Preimplantation genetic testing and prenatal diagnosis of TANGO2 deficiency disorder with biallelic pathogenic...

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).

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).

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.

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.