Prenatal diagnosis and preimplantation genetic diagnosis: novel technologies and state of the art of PGD in different regions of the world

Abstract

Prenatal diagnosis (PND) aims to provide accurate, rapid results as early in pregnancy as possible. Conventional PND involves sampling cells of foetal origin by chorionic villus sampling at 11-14th weeks of pregnancy or amniocentesis after 15th week. These are invasive procedures and have a small but significant rate of 0.5% to 1% for loss of pregnancy. An alternative to existing methods for conventional PND for couples at risk of transmitting a genetic disease to their child is preimplantation genetic diagnosis (PGD). PGD is a newly emerging form of a very early prenatal diagnosis. The technique combines assisted reproductive technology with molecular genetics and cytogenetics to allow the identification of abnormality in embryos prior to implantation. The diagnosis of genetic disease in human preimplantation embryos was pioneered in the late 1980s for testing of aneuploidy, single gene and X-linked disease, such as cystic fibrosis, haemophilia and chromosomal abnormalities. The PGD-related legal and ethical issues have been debated at many levels both nationally and internationally. The attitude towards PGD varies substantially not only in different parts of the world but also within the Europe, owing to scientific, cultural and religious differences. PGD has become widely practised throughout the world for various indications and can substantially decrease the eventual risks of passing a genetic undesired condition of the offspring. Nevertheless, its extension to some new and non-medical indications has raised ethical concerns, in particular its potential eugenic dimension.

Hemophilia B: molecular pathogenesis and mutation analysis

“…Early PND at 11-14 weeks of gestation, amniocentesis at 16-18 weeks, and late gestation analysis at ≥ 32 weeks, also using amniocentesis, are all available, the last to inform delivery management for known carriers [54]. Examination of free fetal DNA in the maternal circulation is being used increasingly for early fetal sex determination, and can be utilized from~10 weeks of gestation to avoid invasive PND analysis [55]. The Italian hemophilia B database records mutations in 373 unrelated patients, and this information has identified 274 carriers of childbearing age.…”

Diagnosis and management of haemophilia

“…23 Preimplantation genetic diagnosis combines assisted reproductive technology with molecular genetics and cytogenetics to allow affected embryos to be identified before implantation. 24 The recent evidence based UK guideline recommends that pregnancy and childbirth be managed in a haemophilia treatment centre by a multidisciplinary team including a (paediatric) haematologist, obstetrician, and anaesthesiologist. 25 The sex of the fetus can be identified by Y chromosome polymerase chain reaction in maternal blood at around 10 weeks' gestation or by ultrasound scan at 18-20 weeks' gestation.…”

Nacionalna priporočila za obravnavo bolnikov s hemofilijo

“…V mednarodni študiji INSIGHT, ki je raziskovala vpliv imunogenetskih dejavnikov in dejavnikov terapije na pojavljanje inhibitorjev pri lahki in srednji stopnji hemofilije A (1.112 bolnikov s FVIII:C od 2-40 %), so ugotovili, da je tveganje za inhibitorje 6,7 % pri 50 ED in 13,3 % pri 100 ED ob sočasno prisotni visokorizični mutaciji (Tabela 10) (243). V veliki študiji, ki je zajela 231 bolnikov z lahko hemofilijo A, se nadomestno zdravljenje s kontinuirano infuzijo ni izkazalo kot dejavnik tveganja za pojav inhibitorjev (259). Inhibitorji se pri lahki HB pojavijo izjemno redko (244).…”