1.Analysis of clinical phenotypes and MMACHC gene variants in 65 children with Methylmalonic acidemia and homocysteinemia.
Chongfen CHEN ; Yaodong ZHANG ; Lili GE ; Lei LIU ; Xiaoman ZHANG ; Shiyue MEI ; Shuying LUO
Chinese Journal of Medical Genetics 2023;40(9):1086-1092
OBJECTIVE:
To carry out Sanger sequencing for MMACHC gene variants among 65 Chinese pedigrees affected with combined methylmalonic aciduria and homocysteinemia, and summarize their genetic and clinical characteristics and prognosis.
METHODS:
Clinical characteristics of the 65 children identified with Methylmalonic acidemia and homocysteinemia at the Children's Hospital Affiliated to Zhengzhou University (Zhengzhou Children's Hospital) from April 2017 to April 2022 were selected as the study subjects. Potential variants of the MMACHC gene were detected by direct sequencing of the PCR products.
RESULTS:
The median age of the 65 children was 3 months (14 days to 17 years old). These included 28 cases (43.08%) from neonatal screening, 11 cases (16.92%) with a history of jaundice, and 9 cases (13.85%) with various degrees of anemia. The main clinical symptoms included development delay, slow growth, epilepsy, hydrocephalus, lethargy, feeding difficulty, regression or decline in motor ability, recurrent respiratory infections, anemia, jaundice, respiratory and heart failures, hydrocephalus, limb weakness, and hypertension. Blood and urine tandem mass spectrometry screening has revealed increase of methylmalonic acid, propionyl carnitine, propionyl carnitine/acetylcarnitine ratio, and propionyl carnitine/free carnitine ratio to various extents, and blood homocysteine was increased in all patients. The detection rate of genetic variants was 98.46% (128/130), and in total 22 types of MMACHC gene variants were detected. The most common ones have included c.609G>A (W203X) (58/128), c.658-660del (K220del) (19/128), and c.80A>G (Q27A) (16/128). Two novel variants have been identified, namely c.565C>T (p.R189C) and c.624_ 625delTG (p.A208Afs), which were respectively predicted as likely pathogenic (PM2_Supporting+PM3+PP2+PP3) and pathogenic (PVS1+PM2_Supporting+PM3+PP2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Exon 4 had the highest frequency for the detection.
CONCLUSION
Identification of MMACHC gene variants has confirmed the diagnosis in the children, among which the c.609G>A variant has the highest frequency. Discovery of the new variants has enriched the mutational spectrum of the MMACHC gene.
Humans
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Amino Acid Metabolism, Inborn Errors/genetics*
;
Hydrocephalus
;
Oxidoreductases
2.Analysis of L1CAM gene mutation in pedigrees with X-linked genetic hydrocephalus.
Shuang HU ; Li WANG ; Ning LIU ; Xiangdong KONG
Chinese Journal of Medical Genetics 2019;36(5):465-467
OBJECTIVE:
To analyze L1CAM gene mutation in a family featuring X-linked recurrent fetal hydrocephalus.
METHODS:
The family had three pregnancies where a male fetus was detected at 22 weeks with hydrocephalus by ultrasonography. DNA was extracted from peripheral blood samples from the parents as well as fetal tissue from the third abortion. The fetal DNA was subjected to testing of folic acid metabolism ability gene and chromosomal microarray analysis (CMA). Next-generation sequencing (NGS) was employed to detect potential mutation of related genes. Suspected mutation was verified by Sanger sequencing.
RESULTS:
Testing of folic acid metabolism ability gene (MTHFR C677T) and CMA were both normal. A c.512G>A (p.Trp171Ter) hemizygous mutation of the L1CAM gene was detected in the fetal tissue, which was inherited from the phenotypically normal mother. The novel mutation was predicted to be pathogenic.
CONCLUSION
The c.512G>A (p.Trp171Ter) mutation of the L1CAM gene probably underlies the X-linked hydrocephalus in this family. Screening of L1CAM gene variations should be carried out for couples experiencing recurrent fetal hydrocephalus affecting the male gender.
