Download Kenner et al

Genomics for Health
Promoting Children’s Health Through Understanding
of Genetics and Genomics
Carole Kenner, Agatha M. Gallo, Kellie D. Bryant
Purpose: To describe the effects of genetics and genomics on children’s health care.
Organizing Construct: The breakthroughs in the Human Genome Project have great potential
for disease prediction, treatment, and prevention in the health care of children with chronic
health conditions. Most childhood conditions based on a single gene are influenced by a
complex interaction of genetic and environmental factors.
Methods: A review of the literature was conducted to determine the most common childhood
diseases linked to genetic causes.
Findings: Two examples were selected to depict how a health professional would use genetic
knowledge to provide holistic health promotion and disease prevention.
Conclusions: Knowledge of the interaction of the genetic profile coupled with a person’s
lifestyle, work environment, and family context provide a more holistic picture of a person’s
health profile. The clinical implications are that this knowledge will provide opportunities
for health professionals to advise families on individualized treatment options or to tailor
health promotion to future disease states based on genes and their interaction with the
environment.
C 2005 SIGMA THETA TAU INTERNATIONAL.
JOURNAL OF NURSING SCHOLARSHIP, 2005; 37:4, 308-314. [Key words: genetic testing, congenital hearing loss, sickle cell disease, Usher syndrome,
pediatric nursing]
*
T
he breakthroughs in the Human Genome Project
have great potential for disease prediction, treatment, and prevention in the health care of children
with a wide range of chronic health conditions (see
Table). Most childhood chronic conditions are influenced
by complex interactions of genetic and environmental factors, but genetic influences vary. A continuum of childhood
conditions range from single-gene conditions with high penetrance (e.g., phenylketonuria, Tay Sachs, sickle cell disease)
to low or variable penetrance (e.g., alpha-1-antitrypsin deficiency; Moore, Khoury, & Bradley, 2005). To provide the
best possible health information and improve health outcomes, professionals caring for children and families should
consider both genetics and genomics: the genome coupled
with environmental influences.
The pathology of a disease is no longer a simple cause
and effect nor result of a single gene but a pattern of interconnections between genes and genotype and between
external environmental factors and the person’s genomic
pattern (Buchanan, DeBaun, Quinn, & Steinberg, 2004).
The view of health becomes one of degrees of influence of
genes on health and illness (Feetham, Thomson, & Hinshaw,
2005). This view requires nurses to look at genetic possibil-
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*
*
ities (Buchanan et al., 2004) to reframe health to include
the person’s genetic make-up and its interaction with other
factors. Although the genotype might not be readily altered,
at least today, the genomics or interaction among genes and
other factors can be changed.
In this article, we will discuss the translation of genomic
knowledge to practice and its influence on children and
their families. Newborn screening and two case exemplars—
Usher syndrome and sickle cell disease (SCD)—are used to
indicate the use of this knowledge in practice.
Carole Kenner, RNC, DNS, FAAN, Beta Delta, Dean and Professor, University of Oklahoma Health Sciences Center, College of Nursing, Oklahoma
City, OK; Agatha M. Gallo, RN, PhD, APN, CPNP, FAAN, Xi Alpha, Professor, University of Illinois at Chicago, College of Nursing, Chicago, IL; Kellie
D. Bryant, RNC, MS, NP, CCE, Kappa Gamma, Assistant Professor, Long
Island University, Brooklyn Campus, Brooklyn, NY. Correspondence to
Dr. Kenner, University of Oklahoma Health Sciences Center, College of Nursing, 1100 North Stonewall Ave., Room 116A, Oklahoma City, OK 73117.
E-mail: [email protected]
Accepted for publication January 8, 2005.
