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GENETIC COUNSELLING IN PRIMARY IMMUNODEFICIENCY DISORDERS Tina-Marié Wessels, MSc(Med) Genetic Counselling !MANDA+RAUSE, MB BCh, PhD Division Human Genetics, School of Pathology, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg, South Africa !"342!#4 The primary immune deficiency disorders are a complex group of disorders. This complexity is also reflected in the genetic heterogeneity. There are a large number of genes implicated in this group and mutations are inherited in an autosomal recessive, dominant and X-linked manner. In addition chromosomal mechanisms, complex inheritance patterns and epigenetic factors have also been shown to be involved in the development of these disorders. Owing to the genetic complexity and heterogeneity, genetic counselling is indicated for the patients and their families. Genetic counselling assists the families in understanding the genetic contributions to disease occurrence and recurrence risks. It plays an important role in facilitating decision making and arranging genetic testing. Genetic counselling plays an important role in the comprehensive management of these patients and geneticists should be an integral part of the healthcare team. perfect and a number of the disorders do not ‘fit’ in the categories identified.2 Investigation of the PIDs continues to identify new molecular and cellular mechanisms involved in these conditions. A recent update by the International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies provides a constantly evolving classification of the PIDs.3 Table I is a condensed version which provides a very brief overview of the classification categories. It is important to note that the classification system is devised to assist with the diagnosis and treatment and is not meant to force patients into specific categories. Table I. Summarised overview of the classification of PIDs ).42/$5#4)/. The immune system is an intricate set of cells, organs and systems which communicate with each other to produce an appropriate and targeted immune response. Without this ability to respond a person is severely compromised and the inability to protect the body against antigens results in serious illness and death. The development of this set of cells, organs and systems involved in the immune system is controlled by a large number of genes. These genes are responsible for the development of the different cells, as well as the mechanisms controlling the expression of genes and the regulation of the different pathways. Mutations resulting in deficiencies at any stage of the development of the immune cells or regulatory pathways cause an immune disorder. The primary immunodeficiencies (PIDs) form a distinct group of immune deficiencies and have a clearer, though not fully understood, genetic basis. /6%26)%7/&4(%#,!33)&)#!4)/./&0)$S PIDs are a complex genetically heterogeneous group of disorders and genetic defects can occur at a number of stages in the various pathways involved in immune responses in both the innate and adaptive immune system.1 Genes involved in the development and functioning of the neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, and T and B lymphocytes have been identified. As a result classifying PIDs has been a difficult task and it has mostly been based on the developmental pathways of stem cells, B cells and T cells. This model is far from 'ROUP .OOF disorders %XAMPLES Combined T- and B-cell immunodeficiency ± 30 ADA deficiency Predominantly antibody deficiencies ±23 X-linked hyper IgM syndrome Other well-defined immunodeficiency syndromes ±16 22q11del, Bloom’s syndrome, ataxia telangietasia Diseases of immune dysregulation ±17 Hermansky-Pudlak disease Congenital defects of phagocyte number, function or both ±29 Severe congenital neutropenia Defects in innate immunity ±10 Anhidrotic ectodermal dysplasia with immunodeficiency Autoinflammatory disorders ±10 Familial Mediterranean fever Complement deficiencies ±24 C1 inhibitor deficiency '%.%4)#-%#(!.)3-3 The complexity of this group of diseases is increasingly becoming more evident. As more genes are discovered and more conditions are added, it is evident that the phenotypic spectrum of these disorders varies considerably. Investigators have found great variability in the effects of different mutations, as well as the effects other genetic, epigenetic and environmental factors have in modifying the disease phenotype. The role of environmental agents on the development of the conditions is significant and our understanding of these mechanisms is far from being clear. By 2007 over 150 PIDs have been described and over 120 genes have been indentified as playing a role in the development of these conditions.1 However, there remains a significant number of PIDs for which the associated gene/s has/ have not yet been identified. Correspondence: Prof Amanda Krause, email [email protected] Current Allergy & Clinical Immunology, November 2012 Vol 25, No.4 199 Fig. 1. Autosomal recessive inheritance. Inheritance of the gene mutations has been shown to be complex in that almost all known genetic mechanisms occur in this group of disorders. Traditional Mendelian inheritance patterns or single-gene disorders which include autosomal dominant, autosomal recessive and X-linked inheritance have been shown to occur.2 In addition chromosomal abnormalities can result