Cerebral Aqueduct
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Female
;
Humans
;
Hydrocephalus
;
genetics
;
Male
;
Mutation
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Neural Cell Adhesion Molecule L1
;
genetics
;
Pedigree
;
Pregnancy
3.β-Catenin Deletion in Regional Neural Progenitors Leads to Congenital Hydrocephalus in Mice.
Lin MA ; Yanhua DU ; Xiangjie XU ; Hexi FENG ; Yi HUI ; Nan LI ; Guanyu JIANG ; Xiaoqing ZHANG ; Xiaocui LI ; Ling LIU
Neuroscience Bulletin 2022;38(1):81-94
Congenital hydrocephalus is a major neurological disorder with high rates of morbidity and mortality; however, the underlying cellular and molecular mechanisms remain largely unknown. Reproducible animal models mirroring both embryonic and postnatal hydrocephalus are also limited. Here, we describe a new mouse model of congenital hydrocephalus through knockout of β-catenin in Nkx2.1-expressing regional neural progenitors. Progressive ventriculomegaly and an enlarged brain were consistently observed in knockout mice from embryonic day 12.5 through to adulthood. Transcriptome profiling revealed severe dysfunctions in progenitor maintenance in the ventricular zone and therefore in cilium biogenesis after β-catenin knockout. Histological analyses also revealed an aberrant neuronal layout in both the ventral and dorsal telencephalon in hydrocephalic mice at both embryonic and postnatal stages. Thus, knockout of β-catenin in regional neural progenitors leads to congenital hydrocephalus and provides a reproducible animal model for studying pathological changes and developing therapeutic interventions for this devastating disease.
Animals
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Disease Models, Animal
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Hydrocephalus/genetics*
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Mice
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Mice, Knockout
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Neurons
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beta Catenin/genetics*
4.Research advances on associated genes and pathogenesis of hydrocephalus.
Jia-jun ZHOU ; Mei-ping DING ; Jian-ren LIU
Journal of Zhejiang University. Medical sciences 2010;39(6):644-649
Hydrocephalus is a common medical condition characterized by abnormalities in the secretion,circulation or resorption of cerebrospinal fluid (CSF), resulting in ventricular dilatation. The pathogenetic mechanism for the hydrocephalus is attributed to: the overproduction of CSF by the choroid plexus; the defect in CSF absorption and obstruction of CSF flow in the cerebral ventricles. However, the underlying etiology is poorly understood. With the development of genetic engineering, a growing body of evidence indicates that genetic factors play an essential role in the pathogenesis of hydrocephalus. It is the aim of this review to summarize these findings.
Animals
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Cerebral Ventricles
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pathology
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Disease Models, Animal
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Hydrocephalus
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genetics
;
pathology
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Mice
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Mice, Knockout
5.Clinical and genetic analysis of a rare fetus with Protein C deficiency due to compound heterozygous variants of PROC gene.
Lulu YAN ; Yifan HUO ; Yingwen LIU ; Yuxin ZHANG ; Chunxiao HAN ; Juan CAO ; Haibo LI
Chinese Journal of Medical Genetics 2023;40(11):1330-1333
OBJECTIVE:
To explore the genetic etiology for a fetus with hydrocephalus and intraventricular hemorrhage.
METHODS:
Trio whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing of the fetus and its parents.
RESULTS:
The fetus was found to harbor c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene, which were respectively inherited from its mother and father. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PVS1_Strong+PM2_Supporting+PP4; PM2_Supporting+PM3+PP1+PP3+PP4).
CONCLUSION
The fetus was diagnosed with Protein C deficiency due to the c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene. Above finding has enriched the spectrum of PROC gene variants and enabled genetic counseling and prenatal diagnosis for the family.
Female
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Pregnancy
;
Humans
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Protein C Deficiency
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Fetus
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Genetic Counseling
;
Genomics
;
Hydrocephalus/genetics*
;
Mutation
6.Analysis of a pedigree affected with HSAS syndrome due to a noval variant of L1CAM gene.
Zhidan HONG ; Ling MA ; Yanhong MAO
Chinese Journal of Medical Genetics 2021;38(1):83-86
OBJECTIVE:
To explore the genetic basis for a fetus with hydrocephalus.
