OBJECTIVE: To explore the clinical characteristics and genetic basis for a child with X-linked lissencephaly with abnormal genitalia (XLAG). METHODS: A child with XLAG who had presented at the Third Affiliated Hospital of Zhengzhou University in May 2021 was selected as the study subject. Peripheral blood samples of the child and his parents were collected and subjected to high-throughput sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the result was analyzed by using bioinformatic software. RESULTS: The child was found to have harbored a hemizygous c.945_948del variant in exon 2 of the ARX gene, which as a frameshifting variant has resulted in a truncated protein. His mother was found to be heterozygous for the variant, whilst his father was of wild type. The variant was unreported previously. CONCLUSION The hemizygous c.945_948del variant of the ARX gene probably underlay the XLAG in this patient. Above finding has provided a basis for the diagnosis and genetic counseling for this family.
Humans ; Child ; Classical Lissencephalies and Subcortical Band Heterotopias ; Exons ; Computational Biology ; Genetic Counseling ; Genitalia ; Transcription Factors ; Homeodomain Proteins

OBJECTIVE: To explore the genetic basis for fetus with bilateral lateral ventriculomegaly. METHODS: Fetus umbilical cord blood and peripheral blood samples of its parents were collected. The fetus was subjected to chromosomal karyotyping, whilst the fetus and its parents were subjected to array comparative genomic hybridization (aCGH). The candidate copy number variation (CNV) were verified by qPCR, Application goldeneye DNA identification system was used to confirm the parental relationship. RESULTS: The fetus was found to have a normal karyotype. aCGH analysis indicated that it has carried a 1.16 Mb deletion at 17p13.3, which partially overlapped with the critical region of Miller-Dieker syndrome (MDS), in addition with a 1.33 Mb deletion at 17p12 region, which is associated with hereditary stress-susceptible peripheral neuropathy (HNPP). Its mother was also found to harbor the 1.33 Mb deletion at 17p12. qPCR analysis confirmed that the expression levels of genes from the 17p13.3 and 17p12 regions were about the half of that in the normal control, as well as the maternal peripheral blood sample. Parental relationship was confirmed between the fetus and its parents. Following genetic counseling, the parents has chosen to continue with the pregnancy. CONCLUSION The fetus was diagnosed with Miller-Dieker syndrome due to the de novo deletion at 17p13.3. Ventriculomegaly may be an important indicator for prenatal ultrasonography in fetuses with MDS.
Pregnancy ; Female ; Humans ; Classical Lissencephalies and Subcortical Band Heterotopias ; Comparative Genomic Hybridization ; DNA Copy Number Variations ; Fetus ; Hydrocephalus ; Prenatal Diagnosis ; Chromosome Deletion

OBJECTIVE: To explore the genetic etiology for a fetus with Walker-Warburg syndrome(WWS). METHODS: A fetus with WWS diagnosed at Gansu Provincial Maternity and Child Health Care Hospital in June 9, 2021 was selected as the study subject. Genomic DNA was extracted from amniotic fluid sample of the fetus and peripheral blood samples from its parents. Trio-Whole exome sequencing (trio-WES) was carried out. Candidate variants were verified by Sanger sequencing. RESULTS: The fetus was found to harbor compound heterozygous variants of the POMT2 gene, namely c.471delC (p.F158Lfs*42) and c.1975C>T (p.R659W), which were respectively inherited from its father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), they were respectively rated as pathogenic (PVS1+PM2_Supporting+PP4) and likely pathogenic (PM2_Supporting+PM3+PP3_Moderate+PP4). CONCLUSION Trio-WES may be used for the prenatal diagnosis of WWS. The compound heterozygous variants of the POMT2 gene probably underlay the disorder in this fetus. Above finding has expanded the mutational spectrum of the POMT2 gene and enabled definite diagnosis and genetic counseling for the family.
Pregnancy ; Child ; Female ; Humans ; Walker-Warburg Syndrome ; Prenatal Diagnosis ; Fetus ; Genetic Counseling ; Genomics ; Mutation

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with recurrent fetal hydrocephalus. METHODS: A couple who had presented at the Affiliated Hospital of Putian College on March 3, 2021 was selected as the study subject. Following elective abortion, fetal tissue and peripheral blood samples were respectively obtained from the abortus and the couple, and were subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: The fetus was found to harbor compound heterozygous variants of the B3GALNT2 gene, namely c.261-2A>G and c.536T>C (p.Leu179Pro), which were inherited from its father and mother, respectively.According to the guidelines of American College of Medical Genetics and Genomics, both variants were classified as pathogenic (PVS1+PM2_Supporting; PM3+PM2_Supporting+PP3+PP4). CONCLUSION The compound heterozygous variants of the B3GALNT2 gene probably underlay the α-dystroglycanopathy in this fetus. Above results have provided a basis for genetic counseling of this pedigree.
Female ; Humans ; Pregnancy ; Aborted Fetus ; Asian People/genetics* ; East Asian People ; Fetus ; Genetic Counseling ; Mutation ; N-Acetylgalactosaminyltransferases ; Pedigree ; Walker-Warburg Syndrome/genetics*

