Preimplantation genetic testing and prenatal diagnosis of TANGO2 deficiency disorder with biallelic pathogenic variants using single-nucleotide polymorphism-based haplotyping and gap-polymerase chain reaction

Abstract

Introduction TANGO2 deficiency disorder (TDD), characterized by developmental delays, intellectual disability, gait incoordination, speech difficulties, seizures, and hypothyroidism, is a rare genetic disease caused by biallelic pathogenic variants of the TANGO2 gene (NM_152906.7). Methods In this study, we aimed to present a comprehensive approach for the management of TDD through preimplantation genetic diagnosis and subsequent prenatal diagnosis using single-nucleotide polymorphism (SNP)-based haplotyping and gap-polymerase chain reaction (PCR). Results Whole-exome sequencing revealed that the proband was a compound heterozygote with c.672C>A (p.Y224*) and an exon 5-6 deletion (c.266_451del (p.E89Tfs*124)). We confirmed these two pathogenic variants using Sanger sequencing and quantitative PCR copy number variation (CNV) analysis, respectively. We successfully constructed an SNP-based haplotype using next-generation sequencing (NGS) in the preclinical phase of preimplantation genetic testing (PGT). In the clinical phase of embryo diagnosis, embryos were subjected to PGT, including NGS-based SNP haplotype linkage and chromosomal CNV analyses. Notably, we successfully identified the exact breakpoints of exon 5-6 deletion (NC_000022.11:g.20053363_20057022delinsAGGT, GRCh38/hg38) using long-range PCR and designed a gap-PCR system based on the location of the breakpoints for subsequent prenatal diagnosis. Discussion Taken together, our study provides a method for PGT and subsequent prenatal diagnosis of TDD using SNP-based haplotyping and gap-PCR. The two novel pathogenic variants identified in this study extend the mutational spectrum of TDD.