Promoting Children’s Health
Table.Childhood Chronic Conditions With Genetic Basis
Disease
Albinism
Angelman syndrome
Antibody deficiencies X-linked agammaglobulinemia (XLA)
Autosomal dominant aolycystic kidney disease (ADPKD)
Autosomal recessive polycystic kidney disease (ARPKD)
CD45 deficiency
Congenital fructose intolerance
Cri du chat syndrome
Down syndrome (Trisomy 21)
Edward’s syndrome (Trisomy 18)
Fabry’s disease
Familial hypercholesterolemia
Fanconi anemia
Fanconi’s syndrome II (Adult-onset)
Fanconi’s syndrome Type I (Child-onset cystinosis)
Fragile-X syndrome
Galactosemia
Gaucher’s disease
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Hartnup’s disease
Hemophilia A (Factor VIII deficiency)
Hemophilia B (Factor IX deficiency)
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu
syndrome)
Hereditary spherocytosis
Homocystinuria
Hunter’s syndrome
Huntington’s disease
Hurler’s syndrome
Immunoglobulin A (IgA) deficiency
Interferon gamma receptor deficiency
Klinefelter’s syndrome (XXY)
Maple syrup urine disease
Marfan’s syndrome
Neurofibromatosis (Von Recklinghausen disease)
Osteogenesis imperfecta
Patau’s syndrome (Trisomy 13)
Phenylketonuria (PKU)
Prader-Willi syndrome
Selective IgA deficiency
Severe combined immunodeficiency (SCID)
Tay-Sachs disease
Thymic aplasia (DiGeorge syndrome)
Tuberous sclerosis
Turner’s syndrome (XO)
Von Hippel-Lindau syndrome
Von Willebrand disease
X-Linked agammaglobulinemia (Bruton’s disease)
XXX syndrome
Genetic linkage
Autosomal recessive
Deletion of part of short arm of chromosome 15, maternal copy
X-linked recessive
Autosomal dominant
Autosomal recessive
Autosomal recessive/autosomal dominant
Autosomal recessive
5p-, deletion of the long arm of chromosome 5
Trisomy 21, with risk increasing with maternal age. Familial form (no age-associated risk) is
translocation t(21,x) in a minority of cases.
Trisomy 18
X-linked recessive
Autosomal dominant
Autosomal recessive
Autosomal recessive
Autosomal recessive
Progressively longer tandem repeats on the long arm of the X-chromosome. The longer the number of
repeats, the worse the syndrome. Tandem repeats tend to accumulate through generations.
Autosomal recessive
Autosomal recessive
X-linked recessive
Autosomal recessive
X-linked recessive
X-linked recessive
Autosomal dominant
Autosomal dominant
Autosomal recessive
X-linked recessive
Autosomal dominant
Autosomal recessive
Autosomal dominant
Autosomal recessive
Nondisjunction of the sex chromosome during Anaphase I of meiosis ——> Trisomy (47,XXY)
Autosomal recessive
Autosomal dominant
Autosomal dominant
Defects in Collagen Type I formation
Trisomy 13
Autosomal recessive
Deletion of part of short arm of chromosome 15, paternal copy. An example of genomic imprinting.
IgA deficiency may be based on failure of heavy-chain gene switching.
Autosomal recessive
Autosomal recessive
Failure of development of the 3rd and 4th pharyngeal pouches
Autosomal dominant.
Nondisjunction of the sex chromosome during Anaphase I of meiosis ——> Monosomy (45,X)
Autosomal dominant
Autosomal dominant and recessive varieties
X-Linked recessive. Mutation in gene coding for tyrosine kinase causes failure of Pre-B cells to
differentiate into B-cells.
Trisomy (47, XXX) and other multiple X-chromosome abnormalities
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Newborn Screening and Testing
Many maternal-child health nurses understand the linkage between genetics and health through their exposure
to prenatal and neonatal screening and testing for genetic diseases. They quickly recognized that, when screening was done for conditions such as phenylketonuria, hypothyroidism, sickle cell disease, and galactosemia, health
consequences of the child might be improved with early detection and treatment. Screening has progressed from conducting fairly broad blood tests examining the DNA to
detect specific alterations and identifying the potential for
future diseases as well as the presence of current conditions (Levy, 2003). Approximately 4 million newborns are
screened annually in the US (Lashley, 2002). The International Society for Newborn Screening (http://www.isnsneoscreening.org/FactSheets/Guidelines.htm) has defined
international guidelines with reporting statistics well defined for Europe. The Pediatrix Medical Group, Inc., Sunrise, Florida has implemented newborn screening programs
in Latin America, Europe, and the Middle East based on
knowledge of population risks. Data from these countries
are not always easy to obtain because of a lack of systematic
reporting in many countries. However, more information
is becoming available as the genetic researchers and practitioners share information at global scientific conferences
and through international journals.