OBJECTIVE: To explore the genetic basis for a fetus with lissencephaly. METHODS: Genomic DNA was extracted from amniotic fluid sample and subjected to copy number variation (CNV) analysis. RESULTS: The fetus was found to harbor a heterozygous 5.2 Mb deletion at 17p13.3p13.2, which encompassed the whole critical region of Miller-Dieker syndrome (MDS) (chr17: 1-2 588 909). CONCLUSION The fetus was diagnosed with MDS. Deletion of the PAFAH1B1 gene may account for the lissencephaly found in the fetus.
1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics* ; Chromosome Deletion ; Chromosomes, Human, Pair 17/genetics* ; Classical Lissencephalies and Subcortical Band Heterotopias/genetics* ; Female ; Fetus ; Genetic Testing ; Humans ; Microtubule-Associated Proteins/genetics* ; Pregnancy ; Prenatal Diagnosis

OBJECTIVE: To carry out genetic diagnosis for a fetus. METHODS: Chromosome G-banding and chromosomal microarray analysis (CMA) were carried out for a fetus with abnormal morphology of lateral cerebral fissure. RESULTS: The karyotype of the fetus was normal, but CMA showed that it has carried a 1.4 Mb deletion at 17p13.3 region, which suggested a diagnosis of Miller-Dieker syndrome (MDS). CONCLUSION Familiarity with clinical features and proper selection of genetic testing method are crucial for the diagnosis of MDS. Attention should be paid to microdeletions and microduplications which can be missed by conventional chromosomal karyotyping.
Chromosome Banding ; Chromosome Deletion ; Chromosomes, Human, Pair 17 ; Classical Lissencephalies and Subcortical Band Heterotopias/genetics* ; Female ; Fetus ; Humans ; Karyotyping ; Pregnancy ; Prenatal Diagnosis

OBJECTIVETo report on prenatal diagnosis of a fetus with Miller-Dieker syndrome (MDS) and explore its genotype - phenotype correlation.

METHODSChromosome karyotyping, bacterial artificial chromosome on beads (BACs-on-Beads, BoBs), fluorescence in situ hybridization (FISH), and single nucleotide polymorphism microarray (SNP array) were applied in conjunction for the prenatal diagnosis of a fetus with abnormal ultrasound findings.

RESULTSA 17p13.3 microdeletion was detected with the BoBs assay, and the result was confirmed by FISH. With the SNP array, the deletion was mapped to chromosome 17, with its range determined to be 5.2 Mb. On high-resolution banding analysis and BoB assay, the deletion was not found in either parent.

CONCLUSIONThe combined use of BoBs, FISH and SNP array has enabled prenatal diagnosis of a fetus with MDS. Attention should be paid to microdeletions and microduplications which can be missed by conventional chromosomal karyotyping analysis.

Adult ; Chromosome Deletion ; Chromosomes, Human, Pair 17 ; Classical Lissencephalies and Subcortical Band Heterotopias ; diagnosis ; genetics ; Female ; Genetic Association Studies ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Polymorphism, Single Nucleotide ; Pregnancy ; Prenatal Diagnosis

OBJECTIVETo perform molecular cytogenetic study on two fetuses with abnormal ultrasound findings and analyze their genotype-phenotype correlation.

METHODSG-banded karyotyping, single nucleotide polymorphism array (SNP array) and fluorescence in situ hybridization (FISH) were performed on amniotic fluid cells from both fetuses and peripheral blood samples from their parents. Results of SNP array were analyzed with bioinformatics software.

RESULTSG-banded karyotyping failed to detect any abnormalities in both fetuses and their parents. SNP array detected a 2.484 Mb terminal deletion at 17p13.3 [arr[hg19] 17p13.3 (83 035-2 567 405)×1] in fetus 1 and a 3.295 Mb terminal deletion at 17p13.3p13.2 [arr[hg19] 17p13.3p13.2 (83 035- 3 377 560)×1] in fetus 2. Both deletions have overlapped with the critical region of Miller-Dieker syndrome (MDS) and involved candidate genes such as PAFAH1B1, YWHAE and CRK. In addition, SNP array and FISH analyses on the parental peripheral blood samples demonstrated that both 17p13.3 and 17p13.3p13.2 deletions were of de novo origin. Metaphase FISH performed on amniotic fluid cells confirmed the presence of 17p13.3 and 17p13.3p13.2 deletions detected by the SNP array, while metaphase FISH performed on the parents excluded any potential chromosome rearrangements.

