Social skills, behavioral problems, and academic competence of students with intellectual disabilities / Habilidades sociais, problemas de comportamento e competência acadêmica de alunos com deficiência intelectual / Habilidades sociales, problemas de conducta y competencia académica de estudiantes con discapacidad intelectual

This study had as general objective to characterize and associate social skills, behavior problems, and academic competence of students with intellectual disabilities in school inclusion and; as specific objectives to verify predictive values for social skills and differences between groups diagnosed with intellectual disability and other associated diagnoses. This was a quantitative, cross-sectional, descriptive, correlational, predictive, and comparative study. Forty-four students with intellectual disability participated (11 of them presented other associated diagnoses), who were evaluated by 42 guardians and 34 teachers. The instruments used were Social Skills Rating System (SSRS-BR) and the Parental Educative Social Skills Interview Script (RE-HSE-P). The evaluation from guardians and teachers were different. Social skills were negatively associated with behavior problems and positively associated with academic competence; behavior problems and diagnosis were negative predictors to social skills. There were significant differences in the groups. The results highlight the importance of intervention programs to develop social skills.(AU)

O estudo teve como objetivo geral caracterizar e associar habilidades sociais, problemas de comportamento e competência acadêmica de alunos com deficiência intelectual em inclusão educacional e; como objetivos específicos verificar valores preditivos para habilidades sociais e diferenças entre grupos com diagnóstico de deficiência intelectual somente e com outros diagnósticos associados. Trata-se de um estudo quantitativo, transversal, descritivo, correlacional, preditivo e comparativo. Participaram 44 alunos com deficiência (11 apresentavam outros diagnósticos associados), que foram avaliados por 42 responsáveis e 34 professoras. Os instrumentos utilizados foram Social Skills Rating System (SSRS-BR) e Roteiro de Entrevista de Habilidades Sociais Educativas Parentais (RE-HSE-P). A avaliação de responsáveis e professores foi diferente. Habilidades sociais foram negativamente associadas aos problemas de comportamento e positivamente associadas a competência acadêmica; problemas de comportamento e diagnósticos associados foram preditores negativos de habilidades sociais. Houve diferença significativa entre grupos. Resultados evidenciam a importância de programas para promoção de habilidades sociais.(AU)

Este estudio tuvo como objetivo general caracterizar y asociar las habilidades sociales, los problemas de conducta y la competencia académica de estudiantes con discapacidad intelectual en la inclusión escolar; y como objetivos específicos verificar los valores predictivos de las habilidades sociales y las diferencias entre grupos diagnosticados con discapacidad intelectual y otros diagnósticos asociados. Se trató de un estudio cuantitativo, transversal, descriptivo, correlacional, predictivo y comparativo. Participaron 44 estudiantes con discapacidad intelectual (11 de ellos presentaban otros diagnósticos asociados), quienes fueron evaluados por 42 tutores y 34 docentes. Los instrumentos utilizados fueron el Sistema de Evaluación de Habilidades Sociales (SSRS-BR) y el Guion de Entrevista de Habilidades Sociales para Educación de los Padres (RE-HSE-P). Las evaluaciones de los tutores y docentes fueron diferentes. Las habilidades sociales se asociaron negativamente con problemas de conducta y positivamente con la competencia académica; los problemas de conducta y el diagnóstico fueron predictores negativos de las habilidades sociales. Hubo diferencias significativas entre los grupos. Los resultados destacan la importancia de los programas de intervención para desarrollar habilidades sociales con la población estudiada.(AU)

¿Qué puede esconder el retraso global del desarrollo? A propósito de un caso de causa genética / What can Global Developmental Delay Conceal? Apropos of a Case with a Genetic Cause

Se presenta un niño de 6 años con antecedente de retraso del lenguaje que llevó a sus padres a realizar múltiples consultas. En un primer momento, su cuadro fue interpretado como parte de un retraso global del desarrollo. Posteriormente, el paciente presentó convulsiones y episodios de descompensación metabólica, comenzando desde entonces su seguimiento por los Servicios de neurología, genética y metabolismo. Finalmente, tras varios estudios complementarios, por medio de un exoma trío se arribó al diagnóstico de síndrome de microduplicación del cromosoma 7q11.23, lo que justifica tanto el retraso global de desarrollo del paciente como su clínica neurológica. (AU)

