The Human Genome Project (HGP), led by the National Institutes of Health, produced a very high-quality version of the human genome sequence that is freely available in public databases. This international project was successfully completed in April, 2003, more than two years ahead of schedule. The HGP revealed that there are probably about 20,500 human genes.   Because of the deciphering work known as The Human Genome Project, hundreds of genetic diseases are now mapped to various locales on human chromosomes. This has spawned techniques, known as DNA sequencing, that collectively comprise a variety of tools for determining a specific individuals’ genetic identity.

DNA sequencing techniques have become increasingly refined in recent years to include simple blood and/or saliva tests that can screen individuals for a wide variety of genetic diseases. This is significant because many of the most severe, and potentially life threatening diseases are autosomal recessive in their inheritance. That is, the carrier of an autosomal recessive disorder does not have the disease but carries only a single copy of the disease and 2 copies are required for the disease to manifest. Many carries are completely unaware of their carrier status until they have a child affected with the disorder. This would then obligate that both parents are carriers. When both parents are carriers, they have a 1 in 4 chance of having an affected child. This is in contradistinction to autosomal dominant disorders. These diseases, such as Marfan’s Syndrome, require only one genetic copy for the disorder to completely manifest. Most families that carry the gene for an autosomal dominant disorder know about the disease, because someone in the family is already affected. Typically, in autosomal dominant disorders, multiple generations in the family are affected and then children of an affected individual, have a 50% chance of inheriting the disorder.

However, carriers of autosomal recessive disorders are most often unaware of their carrier status. This is also generally of no consequence since carriers are symptomatic. However, couples who are intending to conceive, now have the ability to take advantage of simple blood tests that can determine carrier status of over 150 autosomal recessive disorders. In particular, some of these diseases are so potentially lethal, at FCI we advocate that at least one member of a couple seeking fertility treatment undergo genetic carrier screening. Particularly, couples who, based on ethnic background, have a greater chance of being a carrier are urged to undergo screening. Cystic fibrosis, for example, is the most common life-threatening autosomal recessive condition among the non-Hispanic white population.

Cystic Fibrosis

Cystic fibrosis is a progressive disease that primarily negatively affects respiratory and gastrointestinal secretions. It is caused by mutations in the CF Transmembrane Regulator (CTFR) gene, located on chromosome 7, and occurs in roughly 1 in 2500 individuals in the non-Hispanic white population and considerably less in other ethnic groups. Though CF is most common among non-Hispanic whites, it is also becoming increasingly difficult to assign specific ethnicity to affected individuals. Therefore genetic screening for CF should be offered to all patients. It was introduced into routine obstetric practice in 2001. However the sensitivity of screening varies among different ethnic groups, ranging from only 50% in those of Asian ancestry, but 94% in the Ashkenazi Jewish population.

However CF testing is offered for only the most common mutations, and therefore negative screening results do not completely eliminate the chance of an individual being an actual CF carrier. This is because to date, more than 1,700 mutations have been indentified for CF. Current guidelines, revised by the American College of Medical Genetics in 2004, use a 23-mutation panel that includes the most common CF mutations. Complete analysis of the CFTR gene by DNA analysis is most appropriate for patients with known CF.

Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is another autosomal recessive disease. It is a neurodegenerative disease that results from degeneration of spinal cord motor neurons leading to atrophy of skeletal muscle and overall weakness. It is cause by a mutation in the gene known as the survival motor neuron gene (SMN1), which is responsible for the production of a protein essential to motor neurons. A great interest in both prenatal and neonatal SMA screening has been prompted by the severity of the disease as well as the relatively high carrier frequency in the population. The incidence of SMA is approximately 1 in 10,000 live births and it is the leading genetic cause of infant death. Carrier frequencies are estimated at 1 in 40 to 1 in 60. In addition, improved techniques for DNA diagnosis of mutations in SMN1 have contributed to widespread population-based screening in the prenatal population.

However the genetics of SMA is complex. There are 2 nearly identical survival motor neuron genes present in humans, known as SMN1 and SMN2. More than 90% of patients with SMA have an abnormality in both SMN genes, caused by a deletion (95%) or other mutation. Humans generally have one, but occasionally two copies of SMN1 per chromosome. They have a variable number of SMN2 gene copies. For diagnosis of SMA, it is sufficient to simply detect the classic SMN1 deletion using DNA analysis in both SMN1 alleles. However this approach is not sufficient to identity patients who are heterozygous, or carriers, for the SMN1 deletion. Carrier testing requires a quantitative polymerase chain reaction (PCR) assay that provides a measure of SMN1 copy number. Detection of a single normal copy of SMN1 indicates carrier status.

