OBJECTIVE: To assess the value of chromosomal microarray analysis (CMA) for the diagnosis of fetuses with anomalies of the central nervous system (CNS) and summarize the outcome of the pregnancies and follow-up. METHODS: A total of 636 fetuses from June 2014 to December 2020 who were referred to the Prenatal Diagnosis Center of Nanjing Drum Tower Hospital due to abnormal CNS prompted by ultrasound were selected as the research subjects. Based on the ultrasound findings, the fetuses were divided into ventricular dilatation group (n = 441), choroid plexus cyst group (n = 41), enlarged posterior fossa group (n = 42), holoprosencephaly group (n = 15), corpus callosum hypoplasia group (n = 22), and other anomaly group (n = 75). Meanwhile, they were also divided into isolated (n = 504) and non-isolated (n = 132) groups based on the presence of additional abnormalities. Prenatal samples (amniotic fluid/chorionic villi/umbilical cord blood) or abortus tissue were collected for the extraction of genomic DNA and CMA assay. Outcome of the pregnancies and postnatal follow-up were summarized and subjected to statistical analysis. RESULTS: In total 636 fetuses with CNS anomalies (including 89 abortus tissues) were included, and 547 cases were followed up. The overall detection rate of CMA was 11.48% (73/636). The detection rates for the holoprosencephaly group, ACC group, choroid plexus cyst group, enlarged posterior fossa group, ventricular dilatation group and other anomaly group were 80% (12/15), 31.82% (7/22), 19.51% (8/41), 14.29% (6/42), 7.48% (33/441) and 9.33% (7/75), respectively. Compared with the isolated CNS anomaly group, the detection rate for the non-isolated CNS anomaly group was significantly higher (6.35% vs. 31.06%) (32/504 vs. 41/132) (χ² = 62.867, P < 0.001). Follow up showed that, for 52 fetuses with abnormal CMA results, 51 couples have opted induced labor, whilst 1 was delivered at full term with normal growth and development. Of the 434 fetuses with normal CMA results, 377 were delivered at full term (6 had developmental delay), and 57 couples had opted induced labor. The rate of adverse pregnancy outcome for non-isolated CNS abnormal fetuses was significantly higher than that of isolated CNS abnormal fetuses (26.56% vs. 10.54%) (17/64 vs. 39/370) (χ² = 12.463, P < 0.001). CONCLUSION Fetuses with CNS anomaly should be tested with CMA to determine the genetic cause. Most fetuses with negative CMA result have a good prognosis, but there is still a possibility for a abnormal neurological phenotype. Fetuses with CNS abnormalities in conjunct with other structural abnormalities are at increased risk for adverse pregnancy outcomes.
Female ; Pregnancy ; Humans ; Holoprosencephaly ; Prenatal Diagnosis/methods* ; Central Nervous System ; Fetus/abnormalities* ; Nervous System Malformations/genetics* ; Microarray Analysis ; Central Nervous System Diseases ; Cysts ; Chromosome Aberrations ; Ultrasonography, Prenatal/methods*

Non-coding RNAs (ncRNAs) are a class of functional RNAs that play critical roles in different diseases. NcRNAs include microRNAs, long ncRNAs, and circular RNAs. They are highly expressed in the brain and are involved in the regulation of physiological and pathophysiological processes of central nervous system (CNS) diseases. Mounting evidence indicates that ncRNAs play key roles in CNS diseases. Further elucidating the mechanisms of ncRNA underlying the process of regulating glial function that may lead to the identification of novel therapeutic targets for CNS diseases.
Humans ; RNA, Untranslated/genetics* ; MicroRNAs/genetics* ; RNA, Long Noncoding/genetics* ; RNA, Circular ; Central Nervous System Diseases/genetics*

Central Nervous System Diseases ; diagnosis ; genetics ; Fragile X Syndrome ; genetics ; Genotype ; Humans ; Molecular Biology ; Phenotype ; Spinocerebellar Ataxias ; diagnosis ; genetics ; Syndrome

OBJECTIVETo detect potential mutation of MLC1 gene in a child affected with megalencephalic leukoencephalopathy with subcortical cysts (MLC).