CONCLUSIONAbnormal ultrasound features for fetuses with MDS mainly include central nervous system anomalies. SNP array can efficiently detect 17p13.3 microdeletions underlying MDS, and accurately map the breakpoints and involved genes, which may facilitate understanding of the genotype and phenotype correlations for MDS.

Chromosome Banding ; Chromosome Deletion ; Chromosomes, Human, Pair 17 ; genetics ; Classical Lissencephalies and Subcortical Band Heterotopias ; diagnostic imaging ; genetics ; Female ; Fetal Diseases ; diagnostic imaging ; genetics ; Genetic Association Studies ; Genetic Predisposition to Disease ; genetics ; Genotype ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Phenotype ; Polymorphism, Single Nucleotide ; Pregnancy ; Ultrasonography, Prenatal ; methods

This paper reports the brain magnetic resonance imaging (MRI) findings of a case of merosin-deficient congenital muscular dystrophy (MDCMD) in a neonate and discusses the spectrum of brain involvement in MDCMD. A neonate presented hypotonia, increased serum creatine kinase levels, and polymicrogyria and subcortical heterotopia on brain MRI involving both posterior temporal and occipital lobes. Although these findings suggested Fukuyama muscular dystrophy, muscle biopsy showed dystrophic changes and an absence of merosin staining. We found that compound heterozygous mutation for c.2049_2050delAG (p.R683fs) and c.5866-2A>G in the LAMA2 gene which encodes Laminin-α2. To our knowledge, this is the second Korean case of MDCMD with polymicrogyria and subcortical heterotopias. This case shows that a range of brain structural malformations can be found in children with MDCMD and that the classification of congenital muscular dystrophy (CMD) is not complete yet, as indicated previously in reports suggesting other unclassified forms of CMD.
Biopsy ; Brain ; Child ; Classical Lissencephalies and Subcortical Band Heterotopias ; Classification ; Creatine Kinase ; Humans ; Infant, Newborn ; Laminin ; Magnetic Resonance Imaging ; Muscle Hypotonia ; Muscular Dystrophies* ; Occipital Lobe ; Polymicrogyria* ; Walker-Warburg Syndrome

OBJECTIVETo elucidate the usefulness of next generation sequencing for diagnosis of inherited myopathy, and to analyze the relevance between clinical phenotype and genotype in inherited myopathy.

METHODRelated genes were selected for SureSelect target enrichment system kit (Panel Version 1 and Panel Version 2). A total of 134 patients who were diagnosed as inherited myopathy clinically underwent next generation sequencing in Department of Pediatrics, Peking University First Hospital from January 2013 to June 2014. Clinical information and gene detection result of the patients were collected and analyzed.

RESULTSeventy-seven of 134 patients (89 males and 45 females, visiting ages from 6-month-old to 26-year-old, average visiting age was 6 years and 1 month) underwent next generation sequencing by Panel Version 1 in 2013, and 57 patients underwent next generation sequencing by Panel Version 2 in 2014. The gene detection revealed that 74 patients had pathogenic gene mutations, and the positive rate of genetic diagnosis was 55.22%. One patient was diagnosed as metabolic myopathy. Five patients were diagnosed as congenital myopathy; 68 were diagnosed as muscular dystrophy, including 22 with congenital muscular dystrophy 1A (MDC1A), 11 with Ullrich congenital muscular dystrophy (UCMD), 6 with Bethlem myopathy (BM), 12 with Duchenne muscular dystrophy (DMD) caused by point mutations in DMD gene, 5 with LMNA-related congenital muscular dystrophy (L-CMD), 1 with Emery-Dreifuss muscular dystrophy (EDMD), 7 with alpha-dystroglycanopathy (α-DG) patients, and 4 with limb-girdle muscular dystrophy (LGMD) patients.

CONCLUSIONNext generation sequencing plays an important role in diagnosis of inherited myopathy. Clinical and biological information analysis was essential for screening pathogenic gene of inherited myopathy.

Adolescent ; Child ; Child, Preschool ; Contracture ; DNA Mutational Analysis ; Female ; Genetic Diseases, Inborn ; diagnosis ; genetics ; Genetic Testing ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; Infant ; Male ; Molecular Diagnostic Techniques ; Muscular Diseases ; diagnosis ; genetics ; Muscular Dystrophies ; congenital ; Muscular Dystrophies, Limb-Girdle ; Muscular Dystrophy, Duchenne ; Muscular Dystrophy, Emery-Dreifuss ; Mutation ; Phenotype ; Sclerosis ; Walker-Warburg Syndrome ; Young Adult