A six-year-old boy presents with a history of language delay that led his parents to make multiple consultations. At first, we interpreted his condition as part of a global developmental delay. Subsequently, the patient presented seizures and episodes of metabolic decompensation, and since then, he had to be followed up by neurology, genetics, and metabolism services. Finally, after several complementary studies, following a trio exome analysis, we diagnosed chromosome 7q11.23 microduplication syndrome, which explains his global developmental delay and neurological symptoms. (AU)

Clinical and genetic characteristics of 9 rare cases with coexistence of dual genetic diagnoses / 中华儿科杂志

Objective: To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses (DGD). Methods: Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively. Results: Among the 9 children, 6 were boys and 3 were girls. The age of last visit or follow-up was 5.0 (2.7,6.8) years. The main clinical manifestations included motor retardation, mental retardation, multiple malformations, and skeletal deformity. Cases 1-4 were all all boys, showed myopathic gait, poor running and jumping, and significantly increased level of serum creatine kinase. Disease-causing variations in Duchenne muscular dystrophy (DMD) gene were confirmed by genetic testing. The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, and cerebral cavernous malformations type 3, respectively. Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1, COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV, Turner syndrome (45, X0/46, XX chimera) with TH gene-related Segawa syndrome, Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1, and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy. DMD was the most common, and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations. Conclusions: Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes. When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease, a second rare genetic disease should be considered, and autosomal dominant diseases caused by de novo heterozygous pathogenic variation should be paid attention to. Trio-based whole-exome sequencing combining a variety of molecular genetic tests would be helpful for precise diagnosis.

Autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations: a report of 8 cases and literature review / 中国当代儿科杂志

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.

Genetic analysis of two children with developmental delay and intellectual disability / 中华医学遗传学杂志

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.

Analysis of a child with X-linked intellectual disability due to a maternal de novo splicing variant of the PAK3 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology for a child with profound intellectual disabilities and obvious behavioral abnormalities.@*METHODS@#A male child who had presented at the Zhongnan Hospital of Wuhan University on December 2, 2020 was selected as the study subject. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. Short tandem repeat (STR) analysis was carried out to determine its parental origin. The splicing variant was also validated in vitro with a minigene assay.@*RESULTS@#WES results revealed that the child had harbored a novel splicing variant of c.176-2A>G in the PAK3 gene, which was inherited from his mother. The results of minigene assay have confirmed aberrant splicing of exon 2. According to the guidelines from the American College of Medical Genetics and Genomics, it was classified as a pathogenic variant (PVS1+PM2_Supporting+PP3).@*CONCLUSION@#The novel splicing variant c.176-2A>G of the PAK3 gene probably underlay the disorder in this child. Above finding has expanded the variation spectrum of the PAK3 gene and provided a basis for genetic counseling and prenatal diagnosis for this family.

Clinical and genetic analysis of a child with Alazami syndrome due to compound heterozygous variants of LARP7 gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and genetic basis of a child with Alazami syndrome (AS).@*METHODS@#A child who presented at Tianjin Children's Hospital on June 13, 2021 was selected as the study subject. The child was subjected to whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing.@*RESULTS@#WES revealed that the child has harbored two frameshifting variants of the LARP7 gene, namely c.429_430delAG (p.Arg143Serfs*17) and c.1056_1057delCT (p.Leu353Glufs*7), which were verified by Sanger sequencing to be respectively inherited from his father and mother.@*CONCLUSION@#The compound heterozygous variants of the LARP7 gene probably underlay the pathogenesis in this child.

