Genotype and phenotype analysis of two monozygotic twins with neurofibromatosis type 1 but inconsistent congenital pseudarthrosis
10.3760/cma.j.cn121113-20220506-00253
- VernacularTitle:两对同卵双胞胎1型神经纤维瘤与骨假关节的基因型与表型分析
- Author:
Yu ZHENG
1
;
Guanghui ZHU
;
Zhengmao HU
;
Yaoxi LIU
;
Yongjia YANG
;
Zhenqing LUO
;
Haibo MEI
Author Information
1. 湖南省儿童医院，湖南儿科医学研究所，长沙 410007
- Keywords:
Pseudarthrosis;
Neurofibromatosis 1;
Genetic testing;
Twins;
Phenotype
- From:
Chinese Journal of Orthopaedics
2022;42(16):1054-1064
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To compare the genotypes and phenotypes between the monozygotic twins via whole genome sequencing to further clarify the autosomal dominant inherited neurofibromatosis type 1 (NF1) variants related to congenital pseudarthrosis (CP).Methods:According to the diagnostic criteria of congenital tibial pseudarthrosis and the clinical diagnostic criteria of NF1, two pairs of monozygotic twins with NF1 were included. Both were female and only one of each pair had congenital pseudarthrosis. The other did not have congenital pseudarthrosis. Whole genome sequencing was performed using the peripheral blood of the two pairs of monozygotic twins. Customized bioinformatics analysis was then performed to identify single nucleotide variants (SNVs), short insertion deletion variants (InDel), copy number variants (CNVs), and structural variants (SVs). Classified the variants according to the American College of Medical Genetics and Genomics (ACMG) and ClinGen criteria. The germline variants within the monozygotic twins were compared to identify the CP patients' unique variants. The shared pathogenic or likely pathogenic germline variants between the unique variants in the CP patients from the twins were also analyzed. Further, the identified disease-causing variants were validated by Sanger sequencing in the family of the twins and their parents. Finally, the genotypes and phenotypes regarding the pathogenic variants of the NF1 gene among the twins were characterized. Results:Both the two monozygotic twins were identified pathogenic variants in the NF1 gene. One with c.3047_3048del (p.Cys1016SerfsTer4), and the other with c.4267A>G (p.Lys1423Glu). By Sanger sequencing validation in family quads, the two CP patients and their siblings harbored de novo heterozygous variants of the NF1 gene. In addition to the NF1 gene, no other genes were identified pathogenic or likely pathogenic variants uniquely in the CP patients compared with their twin sisters, as well as SVs and CNVs. In addition, by analyzing the rare and damaging variants in the two CP patients from the two twins, they had no overlapping genes against the SNVs, InDels, SVs, or CNVs. Conclusion:Whole genome sequencing revealed that both the two monozygotic twins with NF1 were detected pathogenic variants of gene NF1. No other pathogenic variants specific to the CP patients among the twins were identified. The two CP patients shared no other common genes from the detected likely pathogenic variants.