In this article, two examples, Usher syndrome and sickle
cell disease (SCD), are used to illustrate how advances in
genetics can influence screening and expanded testing beyond the newborn period. These cases are also used to show
that early intervention has the potential to diminish or prevent long-term complications if adequate follow-up care is
in place.
Congenital Hearing Loss: Usher Syndrome
In the US, about 0.05% to 0.1% of more than four million newborns have severe to profound hearing loss (Martin
et al., 2003; Smith, Green, & Van Camp, 2003). Although
not all forms of hearing loss in newborns can be attributed to
a genetic mutation, over half of prelingual deafness is caused
by a genetic disorder (Smith et al., 2003). Recent advancements in genetics have helped to identify congenital hearing
disorders and to develop new screening methods. Early diagnosis of hearing disorders can lead to early interventions that
can prevent delays in speech, language, and learning. One
example of a genetic hearing disorder is Usher syndrome.
Usher syndrome is a Mendelian disorder with an autosomal recessive pattern of inheritance that results in hearing
impairment and progressive retinitis pigmentosa. Estimates
are that about 50% of people who are deaf and blind have
a form of Usher syndrome (Kimberling, Weston, & PiekeDahl, 2004). Approximately 30,000 to 40,000 people in
the US have Usher syndrome (Boys Town National Research
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Hospital, n.d.). There are three subtypes of Usher syndrome,
each with varying degrees of morbidity and clinical manifestations. Because of recent identification of gene mutations
that cause Usher syndrome, a clinical test is now available
for one form of Usher syndrome (Usher syndrome Type II,
2005); and we expect that more clinical genetic testing will
be developed. These clinical tests can contribute significantly
to clinical practice by increasing early detection and intervention in children with congenital hearing disorders.
Usher Syndrome Type I
Usher syndrome type I is the most severe and debilitating subtype. The manifestations of Usher syndrome type
I are prelingual sensorineural hearing loss, vestibular areflexia, and adolescent onset retinitis pigmentosa (Kimberling et al., 2004). Without the early insertion of cochlear
implants, children with Usher syndrome type I usually do
not develop speech. As a child with this disorder enters the
second decade of life, progressive degeneration of the retina
results in night blindness and tunnel vision. The progression of visual acuity has been shown to have intra- and interfamilial variability (Kimberling et al., 2004). The onset
and progression of retinitis pigmentosa and hearing loss can
vary significantly among family members. Usher syndrome
type I is usually different from other subtypes, with delayed
walking resulting from vestibular areflexia (Kimberling
et al., 2004). Vestibular areflexia and decreased visual acuity
in combination cause an increase in accidental injuries.
Through direct DNA testing, seven mutations (USH1A,
MYO7A, USH1C, CDH23, USH1E, PCDH15, and
USH1G) have been identified as causes of Usher syndrome
type I (Kimberling et al., 2004). Mutations in the CDH23
gene have been found to have a genotype-phenotype correlation involving vision loss, hearing impairment, and vestibular findings (Kimberling et al., 2004). In 2003, a mutation
(R245X) on the PCDH15 gene was found to represent a
large proportion of Usher syndrome type I in the Ashkenazi
Jewish population (Early diagnosis of Usher syndrome type
1 made possible by new findings, 2003). Continued progress
in identification of specific gene mutations and the effects
of genes can lead to improved diagnosis. Currently, genetic
testing for Usher syndrome type I is on a research basis only
with no available commercial testing on the market.
Usher Syndrome Type II
Usher syndrome type II is often misdiagnosed and is estimated to be three times more prevalent than Usher syndrome
type I (Usher Syndrome Type II, 2005). Clinical manifestations are similar to Usher syndrome type I, but hearing loss
tends to be less severe and vestibular areflexia is not present.
