The speciality of medical genetics is concerned with the study
of human biological variation and its relationship to health and
disease. It encompasses mechanisms of inheritance,
cytogenetics, molecular genetics and biochemical genetics as
well as formal, statistical and population genetics. Clinical
genetics is the branch of the specialty involved with the
diagnosis and management of genetic disorders affecting
individuals and their families.
Saturday, April 11, 2009
Genetic disease
Genetic disorders place considerable health and economic
burdens not only on affected individuals and their families but
also on the community. As more environmental diseases are
successfully controlled those that are wholly or partly
genetically determined are becoming more important. Despite
a general fall in the perinatal mortality rate, the incidence of
lethal malformations in newborn infants remains constant.
Between 2 and 5% of all liveborn infants have genetic disorders
or congenital malformations. These disorders have been
estimated to account for one third of admissions to paediatric
wards, and they contribute appreciably to perinatal and
childhood mortality. Many common diseases in adult life also
have a considerable genetic predisposition, including coronary
heart disease, diabetes and cancer.
burdens not only on affected individuals and their families but
also on the community. As more environmental diseases are
successfully controlled those that are wholly or partly
genetically determined are becoming more important. Despite
a general fall in the perinatal mortality rate, the incidence of
lethal malformations in newborn infants remains constant.
Between 2 and 5% of all liveborn infants have genetic disorders
or congenital malformations. These disorders have been
estimated to account for one third of admissions to paediatric
wards, and they contribute appreciably to perinatal and
childhood mortality. Many common diseases in adult life also
have a considerable genetic predisposition, including coronary
heart disease, diabetes and cancer.
genetic origin
Though diseases of wholly genetic origin are individually
rare, they are numerous (several thousand single gene
disorders are described) and are therefore important. Genetic
disorders are incurable and often severe. Some are amenable to
treatment but many are not, so that the emphasis is often
placed on prevention, either of recurrence within an affected
family, or of complications in a person who is already affected.
rare, they are numerous (several thousand single gene
disorders are described) and are therefore important. Genetic
disorders are incurable and often severe. Some are amenable to
treatment but many are not, so that the emphasis is often
placed on prevention, either of recurrence within an affected
family, or of complications in a person who is already affected.
Increasing awareness
Increasing awareness, both within the medical profession and
in the general population, of the genetic contribution to disease
and the potential implications of a positive family history, has led
to an increasing demand for specialist clinical genetic services.
Some aspects of genetics are well established and do not require
referral to a specialist genetics clinic – for example, the provision
of amniocentesis to exclude Down syndrome in pregnancies at
increased risk. Other aspects are less well understood – for
example the application of molecular genetic analysis in clinical
practice, which is an area of rapidly advancing technology
requiring the facilities of a specialised genetics centre.
in the general population, of the genetic contribution to disease
and the potential implications of a positive family history, has led
to an increasing demand for specialist clinical genetic services.
Some aspects of genetics are well established and do not require
referral to a specialist genetics clinic – for example, the provision
of amniocentesis to exclude Down syndrome in pregnancies at
increased risk. Other aspects are less well understood – for
example the application of molecular genetic analysis in clinical
practice, which is an area of rapidly advancing technology
requiring the facilities of a specialised genetics centre.
Organisation of genetic services
In the UK, NHS genetic services are provided in integrated
regional centres based in teaching hospitals, incorporating
clinical and laboratory departments usually in close liaison with
academic departments of human genetics.
regional centres based in teaching hospitals, incorporating
clinical and laboratory departments usually in close liaison with
academic departments of human genetics.