METHODSClinical symptoms of the patient were retrieved. Peripheral blood DNA samples from the patient, her parents and healthy controls were collected. Potential mutation of the MLC1 gene was detected by polymerase chain reaction and Sanger sequencing.

RESULTSThe patient presented with severe motor developmental delay and a giant skull. Magnetic resonance scan showed diffuse white matter swelling in bilateral hemispheres. DNA sequencing identified a novel homozygous c.177-c.180delC mutation of the MLC1 gene. The parents of the patient both carried a heterozygous mutation c.177-c.180delC but had a normal phenotype.

CONCLUSIONA novel MLC1 mutation c.177-c.180delC has been identified in a patient with MLC. The mutation is presumably disease-causing and has derived from parents who are both carriers.

Child, Preschool ; Cysts ; genetics ; Female ; Hereditary Central Nervous System Demyelinating Diseases ; genetics ; Humans ; Membrane Proteins ; genetics ; Mutation

The clinical data of a patient with megalencephalic leukoencephalopathy (MLC) with subcortical cysts and her parents were collected. MLC1 gene mutation was detected by polymerase chain reaction and direct DNA sequencing. The patient presented with motor developmental delay and giant skull, and brain magnetic resonance imaging showed diffuse white matter swelling accompanied by subcortical cysts in bilateral frontal and parietal lobes. Gene sequencing identified two heterozygous mutations of MLC1, including missense mutation in exon 3 (c.217G>A, p.Gly73Arg) and splice site mutation in intron 9 (c.772-1G>C in IVS9-1). The patient's parents both had heterozygous mutation c.772-1G>C in IVS9-1 with normal phenotype. It can be presumed that c.772-1G>C in IVS9-1 comes from the parents, and c.217G>A (p.Gly73Arg) is a de novo mutation.
Asian Continental Ancestry Group ; genetics ; Cysts ; genetics ; Female ; Hereditary Central Nervous System Demyelinating Diseases ; genetics ; Humans ; Infant ; Membrane Proteins ; genetics ; Mutation

OBJECTIVE: To explore the clinical features and genetic variant in a child featuring megalencephalic leukoencephalopathy with subcortical cyst (MLC) type 2B. METHODS: Clinical and imaging data of the child was collected. Potential variant of hepatocyte adhesion molecule (HEPACAM) gene was detected by Sanger sequencing. The growth and development of her mother and uncle was also reviewed. RESULTS: The patient, a 1-year-and-7-month female, presented with convulsion, mental retardation and abnormally increased head circumference. Cranial MRI revealed extensive long T1 long T2 signals in the white matter of bilateral cerebral hemisphere, right anterior sac cyst, cerebral gyrus widening, and shallow sulcus. Sanger sequencing identified a c.437C>T missense variant in exon 3 of the HEPACAM gene. The same variant was detected in her mother but not father. Her mother and maternal uncle both had a history of increased head circumference when they were young. In their adulthood, the head circumference was in the normal range but still greater than the average. CONCLUSION The heterozygous variant of the HEPACAM gene probably underlies the MLC2B in this child. The variant has derived from her asymptomatic mother, which suggested incomplete penetrance of the MLC2B.
Adult ; Cell Cycle Proteins ; genetics ; Cerebrum ; diagnostic imaging ; Cysts ; diagnostic imaging ; genetics ; Female ; Genetic Variation ; Hereditary Central Nervous System Demyelinating Diseases ; diagnostic imaging ; genetics ; Humans ; Infant

