystem disorder characterized by developmental delay and mental retardation, distinctive craniofacial features, sleep disturbance and behavioral problems. Array comparative genomic hybridization (array CGH) finely mapped the deletion on 17p11.2.

Child, Preschool ; Chromosome Deletion ; Chromosomes, Human, Pair 17 ; Female ; Humans ; Intellectual Disability ; Karyotyping ; Smith-Magenis Syndrome ; diagnosis ; genetics

OBJECTIVETo investigate the relationship between subtelomeric rearrangements and idiopathic mental retardation (MR).

METHODSThirty unrelated patients were recruited using strict selection criteria. Patients were screened by multiplex ligation-dependent probe amplification (MLPA) for subtelomeric imbalance.

RESULTSFive subtelomeric deletions/duplications were identified. They were: 4p deletion, 21p duplication, 10p duplication combined with 4p deletion, 15p duplication, and 9p deletion combined with 3p duplication. These subtelomeric rearrangements were previously unidentified by conventional technique.

CONCLUSIONChildren with unexplained mental retardation are related with subtelomeric rearrangements. MLPA is a rapid and an effective technique for detecting genetic abnormalities in patients with idiopathic MR.

Child ; Chromosome Aberrations ; Female ; Gene Deletion ; Gene Duplication ; Humans ; Intellectual Disability ; diagnosis ; genetics ; Ligase Chain Reaction ; methods ; Male

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*

OBJECTIVE: To explore the genetic basis of two children with unexplained psychomotor developmental delay and facial dysmorphisms suggestive of Coffin-Siris syndrome (CSS). METHODS: A boy and a girl suspected for CSS at the 980th Hospital of the People's Liberation Army Joint Service Support Force respectively in July 2019 and January 2021, and seven members from their families, were selected as the study subjects. Clinical data and family history of the children were collected, and detailed physical examination was carried out, in addition with laboratory and related auxiliary examinations. Potential variants and copy number variations (CNVs) were detected by whole exome sequencing (WES) and copy number variation sequencing (CNV-seq). RESULTS: Child 1, an 8-month-old female, had featured microcephaly, atrial septal defect, curving of fifth finger/toe, and low limb muscle tone. Child 2 was a 2.5-year-old male with language delay, social impairment, dense hair but no curving of the fifth fingers. Genetic testing revealed that child 1 had loss of heterozygosity for exons 8 to 21 of the ARID1B gene, which was unreported previously. Family verification showed that both of her parents were of the wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and American Society of Molecular Pathology (AMP), the variant was rated as pathogenic (PVS1+PS2+PM2-supporting). Child 2 was found to harbor a heterozygous c.4263-6 (IVS17) T>G variant of the ARID1B gene. Transcriptome sequencing confirmed that the variant can affect the normal splicing, resulting in retention of a 5 bp sequence in intron 17. Family verification showed that both of his parents were of the wild type. Based on the guidelines from the ACMG, the variant was rated as pathogenic (PS2+PM2-supporting+PP3+PS3). CONCLUSION WES and RNA-seq have confirmed the diagnosis of CSS in both children. Discovery of the novel variants has expanded the spectrum of pathogenic mutations underlying CSS, and provided a basis for the genetic counseling.
Child, Preschool ; Female ; Humans ; Infant ; Male ; Abnormalities, Multiple/diagnosis* ; DNA Copy Number Variations ; DNA-Binding Proteins/genetics* ; Intellectual Disability/diagnosis* ; Micrognathism/genetics* ; Mutation ; Transcription Factors/genetics*

OBJECTIVETo analyze the potential pathogenic genomic imbalance in children with unexplained intellectual disability (ID) and/or developmental delay (DD) and its association with phenotypes, and to investigate the value of array-based comparative genomic hybridization (array-CGH) in clinical molecular genetic diagnosis.

METHODSThe whole genome of 16 children with ID/DD was scanned by the array-CGH for detection of genomic copy number variations (CNVs), and the revealed genomic imbalance was confirmed by multiplex ligation-dependent probe amplification.

RESULTSG-band karyotyping of peripheral blood cells showed no abnormalities in the 16 children. The results of the array-CGH revealed that 6 (38%) of the 16 patients had genomic CNVs, and 3 cases of CNVs were normal polymorphic changes; 1 CNV was a microdeletion of 4p16.3, which was the critical region for Wolf-Hirschhorn syndrome, and 1 CNV was a microdeletion of 7q11.23, which was the critical region for Williams-Beuren syndrome. Moreover, a CNV was identified with two duplications at 2q22.2 and 15q21.3 in a boy, which proved to have a clinical significance due to its association with ID, brain DD, unusual facies, cryptorchidism, irregular dentition, etc.

CONCLUSIONSArray-CGH allows for the etiological diagnosis in some of the children with unexplained ID/DD. As a high-throughput and rapid tool, it has a great clinical significance in the etiological diagnosis of ID/DD.

Adolescent ; Child ; Comparative Genomic Hybridization ; methods ; Developmental Disabilities ; diagnosis ; genetics ; Female ; Humans ; Infant ; Intellectual Disability ; diagnosis ; genetics ; Male ; Multiplex Polymerase Chain Reaction