Clinical genetics
Clinical services are provided by consultant clinical geneticists,
specialist registrars and genetic associates (nurses or graduates
with specialist training in genetics and counselling). Most
clinical genetic departments provide a “hub and spoke” service,
undertaking clinics in district hospitals as well as at the regional
centre. Patients referred to the genetic clinic are contacted
initially by the genetic associate and many are visited at home
before attending the clinic. The purpose of the home visit is to
explain the nature of the genetic clinic appointment,
determine the issues of importance to the family and obtain
relevant family history information. The genetic associate is
usually present at the clinic appointment and participates in
the counselling process with the clinical geneticist. At the clinic
appointment genetic investigations may be instituted to
establish or confirm a diagnosis and information is given to the
individual or family about the condition regarding diagnosis,
prognosis, investigation, management and genetic
consequences. Written information is usually provided after the
clinic appointment so that the family have a record of the
various aspects discussed. After the appointment, follow-up
visits at home or in the clinic are arranged as necessary. The
genetic associate plays an important role in liaising with
primary care and other agencies involved with the family.
specialist registrars and genetic associates (nurses or graduates
with specialist training in genetics and counselling). Most
clinical genetic departments provide a “hub and spoke” service,
undertaking clinics in district hospitals as well as at the regional
centre. Patients referred to the genetic clinic are contacted
initially by the genetic associate and many are visited at home
before attending the clinic. The purpose of the home visit is to
explain the nature of the genetic clinic appointment,
determine the issues of importance to the family and obtain
relevant family history information. The genetic associate is
usually present at the clinic appointment and participates in
the counselling process with the clinical geneticist. At the clinic
appointment genetic investigations may be instituted to
establish or confirm a diagnosis and information is given to the
individual or family about the condition regarding diagnosis,
prognosis, investigation, management and genetic
consequences. Written information is usually provided after the
clinic appointment so that the family have a record of the
various aspects discussed. After the appointment, follow-up
visits at home or in the clinic are arranged as necessary. The
genetic associate plays an important role in liaising with
primary care and other agencies involved with the family.
genetic disorde
There are a wide variety of reasons leading to referral to the
genetic clinic. The referral may be for diagnosis in cases where
a genetic disorder is suspected; for counselling when a genetic
condition has been identified; for genetic investigation of
family members when there is a family history of an inherited
disorder; or for information regarding prenatal diagnosis. The
disorders seen include sporadic birth defects and chromosomal
syndromes as well as mendelian, mitochondrial and
multifactorial conditions. Specialist or multidisciplinary clinics
are provided by some genetic centres, such as for
dysmorphology, inherited cancers, neuromuscular disorders,
Huntington disease, Marfan syndrome, ophthalmic disorders or
hereditary deafness.
genetic clinic. The referral may be for diagnosis in cases where
a genetic disorder is suspected; for counselling when a genetic
condition has been identified; for genetic investigation of
family members when there is a family history of an inherited
disorder; or for information regarding prenatal diagnosis. The
disorders seen include sporadic birth defects and chromosomal
syndromes as well as mendelian, mitochondrial and
multifactorial conditions. Specialist or multidisciplinary clinics
are provided by some genetic centres, such as for
dysmorphology, inherited cancers, neuromuscular disorders,
Huntington disease, Marfan syndrome, ophthalmic disorders or
hereditary deafness.
Cytogenetics
Cytogenetic laboratories undertake chromosomal analysis on a
variety of samples including whole blood (collected into
lithium heparin), amniotic fluid, chorion villus or placental
samples, cultures of solid tissues and bone marrow aspirates.
Analysis is undertaken to diagnose chromosomal disorders
when a diagnosis is suspected clinically, to identify carriers of
familial chromosomal rearrangements when there is a family
history and to provide information related to therapy and
prognosis in certain neoplastic conditions. Some of the main
indications for performing chromosomal analysis are listed in
the box.
variety of samples including whole blood (collected into
lithium heparin), amniotic fluid, chorion villus or placental
samples, cultures of solid tissues and bone marrow aspirates.
Analysis is undertaken to diagnose chromosomal disorders
when a diagnosis is suspected clinically, to identify carriers of
familial chromosomal rearrangements when there is a family
history and to provide information related to therapy and
prognosis in certain neoplastic conditions. Some of the main
indications for performing chromosomal analysis are listed in
the box.