in PID. The role of environmental factors is as yet unclear but it is known that these play a particularly prominent role in PIDs which have sporadic occurrences and show complex inheritance patterns. With the identification of epigenetic mechanisms, the role that these play is also becoming increasingly evident. The basis of these different genetic mechanisms rests on mutations or regulatory changes in the implicated genes. Mutations in genes result in an abnormality or an absence of the normal product. Autosomal recessive inheritance The most common mechanism identified as being involved in the largest number of PIDs is autosomal recessive inheritance. For conditions inherited in a recessive manner, both copies of the gene involved in the condition are mutated and the individual manifests the symptoms.4 If one functional and one mutated copy are present, the individual is a carrier and generally has no disease symptoms (although they may have some detectable features on detailed testing). Two carriers have a 1 in 4 or 25% chance of having an affected child. The general principle in autosomal recessive inheritance is that the parents of a child with a recessive condition are almost always carriers. The risk of having a child with an autosomal recessive form of PID is increased in consanguineous marriages as the chance of the couple both carrying the same rare recessive mutation is increased. The pedigree in Figure 1 illustrates a typical recessive inheritance pattern where an affected child (black symbol) is born to normal parents (grey symbols indicating carrier status) with a lack of other affected family members. The diagram next to the pedigree shows how the risk of 1 in 4 is derived and that a carrier couple (grey) has a 1 in 4 chance of having an affected child (black), a 2 in 4 chance of having children who are carriers (grey) and a 1 in 4 chance of having an unaffected child. There are over 27 severe combined immune deficiency conditions that follow autosomal recessive inheritance. One example is adenosine deaminase-deficient severe combined immunodeficiency disease (ADA deficiency). Autosomal dominant inheritance A number of PIDs have an autosomal dominant pattern of inheritance. In dominant inheritance an affected individual has one normal functioning gene and one gene with a mutation.4 One copy of the mutation is enough to cause the condition. An affected individual Fig. 2. Autosomal dominant inheritance. 200 Current Allergy & Clinical Immunology, November 2012 Vol 25, No.4 is then at a 1 in 2 or 50% risk of passing the mutation on to offspring who will then also be affected. As the pedigree (Fig. 2) illustrates, the mutation can be passed on from males to females and females to males, and individuals are present in subsequent generations. The diagram shows that the affected individual (black) can pass the mutation to both boys and girls and the risk is 1 in 2 or 50%. With autosomal dominant mutations, the mutation in the affected individual could be de novo which means that neither of the parents has the mutation and therefore the risk of having another affected child is lower. In a number of cases, but varying from condition to condition, the risk could be as high as 30%, as one of the parents could have a germ line mutation which is not evident or identifiable in somatic cells. In such cases although a mutation is not present in the somatic cells of one of the parents, the couple is still at a significant risk of having another affected child. Autosomal dominant mutations are further complicated by the fact that the degree of disease phenotype expressed is different in individuals carrying the same mutation (variable expressivity) and that the same mutation does not necessarily result in disease phenotype in all individuals (incomplete penetrance). An example of an autosomal dominant PID is severe congenital neutropenia. X-linked or sex-linked inheritance X-linked or sex-linked inheritance is another of the common inheritance mechanisms in PID. In X-linked inheritance the mutation is in a gene on the X chromosome whereas in recessive and dominant mutations the genes are on the autosomes.4 As a result females who have two X chromosomes and males who have an X and a Y chromosome manifest the condition differently. An X-linked mutation in a female will mostly result in her not manifesting the condition but being a carrier, whereas a male with the mutation will manifest the condition as he does not have a second X-chromosome to take on the functions of the defective gene. X-linked inheritance is characterised in a family pedigree by related unaffected females (grey) having affected boys (black) as shown in Figure 3. A carrier female (grey) is at 1 in 2 or 50% risk of having an affected boy (black) and the same chance of having a carrier daughter (grey). All the daughters of an affected male will be carriers as only the affected X chromosome will be passed on. His daughters are therefore obligate carriers. However there are also exceptions in X-linked conditions as skewed X-inactivation can result in carrier females displaying symptoms of the condition as a larger proportion of their normal X chromosomes are inactivated. As a general principle, de novo mutations occur in 1 in 3 of X-linked disorders and the mother of an affected boy in the absence of a family history has a 2 in 3 chance of being a carrier. An example of an