Relevance of family history

Let us consider the example of Fragile X syndrome, which is the most common inherited cause of intellectual disability . It is caused by an expansion in the CGG trinucleotide repeat in the FMR1 gene on the X chromosome. A full mutation, characterised by more than 200 CGG repeats, causes intellectual disability in males and milder intellectual disability in a proportion of affected females. Premutation carriers (55-200 repeats) are at risk of late-onset cerebellar ataxia (mainly males) and premature ovarian failure in females. Female premutation carriers can have children with full mutations as a result of expansion of the CGG repeats. As female premutation carriers may have no relevant family history, it has been proposed that carrier screening should be offered to inform reproductive options. Currently, the American College of Medical Genetics and Genomics recommends carrier testing only for women with relevant family history of intellectual disability . The guideline argues against population screening on the basis of the complex genetics of FMR1-related disorders, which is mainly associated with the variable phenotype in premutation carriers and female full mutation carriers and the relevant counselling challenges. A systematic review by Hill et al. has identified evidence that offering screening for Fragile X in either the preconception or prenatal settings would be acceptable by women but argued that targeted counselling by appropriately trained professionals should be developed to support individual choice . More research is needed before Fragile X testing can be offered consistently to women without a relevant family history, and emphasis should be placed on developing appropriate counselling to address the complexities of the genetics of the condition and allow informed choice .

Genetic screening and relevance of ethnicity

Mutation screening is particularly relevant in autosomal recessive conditions . In these conditions, the majority of mutated alleles are found in heterozygote carriers who are themselves unaffected by the condition and may be unaware of their carrier status. The genogram may not identify any specific clues, and a child with an autosomal recessive condition may be the only affected individual in the family. The carrier frequency for specific autosomal recessive disorders varies significantly between different populations and sub-populations and is linked to ethnic background.

On a global scale, cystic fibrosis, thalassaemia, sickle cell disease and Tay–Sachs disease represent common autosomal recessive conditions in terms of carrier frequency, with significant variation in different populations . For example, the carrier frequency for mutations in the HBB gene (which codes for the beta globin chain of haemoglobin), which are associated with beta thalassaemia, is high in countries in the Mediterranean basin and estimated to be 1 in 7 in Cyprus . Another haemoglobinopathy caused by a mutation in the HBB gene is sickle cell disease, and individuals of African origin have a high carrier frequency, depending on the specific population. Mutations in the HBA1 and HBA2 genes, which cause alpha thalassaemia, are frequent in Southeast Asian populations. The carrier frequency for mutations in the CFTR gene, which cause cystic fibrosis, is high in individuals from Northern European populations (1 in 25), and the carrier rate for Tay–Sachs disease, a metabolic condition caused by deficiency in Hexosaminidase A enzyme leading to progressive neurodegeneration, is 1 in 30 in individuals with Ashkenazi Jewish background.

The seriousness of the conditions and their relatively high prevalence in specific populations have led to the consideration of offering carrier screening to identify prospective parents who may be heterozygous for pathogenic mutations. Technically, such screening takes the form of either a genetic mutation test (such as in cystic fibrosis) or electrophoresis or high-performance liquid chromatography for haemoglobinopathies. If both prospective parents are identified as carriers of an autosomal recessive disorder, they will have a 1 in 4 chance of having an affected child in a subsequent pregnancy. Confirmation of carrier status at the preconception stage allows prospective parents to make informed decisions in relation to their reproductive options. If they are concerned about the probability of having an affected child, they may opt for preimplantation genetic diagnosis so that embryos produced with assisted reproductive techniques can be tested before being implanted back into the uterus . There may also consider options such as the use of donor gametes, avoidance of having children or adoption. Clearly, these are options that would not have been available to the prospective parents if their carrier status is identified after conception. Alternatively, prospective parents may decide to proceed with a pregnancy and opt for early prenatal diagnosis and have the option of a termination of an affected pregnancy or planning for the birth of an affected child.