Clinical features and genetic analysis of a child with EAST/SeSAME syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a EAST/SeSAME syndrome child featuring epilepsy, ataxia, sensorineural deafness and intellectual disability.@*METHODS@#A child with EAST/SeSAME syndrome who had presented at the Third Affiliated Hospital of Zhengzhou University in January 2021 was selected as the study object. Peripheral blood samples of the child and her parents were collected and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing.@*RESULTS@#Genetic testing revealed that the child has harbored compound heterozygous variants of the KCNJ10 gene, namely c.557T>C (p.Val186Ala) and c.386T>A (p.Ile129Asn), which were inherited from her mother and father, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted as likely pathogenic (PM1+PM2_Supporting+PP3+PP4; PM1+PM2_Supporting+PM3+PP3+PP4).@*CONCLUSION@#The patient was diagnosed with EAST/SeSAME syndrome due to the compound heterozygous variants of the KCNJ10 gene.

Analysis of genetic variants and clinical manifestations of two children with Kabuki syndrome / 中华医学遗传学杂志

OBJECTIVE@#To report on two children with Kabuki syndrome due to variants of the KMT2D gene and summarize their clinical and genetic characteristics.@*METHODS@#Two children who had presented at the Ningbo Women and Children's Hospital respectively on August 19 and November 10, 2021 were selected as the study subjects. Clinical data were collected. Both children were subjected to whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing.@*RESULTS@#Both children had featured motor and language developmental delay, facial dysmorphism and mental retardation. Genetic testing revealed that both had harbored de novo heterozygous variants of the KMT2D gene, namely c.10205del (p.Leu3402Argfs*3) and c.5104C>T (p.Arg1702*), both of which were rated as pathogenic variants based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*CONCLUSION@#The c.10205del (p.Leu3402Argfs*3) and c.5104C>T (p.Arg1702*) variants of the KMT2D gene probably underlay the pathogenesis in these two children. Above finding has not only provided a basis for their diagnosis and genetic counseling, but also enriched the spectrum of KMT2D gene variants.

Clinical and genetic analysis of a child with Mental retardation autosomal dominant 51 / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic basis of a child with Mental retardation autosomal dominant 51 (MRD51).@*METHODS@#A child with MRD51 who was hospitalized at Guangzhou Women and Children's Medical Center on March 4, 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her parents were collected and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#The child, a 5-year-and-3-month-old girl, had manifested autism spectrum disorder (ASD), mental retardation (MR), recurrent febrile convulsions and facial dysmorphism. WES revealed that she has harbored a novel heterozygous variant of c.142G>T (p.Glu48Ter) in the KMT5B gene. Sanger sequencing confirmed that neither of her parents has carried the same variant. The variant has not been recorded in the ClinVar, OMIM and HGMD, ESP, ExAC and 1000 Genomes databases. Analysis with online software including Mutation Taster, GERP++ and CADD indicated it to be pathogenic. Prediction with SWISS-MODEL online software suggested that the variant may have a significant impact on the structure of KMT5B protein. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic.@*CONCLUSION@#The c.142G>T (p.Glu48Ter) variant of the KMT5B gene probably underlay the MRD51 in this child. Above finding has expanded the spectrum of KMT5B gene mutations and provided a reference for clinical diagnosis and genetic counseling for this family.

Genetic analysis of a child with Pitt-Hopkins syndrome due to a novel variant of TCF4 gene derived from low percentage maternal mosaicism / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a child with Pitt-Hopkins syndrome.@*METHODS@#A child who had presented at the Medical Genetics Center of Gansu Provincial Maternal and Child Health Care Hospital on February 24, 2021 and his parents were selected as the study subjects. Clinical data of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to trio-whole exome sequencing (trio-WES). Candidate variant was verified by Sanger sequencing. Karyotype analysis was also carried out for the child, and her mother was subjected to ultra-deep sequencing and prenatal diagnosis upon her subsequent pregnancy.@*RESULTS@#The clinical manifestations of the proband included facial dysmorphism, Simian crease, and mental retardation. Genetic testing revealed that he has carried a heterozygous c.1762C>T (p.Arg588Cys) variant of the TCF4 gene, for which both parents had a wild-type. The variant was unreported previously and was rated as likely pathogenic based on the guidelines of the American College of Medical Genetics and Genomics (ACMG). Ultra-deep sequencing indicated that the variant has a proportion of 2.63% in the mother, suggesting the presence of low percentage mosaicism. Prenatal diagnosis of amniotic fluid sample suggested that the fetus did not carry the same variant.@*CONCLUSION@#The heterozygous c.1762C>T variant of the TCF4 gene probably underlay the disease in this child and has derived from the low percentage mosaicism in his mother.

