Identification of variants in TNNI3 gene in two children with restrictive cardiomyopathy / 中华医学遗传学杂志

OBJECTIVE@#To identify the pathogenesis in two patients of restrictive cardiomyopathy (RCM) using high-throughput sequencing.@*METHODS@#Peripheral blood samples from the two patients and their parents were collected and genomic DNAs were extracted to conduct targeted next generation sequencing or whole exome sequencing. Bioinformation analysis was performed to identify the pathogenic variants in genes associated with cardiomyopathy, which were further validated by Sanger sequencing.@*RESULTS@#By high throughput sequencing, we detected a de novo heterozygous variant c.549+1G>T in TNNI3 gene in patient 1. The variant has not been reported previously and was predicted to be pathogenic in line with American College of Medical Genetics and Genomics (ACMG) guidelines (PVS1+PS2+PM2). Another heterozygous variant c.433C>T (p.Arg145Trp) in TNNI3 gene was identified in patient 2 and his father. The variant had been reported as pathogenic variant in Clinvar and HGMD databases; based on ACMG guidelines, the variant was predicted to be likely pathogenic (PS3+PM1+PP3).@*CONCLUSION@#TNNI3 variants may be the causative gene responsible for restrictive cardiomyopathy in the two patients. High throughput sequencing results provide bases for the diagnosis of restrictive cardiomyopathy.

Analysis of SMARCA2 gene mutation in a child with Nicolaides-Baraitser syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the molecular basisfor a child featuring short stature, abnormal facial features and developmental delay.@*METHODS@#Genomic DNA was extracted from peripheral blood samples from the child and his family members. Next-generation sequencing was carried out to screen the whole exomes of the core family. Detected variants were filtered and analyzed according to the standards and guidelines for the interpretation of sequence variants recommended by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.@*RESULTS@#Trio-based sequencing has identified a de novo variant c.3593T>G (p.Val1198Gly) in the SMARCA2 gene in the patient. The variant was located in the Helicase C-terminal domain and was classified as pathogenic based on the guidelines.@*CONCLUSION@#The patient was diagnosed with Nicolaides-Baraitser syndrome caused by SMARCA2 gene mutation.

Molecular diagnosis and functional study of a pedigree affected with Lubs X-linked mental retardation syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a pedigree affected with X-linked mental retardation.@*METHODS@#The proband was subjected to chromosomal karyotyping, FMR1 mutation testing and copy number variation analysis with a single nucleotide polymorphism microarray (SNP array). His family members were subjected to multiplex ligation-dependent probe amplification (MLPA) assaying. Expression of genes within the repeated region were analyzed.@*RESULTS@#The proband had a normal chromosomal karyotype and normal number of CGG repeats within the FMR1 gene. SNP array identified a 370 kb duplication in Xq28 (ChrX: 153 027 633-153 398 515), which encompassed 14 genes including MECP2. The patient was diagnosed as Lubs X-linked mental retardation syndrome (MRXSL). MLPA confirmed the presence of copy number variation, its co-segregation with the disease, in addition with the carrier status of females. Genes from the duplicated region showed higher levels of expression (1.79 to 5.38 folds) within peripheral blood nucleated cells of the proband.@*CONCLUSION@#The patients were diagnosed with MRXSL. The expression of affected genes was up-regulated due to the duplication. Genetic counseling and prenatal diagnosis may be provided based on the results.

Analysis of SMARCA2 gene mutation in a child with Nicolaides-Baraitser syndrome / 中华医学遗传学杂志

Objective@#To explore the molecular basisfor a child featuring short stature, abnormal facial features and developmental delay.@*Methods@#Genomic DNA was extracted from peripheral blood samples from the child and his family members. Next-generation sequencing was carried out to screen the whole exomes of the core family. Detected variants were filtered and analyzed according to the standards and guidelines for the interpretation of sequence variants recommended by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.@*Results@#Trio-based sequencing has identified a de novo variant c. 3593T>G (p.Val1198Gly) in the SMARCA2gene in the patient. The variant was located in the Helicase C-terminal domain and was classified as pathogenic based on the guidelines.@*Conclusion@#The patient was diagnosed with Nicolaides-Baraitser syndrome caused by SMARCA2 gene mutation.

Genetic diagnosis and analysis for two cases of ring chromosome 22 / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To confirm the genetic diagnosis of two patients with ring chromosome 22 syndrome and investigate the mechanism underlying the formation of r(22) and potential genetic causes for the clinical phenotypes.</p><p><b>METHODS</b>Cytogenetic and molecular analyses using standard G-banding, fluorescence in situ hybridization and single nucleotide polymorphism array (SNP array) were performed.</p><p><b>RESULTS</b>For case 1, the karyotype was 46,XY,r(22)(p11q13). SNP array has identified a 7.0 Mb heterozygous deletion at 22q13.2q13.33. For case 2, the karyotype was 46,XY,r(22)(p11q13)[84]/45,XY,-22[6]; SNP array has detected a heterozygous microdeletion of 1.6 Mb at 22q13.33.</p><p><b>CONCLUSION</b>With combined application of genetic testing, 2 cases of r(22) syndrome were diagnosed, which has improved the understanding of the genotype-phenotype correlation of r(22).</p>