Dyskeratosis Congenita/genetics* ; Enterocolitis/genetics* ; Fetal Growth Retardation ; Humans ; Intellectual Disability/genetics* ; Microcephaly/genetics*

OBJECTIVE: To summarize the clinical phenotype and genotype of a Chinese child affected with Mowat-Wilson syndrome (MWS). METHODS: Clinical data of the patient were collected. The patient was analyzed by whole-exome sequencing (WES) as well as Sanger sequencing. RESULTS: The patient was a male infant with recurrent fever and slow growth. He also had characteristic facies, recurrent spasm, and growth retardation. WES revealed that he has carried a heterozygous nonsense c.2609C>G (p.Ser870X) variant of the ZEB2 gene (30% mosaicism). Based on the American College of Medical Genetics and Genomics standards and guidelines, the variant was predicted to be pathogenic (PVS1+PS1+PS2+PM2). CONCLUSION The c.2609C>G variant of the ZEB2 gene probably underlay the MWS in this child. The mosaicism of the variant may explain his mild symptoms.
Child ; Facies ; Hirschsprung Disease/genetics* ; Humans ; Infant ; Intellectual Disability/genetics* ; Male ; Microcephaly/genetics* ; Mutation

OBJECTIVE: To explore the genetic basis of three children with unexplained mental retardation/developmental delay. METHODS: Peripheral venous blood samples were collected for routine G-banding karyotyping analysis and chromosomal microarray analysis (CMA). Whole exome sequencing (WES) was also carried out for patient 3. RESULTS: The karyotypes of the 3 children were normal. The result of CMA analysis of patient 1 was arr[GRCh37]: 2q22/3(145 128 071-145 159 029)×1, with a 31 kb deletion, which was predicted to be a pathogenic copy number variation. The deletion has involved exons 8 to 10 of the ZEB2 gene. Patient 2 was arr[hg19]:2q22.3 (145 071 457-146 881 759)×1, with a 1.81 Mb deletion involving the ZEB2 and GTDC1 genes. Patient 3 was arr[GRCh37]: 9p23p23(11 698 261-12 106 261)×1, with a 408 kb deletion containing no disease-associated gene. WES has identified a c.2102C>A (p.Ser701*) variant in exon 8 of the ZEB2 gene, which was included in ClinVar database and rated as pathogenic, and verified by Sanger sequencing as a de novo variant. CONCLUSION For the substantial clinical and genetic heterogeneity of Mowat-Wilson-syndrome, CMA and WES are helpful to identify the etiology of children with developmental delay/mental retardation of unknown causes, particularly those with peculiar facial features and multiple congenital malformations.
Child ; DNA Copy Number Variations ; Facies ; Glycosyltransferases/genetics* ; Hirschsprung Disease ; Humans ; Intellectual Disability/genetics* ; Microcephaly/genetics*

OBJECTIVE: To explore the genetic etiology of a child with microcephaly-cortical blind syndrome. METHODS: Clinical data of the child was collected. The child and her parents were subjected to whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing. RESULTS: WES revealed that the child has harbored compound heterozygous variants c.1051C>T and c.609delA of the DIAPH1 gene. CONCLUSION The compound heterozygous variation c.1051C>T (p.R351X) and c.609delA (p.E203Efs*19) of the DIAPH1 gene probably underlay the microcephaly-cortical blindness syndrome in this child.
Blindness/genetics* ; Child ; Female ; Formins/genetics* ; Genetic Testing ; Humans ; Microcephaly/genetics* ; Mutation ; Pedigree ; Exome Sequencing

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.
Female ; Humans ; Dwarfism/genetics* ; Exome Sequencing ; Intellectual Disability/genetics* ; Microcephaly ; Mothers ; Mutation ; Male ; Child

OBJECTIVE: Two brothes with Seckel's syndrome 1(SCKL1) were reported and a literature review was carried to provide clinical and genetic information of this rare disease. METHODS: Clinical data of the two children were collected, and the peripheral blood was extracted for whole exome sequencing. Literature of the disease were reviewed. RESULTS: The two patients were 11 years and 9.5 years old when examined for short stature. They presented with intrauterine growth retardation, intellectual disability, microcephaly, birdhead-like face and coffee au lait spots. The bone age was more than 2 years behind the chronical age and the growth hormone levels were normal. Whole exome sequencing revealed novel compound heterozygous variants c.1A>G (p.M1?) and c.4853-18A>G of ART gene in both children. CONCLUSION Children with prenatal onset short stature, developmental delay, microcephaly and special facial featuresshould be considered for the possibility of Seckel's syndrome, whole exome sequencing could help to confirm the clinical diagnosis.
Ataxia Telangiectasia Mutated Proteins/genetics* ; Child ; Dwarfism/genetics* ; Humans ; Intellectual Disability/genetics* ; Male ; Microcephaly/genetics* ; Siblings ; Whole Exome Sequencing

OBJECTIVETo clarify the possible association between the Zika virus (ZIKV) and microcephaly and understand where we are in terms of research and the debate on the causation between mild maternal clinical features and severe fetal microcephaly.

DATA SOURCESWe did a comprehensive literature review with the keywords "zika" and/or "microcephaly" from inception to May 27, 2016, with PubMed.

STUDY SELECTIONStudies were included and analyzed if they met all of the following criteria: "probable or confirmed infant microcephaly" and "probable or confirmed ZIKV infection among mothers or infants".

RESULTSWe emphasize the diagnosis of ZIKV infection, including maternal clinical manifestations, maternal and fetal laboratory confirmation, and possible autopsy if need. Other confounders that may lead to microcephaly should be excluded from the study. We presented the results from clinical manifestations of ZIKV infection, testing methods evolving but the mechanism of microcephaly uncertain, flexible definition challenging the diagnosis of microcephaly, and limited causal reference on pregnant women. We made analog comparison of severe acute respiratory syndrome and chikungunya virus in terms of DNA mutation and global movement to provide further research recommendation. The chance of catch-up growth may decrease the number of pervious "diagnosed" microcephaly.

CONCLUSIONSThere are some evidence available through mice models and direct isolation of ZIKV in affected pregnancies on kindly causal relationship but not convincible enough. We analyzed and presented the weakness or limitation of published reports with the desire to shed light to further study directions.

Animals ; Female ; Humans ; Microcephaly ; diagnosis ; etiology ; genetics ; Mutation ; Pregnancy ; Zika Virus ; pathogenicity ; Zika Virus Infection ; complications

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 detect potential mutation of the ASPM gene in a Chinese pedigree affected with autosomal recessive primary microcephaly 5 (MCPH5). METHODS: Peripheral venous blood samples were collected from the proband and her parents. Amniotic fluid sample was also collected upon her mother' s subsequent pregnancy. Following extraction of genomic DNA, PCR and Sanger sequencing were carried out to identify potential variants of the ASPM gene. RESULTS: The proband was found to harbor compound heterozygous variants of the ASPM gene, namely c.8214dupT (p.Q2739fs) in exon 18 and c.9541C>T (p.R3181X) in exon 23, which were respectively inherited from her father and mother. The fetus has found to have inherited the c.9541C>T (p.R3181X) variant only. CONCLUSION The c.8214dupT (p.Q2739fs) and c.9541C>T (p.R3181X) compound heterozygous variants of the ASPM gene probably underlay the pathogenesis of MCPH5 in this patient. Above finding has enabled genetic counseling and prenatal diagnosis for her family.
China ; Counseling ; Female ; Humans ; Microcephaly ; Mutation ; Nerve Tissue Proteins/genetics* ; Pedigree ; Pregnancy

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