X-linked PID is X-linked hyper IgM syndrome (HIGM1). Chromosomal abnormalities Abnormalities relating to the structure of chromosomes are a further mechanism associated with the cause of some of the PIDs. 22q11 deletion syndrome (DiGeorge) is an example of a microdeletion condition. As there are a number of genes on any chromosome, a deletion of a section of the chromosome can involve more than one gene, thus resulting in a complex phenotype. This region is called the 22q11 region. Originally one gene UFD1L was thought to be the cause of the symptoms; however attention has shifted to another gene TBX1. Identification of the deletion is done by cytogenetic testing (FISH) and is found in 95% of patients. Some deletions are too small to see on routine chromosome analysis and require specific testing (such as FISH) targeted at the region. Genotype-phenotype correlations are difficult because of the great inter- and intra-familial variability seen in patients who have the same large deletion. Though the deletion is inherited in an autosomal dominant manner, in 93% of cases the affected child has a de novo deletion. Seemingly unaffected parents can have a deletion as the phenotype can be very mild or the parent can also have somatic mosaicism. In cases of a de novo deletion the risk of recurrence is negligible, while in cases where the deletion is familial, the risk of recurrence is 50%. The cause of the deletion can also be a translocation. Ataxia telangiectasia and Bloom’s syndrome are examples of chromosome breakage disorders. Although they are single-gene disorders, chromosome breakage can be used to diagnose the conditions. In these disorders, as a result of a defect in DNA repair mechanisms or genomic instability, the stability of the chromosome is decreased which results in multiple chromosomal rearrangements. In 5-15% of patients with ataxia telangiectasia the condition is associated with an acquired translocation between chromosome 7 and chromosome 14 which involves the T-cell receptor locus (14q11) and the B-cell receptor locus (14q32). Other mechanisms The term complex inheritance mechanisms is used to describe disorders in which several genes and Fig. 3. X-linked inheritance. Current Allergy & Clinical Immunology, November 2012 Vol 25, No.4 201 environmental factors play a role in the development of the phenotype. The effect each has on the development of the phenotype is mostly not well understood and best describes the differences seen between individuals who apparently have the same mutation. A more recently discovered mechanism, epigenetics, which is thought to involve the control of gene expression and regulation, has also been implicated in PIDs. As research is progressing, the effect of epigenetic mechanisms is expected to become more evident. '%.%4)#4%34).' The option of genetic testing in PIDs can only be offered to families if the disease-causing gene has been identified, and even if the disease-causing gene is known, genetic testing is complex and can be expensive. Genetic testing involves a number of different techniques of which chromosome analysis, FISH, DNA sequencing, deletion/duplication analysis and targeted mutation analysis are most commonly used. Current testing methods are able to detect most disease-causing mutations if the gene/s involved in the condition has/have been identified. However current testing is unable to detect large deletions and there are difficulties in interpreting the result if novel mutations are identified. Testing is further complicated by the fact that more than one gene can be associated with the specific condition and more than one mutation can be implicated in disease development. As a result of this, in a number of cases, genetic testing may not identify a disease causing mutation/s in the affected individual. Consequently requesting a genetic test to make a clinical diagnosis can be inappropriate as the available testing might not be sensitive enough. Genetic testing should be directed by the clinical diagnosis, especially in the PIDs where there are a number of genes, as well as clear clinical overlap. This clinical overlap further complicates the testing process as mutations in one gene can result in distinct conditions with very different phenotypes. In the same way a distinct phenotype can be the result of different mutations in the same gene or different genes. Genetic testing can assist with phenotype predictions in those cases where correlations are evident. Limited testing for PID is available in South Africa on a diagnostic basis. Most testing therefore is required to be done in overseas laboratories. Even in these instances testing options may be limited and might only be available on a research basis. It is therefore important to consider several aspects when directing testing for individual families. It is critical that a DNA sample is obtained from the proband and banked for future testing or research. Testing is indicated to confirm a diagnosis, as well as in at-risk family members to identify carrier status. Those identified as carriers have the options of having prenatal diagnosis. Prenatal diagnosis can only be offered if all the diseasecausing mutations are identified. In some instances protein levels can be tested on a prenatal sample for which experienced laboratory staff who can interpret the results accurately are of great importance. There are several prenatal