If carrier screening is offered, it should be comprehensively supported by genetic counselling by an appropriately trained healthcare professional and should be based on the principle of informed consent . Counselling should encompass a description of the disorders for which testing is being offered and the currently available treatments, the nature of the test being offered and any limitations associated with it, including any residual risk following a negative result, and a detailed discussion of the available reproductive options as outlined above. Moreover, the potential problems and pitfalls associated with genetic screening such as the potential psychological impact and increased stress levels and possible stigmatisation should be explored . However, a number of studies have identified perceived advantages amongst prospective parents participating in genetic screening, mainly as a result of the individuals feeling empowered to make informed decisions .

Recommendations for genetic carrier screening either to the general population or to specific sub-populations and ethnic groups are determined at a national level. In the Unites States, various professional bodies such as the American College of Obstetricians and Gynaecologists, the American College of Medical Genetics and Genomics, and the National Society of Genetic Counsellors recommend screening all women of reproductive age regardless of ethnicity or ancestry for cystic fibrosis . This panethnic screening approach is based on genetic screening for the most common mutations in the population. Particular emphasis was placed on including mutations that are known to be associated with classical cystic fibrosis and not with milder or variable phenotypic variants so as to avoid putting prospective parents in a difficult position . The panel of mutations included in the screening is reviewed depending on the evidence of carrier detection rates, and a study conducted 8 years after the introduction of screening determined that no additional mutations are needed to be incorporated in the test . In the Netherlands, a report on preconception care identified cystic fibrosis as a clear candidate for consideration of implementation of carrier screening but stopped short of recommending the introduction of such testing across the nation and suggested additional studies to be performed to assess potential benefits . In the United Kingdom, a Cochrane review on genetic risk assessment for common autosomal recessive disorders identified evidence from observational studies of potential benefits of the introduction of preconception carrier screening but indicated the lack of relevant randomised controlled trials .

In the case of haemoglobinopathies, the United Kingdom has a national programme that offers screening to all pregnant women and, subsequently, to their partners if women are shown to be carriers . A limitation of this approach is that it affords limited options to carrier parents as the pregnancy is already established. Moreover, there is evidence that the way screening is offered, as part of a wider array of prenatal tests, affects the quality of pre-screening education and counselling . The screening recommendation by the American College of Obstetricians and Gynaecologists is based on ethnic background and uses a combination of assessment of haematological indices (mean cell volume and iron studies), haemoglobin electrophoresis and molecular genetic analysis of the HBA1, 2 genes . In the Netherlands, as in the case of cystic fibrosis, the report by the National Health Council identifies the benefit of preconception screening for these conditions but states that more evidence is needed before deciding how it can be implemented on a national basis . A systematic, preconception, nationwide screening programme for thalassaemia has been implemented in Cyprus for a number of years and has resulted in a very significant reduction in the incidence of beta thalassaemia .

Carrier screening for a number of autosomal recessive conditions is offered to individuals with Ashkenazi Jewish background in the United States . The American College of Obstetricians and Gynaecologists in 2009 recommended offering screening for Tay–Sachs disease, cystic fibrosis, Canavan disease and familial dysautonomia. The American College of Medical Genetic and Genomics is making further recommendations in addition to the conditions described above . In the case of Tay–Sachs disease, the screening programme has resulted in a dramatic reduction in the incidence of the disorder .

Consanguinity

Consanguineous marriages are common in many countries and are frequently encountered in certain migrant communities in the western world. Consanguineous marriages are associated with an increased probability of children being born with an autosomal recessive condition because the prospective parents are related to each other and are more likely to both transmit a common deleterious mutation to their offspring . The genetic risk involved depends on the degree of relationship: first cousin partnerships are associated with a 3-5% risk of a congenital malformation, genetic disease or adverse pregnancy outcome such as stillbirth or neonatal death . This should be compared with a 2-3% risk for such adverse pregnancy outcomes in the general population. When counselling consanguineous couples, a detailed family history must be taken, and the identification of a genetic diagnosis will inform any appropriate referrals and the advice given to the prospective parents. In addition to counselling about the general risks associated with consanguinity, carrier screening can be offered for conditions that are relevant for the specific population/ethnic group according to existing national recommendations . An issue that is relevant to preconception counselling is perceived challenges in inquiring about consanguinity in the first place, and a study of the practice of Australian midwives suggested that they were reluctant to inquire directly about this issue when taking a family history . The authors suggested specific training into how to raise this issue as part of the routine family history so as to ensure that this type of important information is accurately recorded.