OBJECTIVE: To explore the clinical characteristics and genetic etiology of a child with Aicardi-Goutières syndrome 3 (AGS3). METHODS: Trio whole exome sequencing was carried out for the child and his parents, and candidate variants were verified by Sanger sequencing. To further clarify their pathogenicity, the crystal structure of the variants was simulated and analyzed, and the plasmid of variants was expressed in vitro. A literature search was also carried out to summarize the phenotypic and genetic characteristics of AGS3. RESULTS: The child was found to harbor novel compound heterozygous variants of the RNASEH2C gene, namely c.434G>T (p.Arg145Leu) and c.494G>C (p.Ter165Ser), which were inherited from his mother and father, respectively. Analysis of protein crystal structure suggested that the c.434G>T (p.Arg145Leu) variant may affect the stability of local structure, and in vitro experiments showed that this variant can lead to protein degradation. The c.494G>C (p.Ter165Ser) variant has destroyed the stop codon, resulting in prolonged variant. CONCLUSION The novel compound heterozygous variants of the RNASEH2C gene probably underlay the AGS3 in this child, which has enriched the phenotypic and mutational spectrum of this disorder.
Humans ; Child ; Mutation ; Autoimmune Diseases of the Nervous System/genetics* ; Nervous System Malformations/genetics*

Developmental Disabilities ; diagnosis ; etiology ; genetics ; Humans ; Nervous System Malformations ; diagnosis ; etiology ; genetics

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*

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

OBJECTIVEAicardi-Goutières syndrome (AGS) is a rare early-onset genetic encephalopathy. The aim of this study was to explore the clinical, imaging and genetic features of a family with AGS, which may contribute to definite diagnosis, genetic counseling and prenatal diagnosis of this rare disease in China. We summarized the characteristics of AGS through reviewing related references.

METHODInformation of the proband and other family members as well as their DNA samples were collected. All the exons and exon-intron boundaries of pathogenic genes were amplified with PCR and were directly sequenced for genomic DNA. And we reviewed the reports of 252 cases.

RESULT(1) The proband was a 6 years plus 7 months old boy. He presented with severe developmental delay and abnormal posture mainly as torsion of limbs. By physical examination he was found to have some chilblain-like skin lesions at the end of limbs and microcephaly. The CT scan of his head displayed multiple calcification, especially in the basal ganglia. The MRI of his head displayed a hypointense signal in T1-weighted (T1W) images and a hyperintense signal in T2-weighted (T2W) in cerebral white matter and cystic lesions in temporal white matter. The younger sister of the proband presented with chilblain-like skin lesions on her face and the end of limbs had no developmental delay. The CT of her head showed multiple calcification, especially in the basal ganglia. (2) Two mutations were identified in TREX1, one was a novel nonsense mutation (c.294_295insA), and the other was a known pathogenic mutation (c.868_885del). (3) The common performances of AGS included mental retardation [92% (231/252) ], dystonia [75% (189/252)], microcephaly [63% (159/252) ], chilblain [42% (106/252) ], basal ganglia calcification [100% (252/252)], brain atrophy[88% (222/252)] and cerebral white matter lesions [86% (217/252)]. TREX1 [38% (96/252) ] and RNASEH2B [23% (58/252)]are the most common pathogenic genes.

CONCLUSIONWe determined pathogenic gene of these patients which is the basis of genetic counseling for this family. c.294_295insA mutation is a novel mutation not reported around the world yet.

Atrophy ; Autoimmune Diseases of the Nervous System ; diagnosis ; genetics ; Calcinosis ; Child ; China ; Exodeoxyribonucleases ; genetics ; Exons ; genetics ; Genetic Testing ; Humans ; Magnetic Resonance Imaging ; Male ; Mutation ; Nervous System Malformations ; diagnosis ; genetics ; Pedigree ; Phosphoproteins ; genetics