Genetic, Prenatal, and Preimplantation Genetic Diagnosis of Glutaric Aciduria Type I

He B,Wang X,Wu Q,Ji X,Song C,Li W,Shi J,Wang L,Qiang R,Shi W

doi:10.18314/cogo.v3i1.2068

Abstract

Purpose: Glutaric Acid Type I (GA-I) is an inherited metabolic disorder. Although the treatment guidelines for GA-I were established a decade ago, they cannot block the vertical heredity. We aim to apply genetic methods to block the inheritance of GA-I and verifies the efficiency of Next-Generation Sequencing (NGS)-based Preimplantation Genetic Testing for Monogenic disease (PGT-M) of GA-I.Materials and methods: A non-consanguineous Chinese family was diagnosed with GA-I by Sanger sequencing. PGT-M and prenatal diagnosis (PND) were performed for the carrier. 5 blastocysts were used for the trophectoderm biopsy. After Whole-Genome Amplification (WGA), the WGA products were used for Sanger sequencing, NGS-based PGT-M and PGT-A. Sanger sequencing-based PND was performed in second trimester to confirm the results of PGT-M.Results: A compound heterozygous mutation was diagnosed in the GCDH gene with co-segregation. One is [c.533G>A (p.G178E)] and another is [c.914C>T (p.S305L)]. 2 blastocysts were diagnosed as normal and one of them was transferred into the mother’s uterus. Finally, a healthy female was born 39 weeks after transplantation.Conclusion: Our study successfully applied NGS-based PGT-M to avoid GA-I and highlights the efficiency of genetic diagnoses. It has significant implications on genetic counseling and genetic diagnosis for GA-I.

Highlights

Preimplantation genetic testing for monogenic disease (PGT-M), known as preimplantation genetic diagnosis (PGD), has become well-established technique to prevent the birth of a child with genetic disorder
A Preimplantation Genetic Testing for Aneuploidy (PGT)-M is performed as part of the in vitro fertilization (IVF) process and has been used to select unaffected embryos from patients suffering from known monogenic diseases, such as autosomal recessive, autosomal dominant, and X-linked disorders [9]
The results showed that the father (I-1) had a heterozygous mutation in glutaryl-CoA dehydrogenase (GCDH) c.914C>T, the mother (I2) had another heterozygous mutation in GCDH c.533G>A, and the proband (II-2) had either mutation c.533G>A or mutation c.914C>T in the GCDH gene (Figure 2A)

Summary

Introduction

Glutaric acidemia type I (GA-I, OMIM 231670) is an autosomal recessive metabolic disorder caused by glutaryl-CoA dehydrogenase (GCDH) deficiency due to mutations in GCDH (NM_000159) gene [1,2]. The efficacy of dietary treatment may fail [8] These treatments can reduce the risk of acute encephalopathic crises, they can neither block the vertical heredity of the pathogenic mutations nor guarantee the quality of life of patients. Preimplantation genetic testing for monogenic disease (PGT-M), known as preimplantation genetic diagnosis (PGD), has become well-established technique to prevent the birth of a child with genetic disorder. To prevent pathogenic mutations from passing down to the generation, the patient was advised to receive PGT-M and PND.

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Results

Conclusion