METHODS:
The fetus was found to have hydrocephalus upon ultrasonography duringthe second trimester. Following induced abortion, fetal tissue was collected for the extraction of DNA and whole exome sequencing.Sanger sequencing was used to verify the suspected variants in the family.
RESULTS:
The fetus was found to harbor a hemizygous c.620A>G (p.Tyr207Cys) variant of the L1CAM gene (OMIM 308840),for which his mother and sister were heterozygous carriers. The same variant was not found in his father, uncle and grandparents.Based on the standards and guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic (PM1+PM2+PP3+PP4).
CONCLUSION
The hemizygous c.620A>G (p.Tyr207Cys) variant of the L1CAM gene probably underlay the hydrocephalus in this fetus.
Adult
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Female
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Heterozygote
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Humans
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Hydrocephalus/genetics*
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Male
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Mutation
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Neural Cell Adhesion Molecule L1/genetics*
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Pedigree
;
Pregnancy
;
Whole Exome Sequencing
7.Diagnosis of a fetus with X-linked hydrocephalus due to mutation of L1CAM gene.
Qichang WU ; Li SUN ; Yasong XU ; Xiaomei YANG ; Shiyu SUN ; Wenbo WANG
Chinese Journal of Medical Genetics 2019;36(9):897-900
OBJECTIVE:
To explore the genetic basis for a case of recurrent fetal congenital hydrocephalus.
METHODS:
Next-generation sequencing was carried out for the fetus, the gravida and two of her sisters.
RESULTS:
The fetus was found to harbor a c.1765T>C (p.Tyr589His) mutation in exon 14 of the L1CAM gene, which was derived from the gravida.
CONCLUSION
Male fetuses with recurrent hydrocephalus should be subjected to testing of the L1CAM gene to facilitate genetic counseling and prenatal diagnosis.
DNA Mutational Analysis
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Female
;
Fetus
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Genetic Diseases, X-Linked
;
diagnosis
;
genetics
;
Humans
;
Hydrocephalus
;
diagnosis
;
genetics
;
Male
;
Mutation
;
Neural Cell Adhesion Molecule L1
;
genetics
;
Pedigree
;
Pregnancy
8.Dscam mutation leads to hydrocephalus and decreased motor function.
Yiliang XU ; Haihong YE ; Yan SHEN ; Qi XU ; Li ZHU ; Jianghong LIU ; Jane Y WU
Protein & Cell 2011;2(8):647-655
The nervous system is one of the most complicated organ systems in invertebrates and vertebrates. Down syndrome cell adhesion molecule (DSCAM) of the immunoglobulin (Ig) superfamily is expressed widely in the nervous system during embryonic development. Previous studies in Drosophila suggest that Dscam plays important roles in neural development including axon branching, dendritic tiling and cell spacing. However, the function of the mammalian DSCAM gene in the formation of the nervous system remains unclear. Here, we show that Dscam ( del17 ) mutant mice exhibit severe hydrocephalus, decreased motor function and impaired motor learning ability. Our data indicate that the mammalian DSCAM gene is critical for the formation of the central nervous system.
Animals
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Cell Adhesion Molecules
;
genetics
;
metabolism
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Corpus Callosum
;
metabolism
;
pathology
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Genotype
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Hydrocephalus
;
genetics
;
metabolism
;
pathology
;
Mice
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Mice, Knockout
;
Motor Activity
;
genetics
;
physiology
;
Mutation
9.Application of chromosome microarray analysis for the delineation of pathogenesis for fetal ventriculomegaly.
Zhouzhou LI ; Fang FU ; Tingying LEI ; Ru LI ; Xiangyi JING ; Xin YANG ; Jin HAN ; Min PAN ; Li ZHEN ; Can LIAO
Chinese Journal of Medical Genetics 2017;34(4):576-582
OBJECTIVETo assess the value of genome-wide high-resolution chromosomal microarray analysis (CMA) for the delineation of pathogenesis for fetal ventriculomegaly diagnosed by ultrasound or magnetic resonance imaging (MRI).
METHODSThree hundred and forty-one cases of fetal ventriculomegaly were collected. The samples were grouped based on the extent of lateral ventricular dilatation, presence of additional features, site of occurrence, and the maternal age. All samples were subjected to karyotyping analysis. For those with a normal karyotype, DNA was extracted and hybridized with an Affymetrix CytoScan HD array. All cases were followed up.
