Genetic analysis of a Chinese pedigree featuring non-simplex blepharocheilodontic syndrome
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目的 探讨1个非单纯性睑-唇-齿综合征(BCDS)家系的遗传学病因。 方法 选取2020年9月28日于宁波市妇女儿童医院就诊的1个BCDS家系为研究对象。通过全外显子组测序对胎儿及其父母和哥哥进行基因与拷贝数变异(CNVs)分析，用Sanger测序和实时荧光定量PCR(qPCR)分别对结果进行验证。 结果 胎儿及其哥哥、父亲、祖父均携带CTNND1基因c.83delG(p.A29Rfs*55)杂合变异，既往未见报道。此外，胎儿的哥哥还携带母源性GJB2基因c.235delC(p.L79Cfs*3)和父源性GJB3基因c.538C>T(p.R180X)双杂合变异；CNVs分析发现母亲17q12区存在1.46 Mb缺失，涉及HNF1B、ZNHIT3等16个OMIM基因，对胎儿的外祖父母进行qPCR验证，证实为新发变异。根据美国医学遗传学和基因组学学会相关指南，c.83delG及c.235delC均评判为致病性变异(PVS1+PP1_Moderate+PM2_Supporting，PVS1+PM3_VeryStrong+PS3_Moderate)；c.538C>T评判为意义不明变异(PS3+PM2_Supporting)；17q12微缺失评判为致病性(pathogenic，total score：1.0)。 结论 CTNND1基因c.83delG(p.A29Rfs*55)变异可能是该非单纯性BCDS家系的遗传学病因。GJB2基因c.235delC和GJB3基因c.538C>T变异可能为哥哥耳聋的致病原因。17q12微缺失可能为母亲双肾囊肿的致病原因。上述发现为该家系的遗传咨询和再生育提供了指导。 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 ofGJB3 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) ofGJB3 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.
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 ofGJB3 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) ofGJB3 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.
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