Clinical practice and outcomes of preimplantation genetic testing for CMT1A using a novel direct detection method

Charcot-Marie-Tooth type 1A (CMT1A), the most frequent type of Charcot-Marie-Tooth disease, is mainly caused by a 1.4-Mb duplication containing the PMP22 gene. There is no effective treatment other than general supportive care and symptomatic treatment. Preimplantation genetic testing for monogenic defects (PGT-M) is an alternative approach for obtaining healthy babies.

A new technology and analysis method based on next-generation sequencing (NGS) was developed to detect duplication mutations directly. Simultaneously, aneuploidy and linkage analyses were performed to achieve a comprehensive and accurate embryo diagnosis.

Eight couples were recruited in this study; PMP22 duplication was validated in seven couples, and PMP22 splicing mutation was found in one. Forty-five embryos from 12 PGT cycles were successfully detected using this novel method. The direct detection results for all embryos were consistent with the linkage analyses, suggesting a 100 % accuracy rate, and the aneuploidy rate of the biopsied blastocysts was 33.3 %. Eventually, 18 of the 45 diagnosed embryos were deemed suitable for transfer. Four healthy babies from three families were delivered and their genetic status confirmed by amniocentesis. Additionally, there were no adverse effects of anesthesia or increased pregnancy complications during PGT-M in female patients with CMT1A.

This study provided a simple, reliable, and efficient method that can directly detect PMP22 mutations based on NGS data and does not require positive family members. A clinical workflow for CMT1A interruption in the offspring before embryo implantation is also summarized.