PURPOSE: Floppy infant, or congenital hypotonia, is caused by various diseases, such as genomic disorders, diseases involving the central or peripheral nervous system, musculoskeletal diseases, and metabolic disorders. We describe here the clinical aspects and the final diagnosis of infants with hypotonia recently diagnosed in a single, tertiary-care hospital in Korea. METHODS: All of the infants evaluated for generalized hypotonia between 2008 and 2012 at Asan Medical Center Children's Hospital were included in our study. The demographic data, physical examination upon initial presentation, the diagnostic tests and results, and the final diagnosis were retrospectively reviewed. RESULTS: A total of 128 infants (68 males, 60 females) were included in the study, and the mean patient age at the time of the diagnosis of hypotonia was 4.8 months. Etiological diagnosis was possible in 80 (62.5%) of the 128 patients, and 57 (44.5%) patients were confirmed by genetic testing. Fifteen patients (11.7%) were categorized as having central nervous system disorders, and 34 (26.6%) patients were diagnosed as having other genomic disorders such as Prader-Willi syndrome (n=17). Disease involving muscle and the peripheral nervous system was detected in 16 (12.5%) patients. Five patients were diagnosed with other skeletal disorders, and metabolic disease was detected in 10 (7.8%) patients. CONCLUSION: With the recent advances in diagnostic tools, including genetic testing, many of the patients with hypotonia can be correctly diagnosed. These data can give practical clues regarding the optimal diagnostic approaches for treating floppy infants in the clinics.
Central Nervous System Diseases ; Chungcheongnam-do ; Diagnosis ; Diagnostic Tests, Routine ; Genetic Testing ; Genetics ; Humans ; Infant* ; Korea ; Male ; Metabolic Diseases ; Muscle Hypotonia ; Musculoskeletal Diseases ; Peripheral Nervous System ; Physical Examination ; Prader-Willi Syndrome ; Retrospective Studies

Central Nervous System Diseases ; etiology ; Child ; Female ; Humans ; Infant ; Lymphohistiocytosis, Hemophagocytic ; complications ; diagnosis ; genetics ; Magnetic Resonance Imaging ; Male ; Mutation ; Perforin ; genetics

Mutations causing genetic disorders can occur during mitotic cell division after fertilization, which is called somatic mutations. This leads to somatic mosaicism, where two or more genetically distinct cells are present in one individual. Somatic mutations are the most well studied in cancer where it plays an important role and also have been associated with some neurodegenerative disorders. The study of somatic mosaicism in Parkinson disease (PD) is only in its infancy, and a case with somatic mutation has not yet been described. However, we can speculate that a somatic mutation affecting cells in the central nervous system including substantia nigra dopaminergic neurons could lead to the development of PD through the same pathomechanisms of genetic PD even in the absence of a germ-line mutation. Theoretically, a number of genes could be candidates for genetic analysis for the presence of somatic mosaicism. Among them, SNCA and PARK2 could be the best candidates to analyze. Because analyzing brain tissues in living patients is impossible, alternative tissues could be used to indicate the genetic status of the brain. Performance of the technology is another factor to consider when analyzing the tissues.
Brain ; Cell Division ; Central Nervous System ; Dopaminergic Neurons ; Fertilization ; Genetics ; Germ-Line Mutation ; Humans ; Mosaicism* ; Neurodegenerative Diseases ; Parkinson Disease* ; Substantia Nigra

OBJECTIVETo explore HEPACAM mutations in a Chinese family with megalencephalic leukoencephaloptathy with subcortical cysts (MLC).

METHODGenomic DNA samples were extracted from peripheral blood of the proband and her parents. All exons and exon-intron boundaries of HEPACAM and MLC1 were amplified in the MLC family by polymerase chain reaction (PCR) followed by direct DNA sequencing.

RESULTTwo heterozygous mutations of HEPACAM located in exon 2, c.203A > T(p.K68M) and c.395C > A(p.T132N), were identified in the proband. The proband's mother had the heterozygous mutations c.203A > T(p.K68M), and her father had the heterozygous mutation-c.395C > A(p.T132N). There was no variation found in MLC1 gene.

CONCLUSIONThe proband was heterozygous compound MLC patient carrying on one allele with the c.203A > T(p.K68M) mutation inherited from her mother, and the other allele with the c.395C > A(p.T132N) mutation inherited from her father. The parents both are heterozygous carriers with normal phenotype. The disease-causing gene for this family was resulted in HEPACAM mutation other than MLC1 mutation.

Asian Continental Ancestry Group ; genetics ; Base Sequence ; Child ; Cysts ; genetics ; pathology ; DNA Mutational Analysis ; Exons ; Female ; Genotype ; Hereditary Central Nervous System Demyelinating Diseases ; genetics ; pathology ; Heterozygote ; Humans ; Membrane Proteins ; genetics ; Mutation ; Pedigree ; Phenotype ; Proteins ; genetics