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*

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