RESULTSAmong the 341 fetuses, 21 (6.2%) were detected with an abnormal karyotype. For the 320 cases with a normal karyotype, 179 (55.9%) have accepted CMA analysis. Potentially pathogenic CNVs were identified in 12 (6.7%) of the 179 cases, whose sizes ranged from 198 kb to 8.71 Mb. These included a 1q21.3q23.1 deletion, a 2q37.3 deletion, a 3p14.1p13 deletion, a 6q25.3 deletion, a 8q11.23 duplication, a 10q21.1 deletion, a 15q11.2 deletion and a 16p13.11p12.3 duplication, a 22q13.33 duplication, a 22q11.21 duplication and a Xp21.1 duplication (Duchenne muscular dystrophy). Pathogenic CNVs were detected respectively in 7.5% and 3.1% of those with mild and severe ventriculomegaly (P=0.615), in 6.1% and 7.4% of those with isolated and non-isolated ventriculomegaly (P=0.732), in 5.6% and 7.9% of those with unilateral and bilateral ventriculomegaly (P=0.511), and in 6.7% of both elderly and non-elderly groups (P=1.000).
CONCLUSIONThe detection rate for abnormal karyotypes among fetuses with ventriculomegaly was 6.2%. CMA can increase the detection rate by approximately 6.7%. There was no significant correlation between ventriculomegaly and presence of pathogenic CNVs. In clinical practice, fetuses with ventriculomegaly and a normal karyotype should be considered for CMA analysis.
Adult ; Chromosome Aberrations ; Female ; Fetus ; abnormalities ; Humans ; Hydrocephalus ; genetics ; Karyotyping ; methods ; Microarray Analysis ; methods ; Pregnancy ; Prenatal Diagnosis ; Young Adult
10.Correlation of fetal ventriculomegaly with copy number variations and pregnancy outcome.
Chunli GAO ; Juan DOU ; Shuiyan YANG
Chinese Journal of Medical Genetics 2021;38(12):1254-1257
OBJECTIVE:
To assess the correlation of borderline fetal ventriculomegaly with genomic copy number variations (CNVs) and outcome of pregnancy.
METHODS:
For 84 singleton pregnancies diagnosed with VM, chromosomal microarray analysis (CMA) was carried out to detect the CNVs of the fetal genome. Outcome of the pregnancy and neonatal development were analyzed. The pregnant women were divided into mild group (10-12 mm), moderate group (12-15 mm) and severe group (>= 15 mm) based on the severity of fetal ventriculomegaly. The detection rate of pathogenic CNVs and pregnancy outcome were compared. Multivariate logistic regression was carried out to analyze the predictors for pregnancy outcome.
RESULTS:
Respectively, 24, 28 and 32 fetuses were assigned into the mild, moderate and severe groups. CMA has detected 15 cases of chromosomal abnormalities, including 11 pathogenic CNVs and 4 abnormal karyotypes. Abnormal pregnancy outcomes were found in 20 fetuses, including 12 with hydrocephalus and 8 with chromosomal microdeletion syndromes. A significant difference was found in the detection rate of fetal pathogenic CNVs and abnormal pregnancy outcome among the three groups (P<0.05). Multivariate logistic regression analysis showed that the largest change of lateral ventricle width (OR = 1.868, 95%CI = 1.120-3.116) and the extent of lateral ventricle widening (OR = 1.571, 95%CI = 1.120-2.206) were the key factors affecting the outcome of pregnancy (P<0.05).
CONCLUSION
Borderline fetal VM is associated with the risk of pathogenic CNVs and adverse pregnancy outcome. A comprehensive examination is required after prenatal ultrasound diagnosis, which is conducive to prenatal consultation and prognostic evaluation of the fetus.
Chromosome Aberrations
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DNA Copy Number Variations
;
Female
;
Fetus
;
Humans
;
Hydrocephalus/genetics*
;
Infant, Newborn
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Microarray Analysis
;
Pregnancy
;
Pregnancy Outcome
;
Prenatal Diagnosis