Identification of a novel nonsense IQSEC2 variant in a child with X-linked intellectual disability / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child featuring X-linked intellectual disability.@*METHODS@#The 1-year-and-6-month-old child presented with growth retardation, intellectual disability and bilateral alternating squint. With DNA extracted from the child and his parents' peripheral venous blood samples, whole exome sequencing was carried out to identify potential variants that can explain his condition. Suspected variants were validated by Sanger sequencing. The impact of variants was predicted by bioinformatic tools.@*RESULTS@#The child was found to harbor a de novo nonsense c.3163C>T (p.Arg1055*) variant of the IQSEC2 gene. The variant, unreported previously, was predicted to be pathogenic based on MutationTaster, PROVEAN and SIFT. Analysis using a HomoloGene system suggested Arg1055 in IQSEC2 residues to be highly conserved evolutionarily, and that replacement of Arg1055 may cause destroy of the PH domain (AA 951-1085) and serious damage to the function of IQSEC2 protein. Analysis with UCSF chimera software suggested that the c.3163C>T (p.Arg1055*) variant can induce serious damages to the secondary structures of IQSEC2 protein, causing loss of its function.@*CONCLUSION@#The patient's condition may be attributed to the de novo nonsense variant c.3163C>T (p.Arg1055*) of the IQSEC2 gene.

Analysis of ARSA gene variant in an infant with late infantile metachromatic leukodystrophy / 中华医学遗传学杂志

Objective@#To detect pathogenic variant of ARSA gene in an infant with late infantile metachromatic leukodystrophy (MLD).@*Methods@#The male proband had an onset of walking dysfunction and seizure at 28 months. Arylsulfatase A activity of his peripheral blood leucocytes was 26.9 nmol/mg.17h, and cranial MRI showed wild symmetrical demyelination. With genomic DNA extracted from his peripheral blood sample, all coding exons and splicing sites of the ARSA gene were subjected to Sanger sequencing. PubMed Protein BLAST system was employed to analyze cross-species conservation of the mutant amino acid. Ucsf chimera software was used to analyze the impact of candidate variants on the secondary structure of the protein product. Impact of potential variants was also analyzed with software including PolyPhen-2, Mutation Taster, SIFT and PROVEAN. Whole-exome sequencing was carried out to identify additional variants which may explain the patient’s condition.@*Results@#The proband was found to harbor compound heterozygous variants of the ARSA gene [c.467G>A (p.Gly156Asp) and c. 960G>A (p.Trp320*)], neither of which was reported previously. As predicted by Ucsf chimera software, the c. 960G>A (p.Trp320*) variant may demolish important secondary structures including α-helix, β-strand and coil of the ARSA protein, causing serious damage to its structure and loss of function. The c. 467G>A (p.Gly156Asp) variant was predicted to be "probably damaging" by PolyPhen-2, Mutation Taster and SIFT software.@*Conclusion@#The patient’s condition may be attributed to the compound heterozygous c. 467G>A (p.Gly156Asp) and c. 960G>A (p.Trp320*) variants of the ARSA gene. Above results have facilitated genetic counseling and prenatal diagnosis for this family.

Analysis of ARSA gene variant in an infant with late infantile metachromatic leukodystrophy / 中华医学遗传学杂志

OBJECTIVE@#To detect pathogenic variant of ARSA gene in an infant with late infantile metachromatic leukodystrophy (MLD).@*METHODS@#The male proband had an onset of walking dysfunction and seizure at 28 months. Arylsulfatase A activity of his peripheral blood leucocytes was 26.9 nmol/mg.17h, and cranial MRI showed wild symmetrical demyelination. With genomic DNA extracted from his peripheral blood sample, all coding exons and splicing sites of the ARSA gene were subjected to Sanger sequencing. PubMed Protein BLAST system was employed to analyze cross-species conservation of the mutant amino acid. Ucsf chimera software was used to analyze the impact of candidate variants on the secondary structure of the protein product. Impact of potential variants was also analyzed with software including PolyPhen-2, Mutation Taster, SIFT and PROVEAN. Whole-exome sequencing was carried out to identify additional variants which may explain the patient's condition.@*RESULTS@#The proband was found to harbor compound heterozygous variants of the ARSA gene [c.467G>A (p.Gly156Asp) and c.960G>A (p.Trp320*)], neither of which was reported previously. As predicted by Ucsf chimera software, the c.960G>A (p.Trp320*) variant may demolish important secondary structures including α-helix, β-strand and coil of the ARSA protein, causing serious damage to its structure and loss of function. The c.467G>A (p.Gly156Asp) variant was predicted to be "probably damaging" by PolyPhen-2, Mutation Taster and SIFT software.@*CONCLUSION@#The patient's condition may be attributed to the compound heterozygous c.467G>A (p.Gly156Asp) and c.960G>A (p.Trp320*) variants of the ARSA gene. Above results have facilitated genetic counseling and prenatal diagnosis for this family.