Routine chromosomal analysis
Routine chromosomal analysis requires the study of
metaphase chromosomes in cultured cells. Results are usually
available in 1–3 weeks. Molecular genetic analysis by
fluorescence in situ hydridisation (FISH) studies is possible for
certain conditions. These studies are usually performed on
cultured cells, but in some cases (such as urgent prenatal
confirmation of trisomy 21) rapid results may be obtained by
analysis of interphase nuclei in uncultured cells.
metaphase chromosomes in cultured cells. Results are usually
available in 1–3 weeks. Molecular genetic analysis by
fluorescence in situ hydridisation (FISH) studies is possible for
certain conditions. These studies are usually performed on
cultured cells, but in some cases (such as urgent prenatal
confirmation of trisomy 21) rapid results may be obtained by
analysis of interphase nuclei in uncultured cells.
Molecular genetics
Molecular genetic laboratories offer a range of DNA tests.
Direct mutation analysis is available for certain conditions and
provides confirmation of clinical diagnosis in affected
individuals, presymptomatic diagnosis for individuals at risk of
specific conditions, carrier detection and prenatal diagnosis.
Mutation analysis for rare disorders is usually undertaken on a
supra-regional or national basis in designated laboratories. For
mendelian disorders in which mutation analysis is not possible,
gene tracking using linked DNA markers may be used to
predict inheritance of certain conditions (for example Marfan
syndrome and Neurofibromatosis type 1) if the family structure
is suitable.
Direct mutation analysis is available for certain conditions and
provides confirmation of clinical diagnosis in affected
individuals, presymptomatic diagnosis for individuals at risk of
specific conditions, carrier detection and prenatal diagnosis.
Mutation analysis for rare disorders is usually undertaken on a
supra-regional or national basis in designated laboratories. For
mendelian disorders in which mutation analysis is not possible,
gene tracking using linked DNA markers may be used to
predict inheritance of certain conditions (for example Marfan
syndrome and Neurofibromatosis type 1) if the family structure
is suitable.
DNA can be extracted from any tissue
DNA can be extracted from any tissue containing nucleated
cells, including stored tissue blocks. Tests are usually performed
on whole blood collected into EDTA anticoagulant, or buccal
samples obtained by scraping the inside of the cheek or by
mouth wash. Once extracted, frozen DNA samples can be
stored indefinitely. Samples can therefore be collected from
family members and stored for future analysis of disorders that
are currently not amenable to molecular analysis.
cells, including stored tissue blocks. Tests are usually performed
on whole blood collected into EDTA anticoagulant, or buccal
samples obtained by scraping the inside of the cheek or by
mouth wash. Once extracted, frozen DNA samples can be
stored indefinitely. Samples can therefore be collected from
family members and stored for future analysis of disorders that
are currently not amenable to molecular analysis.
Biochemical genetics
Specialised biochemical genetic departments offer clinical and
laboratory services for a range of inherited metabolic disorders.
Routine neonatal screening for conditions such as
phenylketonuria (PKU) and congenital hypothyroidism are
undertaken on neonatal blood samples taken from all newborn
babies. Investigations performed on children presenting with
other metabolic disorders are carried out on a range of samples
including urine, blood, CSF, cultured fibroblasts and muscle
biopsies. Tests are undertaken to identify conditions such as
disorders of amino acids, organic acids and
mucopolysaccharides, lysosomal and lipid storage diseases, and
peroxisomal and mitochondrial disorders. Tests for other
metabolites or enzymes are performed when a diagnosis of a
specific disorder is being considered. In the UK, the Society for
the Study of Inborn Errors of Metabolism publishes
information on centres providing biochemical genetic tests.
laboratory services for a range of inherited metabolic disorders.