options available to at-risk families. Most commonly used are chorionic villus sampling (CVS) and amniocentesis. CVS can be performed at around 11-13 weeks’ gestation while amniocentesis is performed around 16-20 weeks’ gestation. As these procedures are invasive there is an associated risk of miscarriage which is around 0.5% for amniocentesis and around 1-2% for CVS in experienced hands. If the fetus is found to be affected with the particular disease 202 for which is is tested, termination of pregnancy is the only option available to the couple if they do not want an affected child. Newer technologies are available and preimplantation genetic diagnosis (PGD) offers couples the option of only implanting unaffected embryos, therefore eliminating the need for termination of pregnancy. PGD involves an in vitro fertilisation process whereby ovulation is stimulated in the female and the oocytes are fertilised in vitro. The embryos are then tested for the identified family-specific mutations. The affected embryos are discarded and only unaffected embryos are implanted. With PGD termination of pregnancy can be avoided as only healthy embryos are implanted. It is recommended that couples still have an invasive test for confirmation but this is becoming less routine. PGD is available to couples in South Africa. '%.%4)##/5.3%,,).' As a result of the complexity of the genetic mechanisms involved in the PIDs, genetic counselling for patients and their families is indicated. Management of families with a PID involves careful consideration and investigation so that the correct information can be provided as it has serious implications for future pregnancies and other relatives. A genetics consultation can assist the affected families in understanding the cause of the condition and the expected prognosis, and importantly what the implications are for them as well as for extended family members. Genetic counselling plays an integral part in the management of patients with PIDs and can assist in genetic testing, directing management guidelines and co-ordination of the multidisciplinary team. Genetic counselling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates the following: s )NTERPRETATIONOFFAMILYANDMEDICALHISTORIESTOASSESS the chance of disease occurrence or recurrence s %DUCATION ABOUT INHERITANCE TESTING MANAGEMENT prevention, resources and research s #OUNSELLING TO PROMOTE INFORMED CHOICES AND adaptation to the risk or condition.5 Genetic counselling is provided by individuals trained in dealing with the issues surrounding genetic conditions. These individuals include medical practitioners with a speciality in medical genetics and master’s level trained genetic counsellors who have followed a specific educational curriculum, as well as nurses trained in genetics. A genetics consultation involves obtaining a comprehensive family and genetic history. This enables the genetics professional to draw a family pedigree. The pedigree information aids in establishing the diagnosis and pattern of inheritance. Medical reports are also used during the assessment process. After the assessment the likely diagnosis can be discussed, as well as the disease progression and the genetic contributions. Based on this, the risk of recurrence for future pregnancies and occurrence in other family members can be discussed. Testing options are discussed and testing of the affected individual, individuals at risk of being carriers and prenatal testing is facilitated. The process is conducted in such as way that the emotional aspects are taken into consideration and the family is supported and assisted in making further decisions with regard to testing and prenatal options. Supporting the family also involves referrals to other appropriate professionals with regard to therapies and parent support groups. Current Allergy & Clinical Immunology, November 2012 Vol 25, No.4 #/.#,53)/. 2%&%2%.#%3 PIDs are a clinically complex group of conditions which have a complex genetic basis. As discussed, all possible genetic mechanisms occur in this group of conditions. With the heterogeneity involved in terms of inheritance and genetic testing, genetic counselling is indicated in the management of these patients. Genetics professionals play a vital role in the management of patients with PIDs and form part of the management team to ensure that the best possible care is provided for the patient and their family. 1. Geha RS, Notarangelo LD, Casanova JL, et al. Primary immunodeficiency diseases: An update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol 2007;120:776794. 2. Hirshhorn R, Hirshhorn K. Immunodeficiency disorders. In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. London: Elsevier Churchilll Livingstone, 2007:1835-1856. 3. International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies. Notarangelo LD, Fischer A, Geha RS et al. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol 2009;124:776-794. 4. Harper PS. Practical genetic counselling. London: Hodder Arnold, 2010. 5. Resta R, Biesecker BB, Bennett RL, et al. The National Society of Genetic Counselor’s Definition Task Force: A New Definition of Genetic Counselling: National Society of Genetic Counselors’ Tasks Force Report. Journal of Genetic Counseling 2006;15:77-83. $ECLARATIONOFCONmICTOFINTEREST The authors declare no conflict of interest. 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