Fragile X Syndrome

Fragile X syndrome is the most common cause of inherited mental retardation, second only to Down syndrome as an etiology for mental retardation. It affects approximately 1 in 4000 males and 1 in 8000 females. Nearly all cases of fragile X syndrome are caused by a mutation in the FMR1 gene where a DNA segment, known as the CGG triplet repeat, is expanded. Normally this DNA segment is repeated from 5 to about 40 times. However in people with Fragile X syndrome, the CGG segment is repeated more than 200 times. It is inherited in an X-linked dominant pattern. Both boys and girls can be affected, but because boys have only one X chromosome, a single fragile X is likely to affect them more severely. People with just 55 to 200 repeats of the CGG segment have a FMR1 premutation (an intermediate variation of the gene). Women with the premutation have an increased risk of having a child with fragile X syndrome. Though unaffected, women with the premutation may also be at risk of premature ovarian failure. Roughly 1 in 250 women are carriers of the fragile X permutation.

Fragile X syndrome is also the most common cause of autism or “autistic like” behaviors. Other associated abnormalities include distinctive facial features in males, enlarged testicles, connective tissue problems, and speech and language problems. These characteristics all tend to become more pronounced with increased age in the individual, leading to some difficulty in identifying the diagnosis in newborns. Affected females overall have more subtle findings, making it difficult to diagnose on the basis of clinical findings alone.

Current guidelines from professional genetic organizations recommend carrier screening only for women with a family history of fragile X syndrome or undiagnosed mental retardation, developmental delay, or autism or for those with ovarian insufficiency. The American College of Obstetricians and Gynecologists (ACOG) concurs with this recommendation and also advocates fragile X carrier screening for all reproductive age women who request screening after genetic counseling about the benefits and limitations of screening.

Tay – Sachs Disease

Tay-Sachs disease (TSD) is a lysosomal storage disease that leads to an accumulation of GM2 gangliosides throughout the body. These gangliosides can specifically accumulate in the central nervous system and lead to a progressive neurologic disease and early childhood death. TSD is caused by a deficiency of the enzyme Hexosaminidase A, and is reported as a percentage of total Hexosaminidase activity. Patients with classic TSD have virtually no Hexosaminidase A activity, and carriers usually have Hexosaminidinase A activity at less than 55% of the total. TSD is an autosomal recessive disease and carrier screening should be offered prior to pregnancy in couples who are considered at high risk, including those of Ashkenazi Jewish, French-Canadian, or Cajun descent. The TSD carrier rate in Jewish individuals of Eastern European descent is approximately 1 in 30. Carrier screening can be performed by molecular analysis, biochemical analysis, or both. Molecular analysis of three mutations will detect 95% of carriers in the Ashkenazi Jewish population, compared with biochemical analysis, which will detect 98% of carriers. Different mutations have been found in other ethnic groups. It is recommended that biochemical analysis should be the screening tool in low risk populations because molecular analysis detects less than 50% of carriers in this population. If biochemical testing is done in women who are pregnant or taking oral contraceptive, then leukocyte testing must be used.

However, if only one member of a couple is high risk, ACOG recommends that this individual be offered screening, even if the other partner is not at high risk. If the high risk individual tests positive for carrier status, the other partner should also be tested. This is particularly important in the modern world, wherein many individuals are uncertain about ancestry. If both partners are determined to be carriers of TSD, genetic counseling and pregenetic diagnosis should be offered.

Carrier screening for specific genetic conditions is often determined by ancestry. Most individuals of Jewish ancestry in North America are descended from Ashkenazi Jewish communities, and then considered at increased risk for having affected offspring with one of these inheritable diseases. The American College of Medical Genetics has recently recommended additional carrier screening for the Ashkenazi Jewish population. The Committee on Genetics reaffirms support for TSD, Canavan Disease, cystic fibrosis, and familial dysautonomia.

Finally, carrier screening is voluntary. Informed consent and assurance of confidentiality are required. For all these disorders, a negative screening test for one or both partners significantly reduces the possibility of an affected child. However, it does not exclude the possibility entirely because the test sensitivity is less than 100%, so not all carriers can be identified.