Routine neonatal screening for conditions such as
phenylketonuria (PKU) and congenital hypothyroidism are
undertaken on neonatal blood samples taken from all newborn
babies. Investigations performed on children presenting with
other metabolic disorders are carried out on a range of samples
including urine, blood, CSF, cultured fibroblasts and muscle
biopsies. Tests are undertaken to identify conditions such as
disorders of amino acids, organic acids and
mucopolysaccharides, lysosomal and lipid storage diseases, and
peroxisomal and mitochondrial disorders. Tests for other
metabolites or enzymes are performed when a diagnosis of a
specific disorder is being considered. In the UK, the Society for
the Study of Inborn Errors of Metabolism publishes
information on centres providing biochemical genetic tests.
Genetic registers
Genetic registers have been in use in the UK for about 30 years
and most genetic centres operate some type of register for
specified disorders. In some cases the register functions as a
reference list of cases for diagnostic information, but generally
the system is used to facilitate patient management.
Ascertainment of cases is usually through referrals made to the
genetic centre. Less often there is an attempt to actively
ascertain all affected cases within a given population. To
function effectively most registers contain information about
relatives at risk as well as affected individuals and may contain
information from genetic test results. Establishment of a
register enables long-term follow up of family members. This is
important for children at risk who may not need counselling
and investigation for many years. A unique aspect of a family
based genetic register is that it includes clinically unaffected
individuals who may require continued surveillance and
enables continued contact with couples at risk of transmitting
disorders to their children.
and most genetic centres operate some type of register for
specified disorders. In some cases the register functions as a
reference list of cases for diagnostic information, but generally
the system is used to facilitate patient management.
Ascertainment of cases is usually through referrals made to the
genetic centre. Less often there is an attempt to actively
ascertain all affected cases within a given population. To
function effectively most registers contain information about
relatives at risk as well as affected individuals and may contain
information from genetic test results. Establishment of a
register enables long-term follow up of family members. This is
important for children at risk who may not need counselling
and investigation for many years. A unique aspect of a family
based genetic register is that it includes clinically unaffected
individuals who may require continued surveillance and
enables continued contact with couples at risk of transmitting
disorders to their children.
disorders amenable to DNA analysis
Registers are particularly useful for disorders amenable to
DNA analysis in which advances of clinical importance are
likely to improve future genetic testing and where families will
need to be updated with new information. Disorders suited to a
register approach include dominant disorders with late onset
such as Huntington disease and myotonic dystrophy where
pre-symptomatic diagnosis may be requested by some family
members or health surveillance is needed by affected
individuals; X linked disorders such as Duchenne and Becker
muscular dystrophy where carrier testing is offered to female
relatives, and chromosomal translocations where relatives
benefit from carrier testing. Registers can also provide data on
the incidence and natural course of disease as well as being
used to monitor the provision and effectiveness of services.
Genetic register information is held on computer and is subject
to the Data Protection Act. No one has his/her details included
on a register without giving informed consent.
DNA analysis in which advances of clinical importance are
likely to improve future genetic testing and where families will
need to be updated with new information. Disorders suited to a
register approach include dominant disorders with late onset
such as Huntington disease and myotonic dystrophy where
pre-symptomatic diagnosis may be requested by some family
members or health surveillance is needed by affected
individuals; X linked disorders such as Duchenne and Becker
muscular dystrophy where carrier testing is offered to female
relatives, and chromosomal translocations where relatives
benefit from carrier testing. Registers can also provide data on
the incidence and natural course of disease as well as being
used to monitor the provision and effectiveness of services.
Genetic register information is held on computer and is subject
to the Data Protection Act. No one has his/her details included
on a register without giving informed consent.
Genetic diagnosis
The role of clinical geneticists is to establish an accurate
diagnosis on which to base counselling and then to provide
information about prognosis and follow up, the risk of
developing or transmitting the disorder, and the ways in which
this may be prevented or ameliorated. Throughout, the family
requires support in adjusting to the implications of genetic
disease and the consequent decisions that may have to be made.
diagnosis on which to base counselling and then to provide
information about prognosis and follow up, the risk of
developing or transmitting the disorder, and the ways in which
this may be prevented or ameliorated. Throughout, the family
requires support in adjusting to the implications of genetic
disease and the consequent decisions that may have to be made.
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