Genetic analysis of a Chinese pedigree featuring non-simplex blepharocheilodontic syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a Chinese pedigree featuring non-simplex blepharocheilodontic syndrome.@*METHODS@#Whole exome sequencing was carried out to detect genetic variant and copy number variations (CNVs) in the pedigree. Suspected variants were verified by Sanger sequencing and qPCR.@*RESULTS@#The fetus and its elder brother, father and grandfather were found to harbor a heterozygous c.83delG (p.A29Rfs*55) variant of the CTNND1 gene, which was unreported previously. In addition, its elder brother was also found to be a double heterozygote for a c.235delC (p.L79Cfs*3) variant of GJB2 gene and a c.538C>T (p.R180X) variant of GJB3 gene, which were respectively inherited from his mother and father. CNVs analysis revealed a de novo heterozygotic deletion (1.46 Mb) at 17q12 in the mother, which was confirmed by qPCR. Based on American College of Medical Genetics and Genomics guidelines, the c.83delG variant, the c.235delC variant and the 17q12 microdeletion were predicted as pathogenic, while the c.538C>T variant was of uncertain significance.@*CONCLUSION@#The c.83delG (p.A29Rfs*55) variant of the CTNND1 gene probably underlay the pathogenesis of non-simplex blepharocheilodontic syndrome in this pedigree. The double heterozygous variants of c.235delC (p.L79Cfs*3) of GJB2 gene and c.538C>T (p.R180X) of GJB3 gene probably underlay the hearing loss in the elder brother. The bilateral renal cysts in the mother may be attributed to the 17q12 microdeletion. Above results have provided guidance for genetic counseling and prenatal diagnosis for this pedigree.

Genetic analysis of a rare fetus with mandibulofacial dysostosis Guion-Almeida type / 中华医学遗传学杂志

OBJECTIVE@#To delineate the clinical and genetic features of a fetus with micrognathia, low-set ears, microtia, polyhydramnios and anechoic stomach by ultrasonography.@*METHODS@#Whole exome sequencing (WES) was carried out to detect genetic variant in the fetus, for which routine chromosomal karyotyping and chromosomal microarray analysis (CMA) yielded no positive finding. Candidate variants were verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#WES revealed that the fetus has carried a de novo nonsense c.2302C>T (p.Q768X) variant in exon 23 of the EFTUD2 gene, which was detected in neither parent. The variant was unreported previously and may lead to premature termination of the translation of EFTUD2 protein at the 768th amino acid. Bioinformatic analysis predicted the amino acid to be highly conserved and may alter the structure and function of the EFTUD2 protein.@*CONCLUSION@#The c.2302C>T variant of the EFTUD2 gene probably underlay the mandibulofacial dysostosis Guion-Almeida type in the fetus. Discovery of the novel variant has enriched variant spectrum of the EFTUD2 gene and provided a basis for genetic counseling and prenatal diagnosis for the family.

Analysis of non-invasive prenatal testing in 14 047 cases of advanced age pregnant women / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of non-invasive prenatal testing (NIPT) for the diagnosis of fetal chromosomal aneuploidies among women with advanced gestational age.@*METHODS@#14 047 pregnant women have voluntarily accepted the NIPT test. The results of NIPT and amniocytic karyotyping analysis were compared, and the outcome of pregnancy was followed up.@*RESULTS@#NIPT has identified 104 cases with a high risk for trisomies 21, 18 and 13, and 44 cases with a high risk for sex chromosome abnormalities. After genetic consultation, 87 of 104 cases have accepted amniocyte chromosomal karyotyping. 63 cases of fetal chromosome abnormality were confirmed, including 46 cases of 21 trisomy, 11 cases of 18 trisomy and 6 cases of 13 trisomy. The positive predictive value was 83.64% (46/55), 61.11% (11/18), and 42.86% (6/14), the specificity was 99.93%, 99.95%, 99.94%, and the sensitivity was 100%. Among the 44 cases, 34 received amniocytic chromosomal karyotyping analysis, 11 cases were confirmed, the positive predictive value was only 32.35%. No aneuploidy was found in the low-risk cases. The negative predictive value was 100%.@*CONCLUSION@#As a prenatal screening method for women with advanced gestational age, NIPT has the highest positive predictive value for trisomy 21 and trisomy 18, but a lower positive predictive value for sex chromosome abnormalities. NIPT has a very low rate of missed diagnosis of trisomies 21, 18 and 13, which can significantly reduce the number of women undergoing invasive prenatal diagnosis.