Diagnostic value of whole exome sequencing for patients with intellectual disability or global developmental delay / 中华医学遗传学杂志

OBJECTIVE@#To assess the diagnostic value of whole exome sequencing (WES) for patients with intellectual disability (ID) or global developmental delay (GDD).@*METHODS@#134 individuals with ID or GDD who presented at Chenzhou First People's Hospital between May 2018 and December 2021 were selected as the study subjects. WES was carried out on peripheral blood samples of the patients and their parents, and candidate variants were verified by Sanger sequencing, copy number variation sequencing (CNV-seq) and co-segregation analysis. The pathogenicity of the variants was predicted based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#A total of 46 pathogenic single nucleotide variants (SNVs) and small insertion/deletion (InDel) variants, 11 pathogenic genomic copy number variants (CNVs), and 1 uniparental diploidy (UPD) were detected, which yielded an overall detection rate of 43.28% (58/134). The 46 pathogenic SNV/InDel have involved 62 mutation sites in 40 genes, among which MECP2 was the most frequent (n = 4). The 11 pathogenic CNVs have included 10 deletions and 1 duplication, which have ranged from 0.76 to 15.02 Mb. A loss of heterozygosity (LOH) region of approximately 15.62 Mb was detected in 15q11.2q12 region in a patient, which was validated as paternal UPD based on the result of trio-WES. The patient was ultimately diagnosed as Angelman syndrome.@*CONCLUSION@#WES can detect not only SNV/InDel, but also CNV and LOH. By integrating family data, WES can accurately determine the origin of the variants and provide a useful tool for uncovering the genetic etiology of patients with ID or GDD.

Clinical characteristics and genetic analysis of two children with Autosomal dominant mental retardation type 21 due to variants of CTCF gene / 中华医学遗传学杂志

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.

Clinical and genetic analysis of two children with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia / 中华医学遗传学杂志

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.

Börjeson -Forssman -Lehmann syndrome: A case report / 中南大学学报(医学版)

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.

Genetic analysis of a pregnant woman with moderate intellectual disability due to variant of DLG4 gene / 中华医学遗传学杂志

OBJECTIVE@#To carry out genetic testing and prenatal diagnosis for a woman featuring moderate intellectual disability (ID).@*METHODS@#The patient had presented at the First Affiliated Hospital of Zhengzhou University on April 28, 2021. With informed consent, peripheral blood and amniotic fluid samples were collected for the extraction of genomic DNA. Pathogenic copy number variations (CNVs) were detected with CNV-seq, and single gene variants were detected by whole exome sequencing (WES) and Sanger sequencing. Candidate variant was verified by Sanger sequencing, and CNV-seq and multiplex ligation-dependent probe amplification (MLPA) were used to detect fetal CNVs.@*RESULTS@#The 23-year-old woman had moderate ID, sideway walking, and unstable holding. Ultrasonography at 18+3 weeks' gestation had revealed no fetal abnormality. No pathogenic CNV was detected in the woman by CNV-Seq, while WES revealed that she has harbored a heterozygous c.1675C>T (p.Arg559*) variant of the DLG4 gene, which was verified by Sanger sequencing. Based on guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic (PVS1+PM2_supporting). Sanger sequencing has confirmed that the fetus has inherited this variant, and CNV-Seq also revealed that that fetus has harbored a 0.1 Mb heterozygous deletion at Xp21.1, which has encompassed the DMD gene, and the result was verified by MLPA.@*CONCLUSION@#The heterozygous c.1675C>T variant of the DLG4 gene probably underlay the mental retardation in this woman, and her fetus was found to harbor the same variant in addition with deletion of the DMD gene, which may predispose to ID type 62.

