Prenatal Diagnosis of Tyrosinemia Type 1 Using Next Generation Sequencing

Abstract

Prenatal diagnosis using conventional molecular genetic techniques may be encountered with some limitations when the disease causing mutation is unknown. Here, we report on prenatal diagnosis of tyrosinemia in a family with consanguineous marriage and two affected children in whom no disease causing mutation had been identified before pregnancy. Mutation analyses of three genes associated with tyrosinemia including FAH, TAT and HPD were carried out in the fetal DNA sample using Next Generation Sequencing. A heterozygous nonsense mutation (p.Arg237Ter) in FAH gene was detected in the fetus. Further investigations suggested that the fetus was carrier of tyrosinemia type 1. This study demonstrates the successful application of Next Generation Sequencing in prenatal diagnosis, when the time is a limiting factor, more than one (especially large) responsible genes are involved, a "founder" or a "previously detected" mutation is not present and hence the conventional molecular genetic investigations cannot be employed.

In utero CRISPR-mediated therapeutic editing of metabolic genes

“…We used Ad vectors for these initial proof-of-concept studies, recognizing that safer alternative methods such as lipid nanoparticles 13,25 will need to be explored and optimized in order for translation to the clinic to occur. This notwithstanding, our work highlights the potential of in utero base editing to target a gene—either by disruption, as done here with Hpd , or potentially by directly correcting disease-causing mutations—for the purpose of treating a congenital genetic disorder that can be diagnosed early in pregnancy 26 . Although HT1 served as a proof-of-concept disease model to investigate in utero base editing, this approach holds greater potential for diseases that have no effective treatment for the majority of patients and result in profound morbidity and mortality shortly after birth.…”

The fetus in the age of the genome

“…In-utero gene therapy has shown its potential in the treatment of Gaucher disease in knock-out mice (Massaro et al 2018 ) and is believed to be promising in hematologic disorders and cystic fibrosis, for example (Almeida-Porada et al 2019 ; Carlon et al 2017 ). Early (definite) diagnosis of a genetic condition via prenatal exome/genome sequencing may allow for specific prenatal and perinatal management to prevent secondary consequences, for example a specific maternal diet in metabolic genetic conditions for the future child (Rafati et al 2016 ), and might in the future even be the first step towards in utero gene editing (Rossidis et al 2018 ). Such early diagnosis can also prepare an appropriate plan for birth management or neonatal follow-up in the case of complex syndromic conditions and help to avoid unnecessary or burdensome prenatal interventions (Laghmani et al 2016 ).…”

Prenatal DNA Sequencing: Clinical, Counseling, and Diagnostic Laboratory Considerations

“…DNA sequencing information may also provide an early warning for perinatal complications for which delivery sites with special facilities or specialists are required to care for the newborn. Prenatal knowledge of an expected metabolic genetic condition in the neonate may allow immediate implementation of an appropriate diet to avoid metabolic decompensation, which may otherwise begin in the first few days or weeks of life before newborn screening results are available . For autosomal recessive conditions in which two pathogenic variants cannot always be identified (e.g., hearing loss that is due to Pendred syndrome), identification of even carrier status in the fetus could lead to more comprehensive clinical follow‐up in the neonatal period, potential early diagnosis and improved clinical care.…”