Hearing loss is more likely to occur in the higher tones, making it difficult for children to hear soft tones. Intra- and interfamilial variability in degrees of hearing loss is common;
audiograms of affected family members show similar sloping appearance. Progression of retinitis pigmentosa begins
Promoting Children’s Health
in late childhood, with unpredictable progression of vision
loss. Genotype-phenotype correlations have not been shown
to explain degrees of hearing loss among people with Usher
syndrome type II (Kimberling, Weston, & Orten, 2004).
Four subtypes of Usher syndrome type II have been identified. Only mutations in MASS1 and USH2A genes have been
identified as causes of Usher syndrome type II (Usher Syndrome Type II, 2005). The gene USH2A has been found to
produce the protein Usherin, which is responsible for the integrity of supportive tissue in the retina and inner ear (Usher
Syndrome Type II, 2005). Clinical testing for mutation to the
USH2A gene is available, which can be used to diagnose approximately 80% of people with Usher syndrome type II.
Usher Syndrome Type III
Usher syndrome type III is the least prevalent and is found
predominately in the Finnish population. The clinical manifestations of Usher syndrome type III are progressive postlingual hearing loss, adolescent onset retinitis pigmentosa, and
varying degrees of vestibular disturbances (Kimberling et al.,
2004). Differentiating Usher syndrome type III from types I
and II can be difficult because of similar clinical manifestations. Infants with this disorder are born with normal hearing, but deafness usually occurs by middle age. Researchers
speculate that Usher syndrome type III is caused by at least
two genes, but only one gene (USH3A) has been identified
(Usher Syndrome Type III, 2005).
Genetic Testing and its Influence
on Clinical Practice
If a family has a strong history of deafness, genetics nurse
specialists can predict the risk of a newborn having a genetic
hearing disorder. The estimate of the risk of a newborn being born with a congenital hearing disorder is based on the
mode of inheritance, audiological characteristics, age of onset, and type of onset (prelingual or postlingual). Couples
who have a strong family history of hearing or visual disorders can be tested before conception to determine whether
they are carriers for Usher syndrome. If parents are found
to be carriers of the disorder, nurses can help the parents
prepare for the possibility of having a child with visual and
hearing impairments.
Initiation of early interventions should occur before visual
and hearing deterioration begins in order to take full advantage of existing sensory input. Studies have shown that this
early intervention can allow speech development similar to a
normal child by the age of 3 years (Brown, 1998). Children
with correctable hearing loss should be fitted for hearing aids
or cochlear implants within the first 6 months of life to prevent delays in speech acquisition (Brown, 1998). Advancements in genetic testing have dramatically improved the
way nurses and other healthcare professionals implement
intervention and educate parents of children with Usher
syndrome. However, the availability of genetic testing does
increase the ethical dilemmas faced by parents who must
decide whether to test their children. Will it benefit the child
to be tested? Could testing the child be more harmful than
beneficial? Should parents wait until the child is old enough
to decide whether to be tested? Although genetic testing is
not a cure for Usher syndrome, genetic testing can lead to
improved quality of life.
Sickle Cell Disease: Genetic Modifiers
of Disease Severity
Sickle cell disease is a group of autosomal recessive genetic conditions characterized by the presence of sickle
hemoglobin (HbS) in red blood cells. HbS is caused by
the amino acid substitution of valine (GTG) for glutamic
acid (GAG) at the sixth position of the beta-globin gene
in codon 6 on chromosome 11p15.5 (Steinberg & Brugnara, 2003). HbS is the world’s most common hemoglobin
variant and is found in people of African, Mediterranean,
Middle Eastern, and Indian decent. Children with sickle
cell disease, who were followed from birth to 18 years of
age, had a survival rate of 86% and a death rate of 0.59
per 100 patient-years (Quinn, Rogers, & Buchanan, 2004).
But children with sickle cell disease, including those with
identical genotypes, are not affected equally by the disease;
some children have no or few clinical consequences while
others show significant anemia and complications. Clinical
courses may vary, including death in childhood, recurrent
painful crisis and multiple organ damage in adulthood, or
being relatively healthy until old age (Chui & Dover, 2001).
