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FEATURE Genetic diaGnosis


“There is evidence that 50% of the first trimester spontaneous abortions are aneuploid”


invasive testing to obtain a definitive diagnosis of certain birth defects. Therefore, most physicians on a regular basis offer diagnostic testing to patients with high-risk pregnancies. Chromosome abnormality, represented


primarily by numerical change (trisomy resulting from non-disjunction or triploidy due to dispermy), is the single greatest contributor to prenatal morbidity and mortality. About 30% of recognized cases of embryonic and foetal death is due to chromosome abnormality. There is an increased risk of non-disjunction associated with either increased maternal age or positive maternal serum screening tests represents the most frequent indication for prenatal cytogenetic diagnosis to rule out or confirm common syndromes like Turner syndrome (45,X), Downs syndrome (Trisomy 21), Edwards syndrome (Trisomy 18), and Patau syndrome (Trisomy 13), The AFP marker, whether alone or as part of the Quad test, can identify 80% of spina bifida, 85% of abdominal wall defects, and 97% of anencephaly. All of these may have a structural chromosomal abnormality as a probable genetic etiology. Morphology ultrasound scans being undertaken on larger sized foetuses than in earlier scans, detect other structural abnormalities such as cardiac and renal tract abnormalities which might also have a numerical or structural chromosomal abnormality as the genetic etiology. Routine chromosome karyotyping


involves analysis for all specimen types on chromosome preparations from proliferating cells. Cells prepared for such analyses are typically blocked in the metaphase stage and GTG banding based on the effects of a protease (trypsin) and stain (Giemsa) on fixed chromosome preparations. Apart from


this Flourescence in situ hybridization (FISH) is offered under Molecular Cytogenetic testing that can be performed on metaphase spreads as well as on interphase nuclei and hence in the latter case is useful in the detection of mosaicism in cell lines. This technique is used widely to document embryonic aneuploidies. Preimplantation genetic diagnosis


(PGD) refers to procedures performed on cleavage embryos prior to implantation. Its main advantage is that it avoids selective termination of pregnancies and this method ensures that the baby will be free of the disease under consideration. The technique is not used to obtaining a specific prenatal diagnosis but rather for screening, properly referred to as preimplantation genetic screening (PGS), to increase the chances of an ongoing pregnancy. PGD is an adjunct to assisted reproductive technology and requires in vitro fertilization to obtain embryos for evaluation. After testing the embryo for the genetic condition or aneuploidies, the unaffected normal embryos are transferred or implanted into the uterus. Currently, PGD is being applied to look


for a specific disorder in couples with a high risk of transmitting an inherited condition that can opt for PGD as it can be easily combined with their IVF treatment.


PGD helps these couples identify embryos carrying a genetic disease or a chromosome abnormality, thus avoiding the difficult choice of termination of pregnancy. This is also applied to screen embryos for chromosome aneuploidies. The common aneuploidies tested using PGD are for chromosomes XY, 13, 14, 15, 16, 18, 21 and 22. Flourescent in situ Hybridzation (FISH)


and Polymerase Chain Reaction (PCR) are the two commonly used, first-generation technologies in PGD. Other approaches that have been proposed are whole genome amplification and comparative genome hybridization. PCR is generally used to diagnose monogenic disorders and FISH is used for the detection of chromosomal abnormalities. Over the past few years, various advancements in PGD testing have allowed for an improvement in the comprehensiveness and accuracy of results available depending on the technology used. PGD for couples at risk of conceptions


for serious genetic disorders is firmly established as a valid reproductive option for couples to consider following appropriate genetic counselling. The developments in prenatal diagnosis and preimplantation genetic diagnosis provide an exciting future in both diagnostic- research and medical-societal arenas. ■


ML MedLab Issue 2 2011 15


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