Prenatal genetic diagnosis of monogenic diseases

Abstract

Prenatal genetic diagnosis of monogenic diseases is a process involving the use of a variety of molecular techniques for the molecular characterization of a potential monogenic disease in the fetus during pregnancy. Prenatal genetic diagnosis can be performed through invasive and non-invasive methods. A distinction must be made between "NIPD" (non-invasive prenatal diagnosis), which is considered to be diagnostic, from "NIPT" (non-invasive prenatal test), which is a screening test that requires subsequent confirmation by invasive methods. The different techniques currently available aim at detecting either, previously characterized pathogenic mutations in the family, the risk haplotype associated with the familial mutation, or potential pathogenic mutation(s) in a gene associated with a diagnostic suspicion. An overview is provided of relevant aspects of prenatal genetic diagnosis of monogenic diseases. The objective of this paper is to describe the main molecular techniques currently available and used in clinical practice. A description is provided of the indications, limitations and analytical recommendations regarding these techniques, and the standards governing genetic counseling. Continuous rapid advances in the clinical applications of genomics have provided increased access to comprehensive molecular characterization. Laboratories are struggling to keep in pace with technology developments.

Keywords: genetic counseling; molecular techniques; monogenic diseases; prenatal genetic diagnostics; recommendations.

Figure 1:

Diagnostic algorithm on suspicion of a monogenic disease in the fetus based on ultrasound findings. ARMS, amplification-refractory mutation system; MLPA, multiplex ligation probe amplification; NGS, next generation sequencing; TP-PCR, triplet repeat primed PCR.

Figure 2:

Diagnostic algorithm to exclude a monogenic disease in the fetus when the mother or the father or the two are affected by or carriers of a monogenic disease. ARMS, amplification-refractory mutation system; HRM, high resolution melting; MLPA, multiplex ligation probe amplification; NGS, next generation sequencing; NIPD, non-invasive prenatal diagnosis; NIPT, non-invasive prenatal test; RHDO, relative haplotype dosage analysis; RMD, relative mutation dosage; TP-PCR, triplet repeat primed PCR.