Solving a mystery and offering hope: Preimplantation diagnosis (PGD) for a new GlyT1 encephalopathy at the Rambam Health Care Campus

Introduction

In 2015 Rambam reopened its PGD unit, the only one serving Northern Israel. This answers an important need for many consanguineous families from this region affected with monogenic disorders and diagnosed in the Rambam Genetics Institute (RGI). We describe the discovery of the genetic cause of a new glycine encephalopathy, followed by a successful PGD diagnosis.

Aim

To establish a model for diagnosis of rare monogenic syndromes in Northern Israel, followed by implementation of PGD services.

Materials and methods

Whole exome next generation sequencing (WE-NGS) and bioinformatic analysis, combined with Sanger sequencing validation was performed. Microsatellite-based linkage analysis PGD combined with direct analysis of the deletion mutation was applied.

Results

A homozygous 5bp deletion in the SLC6A9 gene (NM_201649.3:c.928_932del:p.Lys310Phefs*31) was identified by WE-NGS in a child of Muslim Arab descent, affected with encephalopathy, hypotonia, respiratory disorder, and arthrogryposis. The SLC6A9 gene encodes the glycine transporter GlyT1, and its inactivity was suggested to cause mild glycine elevation in the CSF, but not serum, and the neurodevelopmental phenotype. Discovery of a second family segregating the same phenotype with a different truncating mutation in SLC6A9 confirmed causality. After a terminated pregnancy due to diagnosis of a homozygous affected fetus, the first family attended the Rambam IVF unit and used the PGD service, resulting in a currently ongoing pregnancy.

Conclusions

A new glycinopathy syndrome was identified at the RGI. The proximity to the joint IVF-Genetics PGD unit streamlined and shortened the transition to clinical practice enabling successful PGD diagnosis within months of discovery.