Genetics & PGD
Genetics
IVF and related procedures permit prevention of multiple genetic diseases which fall into several distinct classes: autosomal recessive and dominant, X-linked, chromosomal and polygenic.
Autosomal recessive conditions require that both genetic parents carry a defective gene and pass it on to the affected child. Carriers are generally not affected so most people do not know their carrier status. Carrier frequency varies in different ethnic groups. If both partners are carriers, about 1 in 4 children will have the disease and half of the children will be carriers. If one partner is a carrier but the other one is not, half of the children will be carriers but none should have the disease. Following are the most common autosomal recessive disorders:
Cystic Fibrosis is quite common in the general Caucasian population with carrier rate of about 1 in 30. CF carriers are healthy whereas affected individuals suffer frequent and serious respiratory infections and usually die in their 20’s or 30’s. Without any testing, the chance of having an affected child is approximately 1 in 3,600.
A very large number of distinct mutations can result in cystic fibrosis so carrier screening tests pick up only the commonest of these mutations. In the Northern European population, the standard panels picks up about 90% of carriers but in the Southern Europeans the detection rate is only 70%. In the Ashkenazi Jewish population the test is 99% sensitive. Thus the test is never 100% sensitive. Consequently, if one partner is a known carrier we recommend that the other partner undergo extensive testing for all the known mutations. Once it is known which mutations are present in the genetic parents, then pre-implantation genetic diagnosis can be performed on their embryos in the laboratory (PGD)
Tay Sachs is relatively common (1 in 30) in Askenazi Jewish, French Canadian and Cajun populations. The enzyme test for Hexaminidase A has high sensitivity and is widely available. The Ashkenazi Jews are also at relatively high risk (~1 in 40) for Canavan’s and Gaucher’s diseases as well as Familial Dysautonomia all of which can also be tested for.
Sickle Cell gene is common in the African-American population with a carrier rate of about 1 in 12. The hemoglobin electrophoresis test is highly sensitive and is widely available.
Thalassemia affects individuals of South-East Asian and Mediterranean descent. MCV is the common screening test for carrier status.
Autosomal dominant conditions include Huntington’s chorea. X-linked diseases include hemophilia which is passed on through females but affects only males. Family history, rather than carrier screening, are the basis for early detection and prevention of these types of conditions.
Fragile X is the most common non-chromosomal cause of mental retardation (Down’s syndrome is the most common cause of mental retardation due to presence of extra chromosome 21) or which detection is available.
Aneuploidy (abnormality in the number of chromosomes) is the most common cause of early miscarriages (Pregnancy Loss, Aneuploidy & PGS). Chromosome number abnormalities increase markedly with maternal age and contribute to the decreasing live birth rate in older women both with and without IVF (What Is Age Fator?).
Poly-genic inheritance, which involves transmission of multiple genes and their interaction with the environment, is currently believed to underlie such common medical conditions as diabetes, high blood pressure and heart disease. Consequently their genetic basis cannot usually be determined by PGD or prenatal genetic testing.PGD (Pre-implantation Genetic Diagnosis)
PGD is an advanced technique which involves biopsy of individual embryos and genetic analysis of 1-2 cells in order to identify embryos that carry defective gene(s) passed on by the genetic parents (Genetics). PGD is an invaluable, if invasive, approach to minimizing transmission of serious genetic illnesses.
Biopsy of an 8-cell embryo
Consider cystic fibrosis (CF) which is the most common autosomal recessive condition in the general Caucasian population. Only people who have 2 defective genes for CF, one from each genetic parent, are affected and have the actual disease. The likelihood that a Caucasian man or woman carries a CF mutation is about 1 in 30. If two carriers have children, the chance that one of the children will have CF is 1 in 4 (25%) while half of the offspring would be carriers for one CF mutation.
In order to detect whether a given embryo has CF mutations from both genetic parents, it is necessary to know the two exact mutations present in the family. To date over 900 deleterious mutations for CF have been described. The standard CF panel includes only the 25 most common mutations. Therefore, extensive additional testing is required on the partner if one genetic parent is known to be a CF carrier. PGD may allow a couple to decide which embryos are safe to transfer and which to discard because of presence of both mutations for CF. While PGD is quite accurate (~95%), it is not as reliable as prenatal diagnosis which tests multiple cells. Therefore prenatal genetic diagnosis is still recommended in pregnancies achieved after PGD in at risk couples.
The other relatively common autosomal recessive conditions which can be detected through PGD include: sickle cell anemia, Tay-Sachs, Thalassemia, Gaucher’s disease and several others. PGD can also be used to detect embryos affected by dominant diseases such as Huntington’s chorea and X-linked diseases such as hemophilia (Genetics).
Overall, however, the genetic diseases with classic Mendelian inheritance patterns are rather uncommon. The much more common diseases with a genetic component, such as diabetes and heart disease, involve inheritance of multiple genes and complex interaction with the environment and thus cannot be currently diagnosed by PGD.