Application of copy number variation sequencing in patients with intellectual disability/developmental delay and autistic spectrum disorder / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of copy number variation sequencing (CNV-seq) for the diagnosis of children with intellectual disability (ID), developmental delay (DD), and autistic spectrum disorder (ASD).@*METHODS@#Forty patients with ID/DD/ASD referred to Nanshan Maternity and Child Health Care Hospital from September 2018 to January 2022 were enrolled. G-banded karyotyping analysis was carried out for the patients. Genomic DNA was extracted from peripheral blood samples and subjected to CNV-Seq analysis to detect chromosome copy number variations (CNVs) in such patients. ClinVar, DECIPHER, OMIM and other database were searched for data annotation.@*RESULTS@#Among the 40 patients (including 30 males and 10 females), 16, 15 and 6 were diagnosed with ID, DD and ASD, respectively. One patient had combined symptoms of ID and DD, whilst the remaining two had combined ID and ASD. Four patients were found with abnormal karyotypes, including 47,XY,+mar, 46,XY,inv(8)(p11.2q21.2), 46,XX,del(5)(p14) and 46,XX[76]/46,X,dup(X)(p21.1q12). Chromosome polymorphism was also found in two other patients. CNV-seq analysis has detected 32 CNVs in 20 patients (50.0%, 20/40). Pathogenic CNVs were found in 10 patients (25.0%), 15 CNVs of uncertain clinical significance were found in 12 patients (30.0%), and 7 likely benign CNVs were found in 4 patients (10.0%).@*CONCLUSION@#Chromosome CNVs play an important role in the pathogenesis of ID/DD/ASD. CNV-seq can detect chromosomal abnormalities including microdeletions and microduplications, which could provide a powerful tool for revealing the genetic etiology of ID/DD/ASD patients.

Analysis of clinical features and genetic variant in a neonate with Au-Kline syndrome due to a de novo variant of the HNRNPK gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical phenotype and genetic basis of a neonate with Au-Kline syndrome (AKS).@*METHODS@#Clinical data and result of genetic testing of a neonate with AKS who was admitted to the Affiliated Provincial Children's Hospital of Anhui Medical University in January 2021 were retrospectively analyzed. Relevant literature was searched from the Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure and PubMed databases using key words "Au Kline syndrome", "Au-Kline syndrome", "HNRNPK" and "AKS". The research period was set as from January 1, 2000 to December 31, 2020.@*RESULTS@#The male newborn has manifested feeding difficulties, hypotonia, absence of the upper jaw to the uvula and facial dysmorphism. Trio-whole exome sequencing revealed that he has harbored a frameshift c.478dupA (p.Ile160AsnfsTer7) variant of the HNRNPK gene, which was varified by Sanger sequencing to have a de novo origin. The variant has not been included in the databases. Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was rated as pathogenic (PVS1+PS2+PM2_Supporting). Literature retrieval has identified 14 children with AKS and de novo mutations of the HNRNPK gene. Their clinical manifestations have included growth and motor retardation, various degree of mental retardation, facial dysmorphism and a high frequency of congenital heart malformations.@*CONCLUSION@#The AKS in this child may be attributed to the c478dupA frameshifting variant of the HNRNPK gene. Diagnosis of AKS should be suspected for children with mental retardation and multiple congenital malformation syndromes including Kabuki syndrome.

Clinical features and genetic analysis of a case of Wiedemann-Steiner syndrome due to variant of KMT2A gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical features and genetic etiology of a child with Wiedemann-Steiner syndrome.@*METHODS@#A child with WSS who was admitted to the Hematology Department of Tianjin Children's Hospital in May 2021 was selected as the subject. Clinical data of the child was collected. Peripheral blood samples were collected from the child and his parents for the extraction of genomic DNA. The child was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing of the child and his parents.@*RESULTS@#The main clinical features of the child have included pancytopenia, growth and mental retardation, and facial dysmorphism. Whole exome sequencing revealed that the child has harbored a heterozygous variant of the KMT2A gene, namely c.7804delA (p.M2602Cfs*39). Sanger sequencing verified the variant to be de novo in origin. The variant was unreported previously and predicted to be pathogenic based on the guidelines of American College of Medical Genetics and Genomics (PVS1+PS2+PM2).@*CONCLUSION@#The heterozygous c.7804delA (p.M2602Cfs*39) variant of the KMT2A gene probably underlay the WSS in this child. Above finding has enriched the mutational spectrum and clinical phenotypes of the KMT2A gene.