Reproductive options for families at risk of Osteogenesis Imperfecta: a review

Abstract

Background: Osteogenesis Imperfecta (OI) is a rare genetic disorder involving bone fragility. OI patients typically suffer from numerous fractures, skeletal deformities, shortness of stature and hearing loss. The disorder is characterised by genetic and clinical heterogeneity. Pathogenic variants in more than 20 different genes can lead to OI, and phenotypes can range from mild to lethal forms. As a genetic disorder which undoubtedly affects quality of life, OI significantly alters the reproductive confidence of families at risk. The current review describes a selection of the latest reproductive approaches which may be suitable for prospective parents faced with a risk of OI. The aim of the review is to alleviate suffering in relation to family planning around OI, by enabling prospective parents to make informed and independent decisions.

Main body: The current review provides a comprehensive overview of possible reproductive options for people with OI and for unaffected carriers of OI pathogenic genetic variants. The review considers reproductive options across all phases of family planning, including pre-pregnancy, fertilisation, pregnancy, and post-pregnancy. Special attention is given to the more modern techniques of assisted reproduction, such as preconception carrier screening, preimplantation genetic testing for monogenic diseases and non-invasive prenatal testing. The review outlines the methodologies of the different reproductive approaches available to OI families and highlights their advantages and disadvantages. These are presented as a decision tree, which takes into account the autosomal dominant and autosomal recessive nature of the OI variants, and the OI-related risks of people without OI. The complex process of decision-making around OI reproductive options is also discussed from an ethical perspective.

Conclusion: The rapid development of molecular techniques has led to the availability of a wide variety of reproductive options for prospective parents faced with a risk of OI. However, such options may raise ethical concerns in terms of methodologies, choice management and good clinical practice in reproductive care, which are yet to be fully addressed.

Keywords: Bone fragility; Ethical decision-making; Ethics of prenatal testing; Family planning; Osteogenesis Imperfecta; Preconception carrier screening; Preimplantation genetic testing; Prenatal diagnosis; Reproduction.

Fig. 1

OI clinical and genetic heterogeneity. OI clinical variability ranges from mild non-deforming OI to severe and lethal OI forms. Genetic diversity of the disorder is characterised by OI pathogenic variants in more than 22 different genes. Autosomal dominant (AD), autosomal recessive (AR) and X-linked recessive (XLR) inheritance patterns were observed among OI families. A – Autosomal chromosome; OI – Osteogenesis Imperfecta; X – X chromosome; Y – Y chromosome

Fig. 2

Overview of pre-pregnancy reproductive options for members of families with OI risk. Pre-pregnancy testing of OI: genetic testing and PCS - preconception carrier screening

Fig. 3

Overview of fertilisation options for couples with OI risk. IVF - in vitro fertilisation with donor gametes / embryo, PGT-M - preimplantation genetic testing, and natural conception

Fig. 4

Overview of prenatal testing options for members of families with OI risk. NIPT – non-invasive prenatal testing, ultrasound, CVS - chorionic villus sampling, cordocentesis, amniocentesis

Fig. 5

Reproductive decision tree for members of families with OI risk. Based on the OI inheritance pattern in the family, and the wishes of the prospective parents, a specific autonomous decision-supportive reproductive strategy could be chosen. AD – Autosomal Dominant; AR – Autosomal recessive; IVF – In Vitro Fertilisation; NIPT – Non-invasive Prenatal testing; OI – Osteogenesis Imperfecta; PCS – Preconception Carrier Screening; PGT-M – Preimplantation Genetic Testing for Monogenic Disease; XLR – X-linked recessive