AB137. Preimplantation genetic diagnosis for rare monogenic disorder: a lesson from pantothenate kinase-associated neurodegeneration

Background and objective: Preimplantation genetic diagnosis (PGD) is a technique to identify the genetic defects in the embryos created through in vitro fertilization (IVF). The purpose of this technology is to assist reproduction in one or both biological parents carrying known genetic abnormalities. Herein, we report on a Thai couple having an experience on the loss of the first child affected by neurodegeneration and died at the age of 2. Brain MRI revealed the tiger-eye-sign, which was suspected for pantothenate kinase-associated neurodegeneration (PKAN). DNA sequencing of PANK2 gene was performed in the whole family members and novel g.21738G>C at the splice site was identified as likely pathogenic variant, relying on autosomal recessive inheritance model. This article aims to develop PGD strategy for PANK2 variant inherited in this family.

Methods: Genetic counseling for PGD was performed to the couples and the ethical clearance was done. IVF and intra cytoplamic sperm injection (ICSI) with PGD was performed. All of embryos were biopsied in the cleavage stage and subsequently performed for whole-genome amplification. Genetic status was diagnosed with the linkage analysis using family-specific short-tandem repeat markers and direct mutation testing using SNaPshot Mini-sequencing. The aneuploidy screening was performed by low-pass whole genome next-generation sequencing (NGS)-based strategy.

Results: Only single cycle of IVF-ICSI was processed. There were seven embryos from these couples: two likely affected, three likely being carriers, one likely unaffected and one failed in the target genome amplification. Aneuploidy screening was done before making decision of embryo transfer and only one unaffected embryo passed the screening. Thereafter, this embryo was transferred in frozen thawed cycle and the pregnancy was successful. The confirmation was done by amniocentesis, which showed the consistent result to PGD. At 38 weeks of gestational age, a healthy male baby was born.

Conclusions: PGD is currently established as a technology to prevent the recurrence of genetic disorders in the family. Here we report the first successful story of PGD for PKAN.

Keywords: Preimplantation genetic diagnosis (PGD); pantothenate kinase-associated neurodegeneration (PKAN); PANK2; in vitro fertilization (IVF); next-generation sequencing (NGS)