Download GENETIC COUNSELLING IN PRIMARY IMMUNODEFICIENCY

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
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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.
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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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Current Allergy & Clinical Immunology, November 2012 Vol 25, No.4
203
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