Abstract
BackgroundOsteogenesis 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 bodyThe 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.ConclusionThe 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.
Highlights
Reproductive options for prospective parents faced with Osteogenesis Imperfecta Before beginning the family planning process, prospective parents faced with a risk of OI must consider some important preliminary issues:
Pre-pregnancy reproductive options for prospective parents faced with Osteogenesis Imperfecta During the pre-pregnancy period, an individualised approach to reproductive options may be developed which incorporates the OI family history and OI phenotype and genotype characteristics, and details regarding prospective parents’ reproductive health, their abilities and their wishes (Table 3, Fig. 2)
Autosomal dominant Osteogenesis Imperfecta Up to 90% of OI cases are caused by autosomal dominant (AD) pathogenic variants in the COL1A1, COL1A2 genes and the IFITM5 (OMIM 614757) gene, with a 50% probability of transmission of the pathogenic variant to the generation [11, 34, 36, 53, 54] (Table 2, Fig. 1)
Summary
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: Reproduction, Osteogenesis Imperfecta, Family planning, Bone fragility, Prenatal diagnosis, Preimplantation genetic testing, Preconception carrier screening, Ethical decision-making, Ethics of prenatal testing
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