Although many factors may be responsible for these variations, genetic modifiers are important in determining sickle
cell disease phenotype. At the NIH conference, “New Directions for Sickle Cell Therapy in the Genome Era,” (NIH,
2003), Steinberg suggested a new view of sickle cell disease in
which HbS is necessary but insufficient to account for sickle
cell pathophysiology. Other modifier genes might determine
the expression of the severity of the disease by modulating
the effects of HbS and interacting with other genes and the
environment. Several genetic modifiers have been studied
to predict the disease severity of sickle cell disease, including the beta-globin genotype, fetal hemoglobin (HbF), beta
S gene cluster haplotype, alpha-thalassemia, and modifiers
related to risk of stroke.
Beta-Globin Genotype
Currently, the most important factor for disease severity
and mortality in sickle cell disease is the beta-globin genotype (Ashley-Koch, Yang, & Olney, 2000; Quinn & Miller,
2004). The four main genotypes are: sickle cell anemia
(HbSS), sickle-hemoglobin C disease (HbSC), and two types
of sickle beta-thalassemia: sickle β + -thalassemia and sickle
β 0 -thalassemia (American Academy of Pediatrics, 2002;
Ashley-Koch, Yang, & Olney, 2000; Vichinsky & Schlis,
2003). Typically, children with sickle cell anemia and sickle
β 0 -thalassemia are more severely affected than are children
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with the other genotypes (Quinn et al., 2004; Vichinsky &
Schlis, 2003). For example, children with sickle cell anemia and sickle β 0 -thalassemia have higher rates of pain,
acute chest syndrome, and stroke, as well as a shorter median life span than do those who have sickle-hemoglobin
C or sickle β + -thalassemia (Quinn & Miller, 2004). For
the most part, the difference is the amount of HbS that is
produced in each condition. The amount of HbS is highest
in children with SCA and sickle β 0 -thalassemia. Children
with sickle-hemoglobin C or sickle β + -thalassemia have less
HbS and produce HbC or small amounts of the normal
HbA.
Other hemoglobin variants in the beta-globin gene when
combined with HbS can modify clinical expression of sickle
cell disease (Beutler, 2001, Chui & Dover, 2001, Luo
et al., 2004; Steinberg, 2001). These include but are not limited to HbD-Punjab, HbLenore, HbD-Los Angeles, HbOArab, HbC-Harlem, HbS-Anilles, HbQuebec Chori, and
HbS-South End. For example, the rare HbQuebec Chori has
similar electrophoresis mobility as normal HbA, but when
combined with HbS can cause sickling; the heterozygous
HbS-Antilles can also cause sickling of the red blood cells.
Children who carry the HbS gene and a normal
hemoglobin gene (HbA) have sickle cell trait (HbSA),
but these children usually have no symptoms because the
amount of HbS is not sufficient to produce sickling of the
red blood cells (Ashley-Koch et al., 2000). Sickle cell trait
varies significantly around the world with higher rates associated with high malaria incidence, because carriers are
somewhat protected against malaria. Among African Americans, the prevalence of sickle cell trait is 8% to 10%, but
it is even higher in other parts of the world where malaria
is endemic including a 25% to 30% prevalence rate in West
Africa (Vichinsky & Schlis, 2003).
Fetal Hemoglobin
The amount of fetal hemoglobin (HbF) in the red blood
cells modifies the expression of sickle cell disease and decreases the clinical severity and mortality in children and
adults. HbF guards against painful episodes, acute chest
syndrome, and leg ulcers in adults. Increased amounts of
HbF protect HbS-containing red blood cells because it prevents the intracellular polymerization process of the deoxygenated HbS (Quinn & Miller, 2004). The benefit of increased amounts of HbF was first noted in newborns who
did not show symptoms of sickle cell anemia because they
normally have higher levels of HbF in the first few months of
life. Murray, Serjeant, and Serjeant (1988) found that children with a rare condition, sickle cell-hereditary persistence
of fetal hemoglobin (S-HPFH), had red blood cells that contained HbS and 20% to 40% of HbF. These people had a
normal life span and no visible symptoms of sickle cell disease. Infants with S-HPFH are now identified by newborn
screening, but they need to be distinguished from infants
with sickle cell anemia. People who have sickle cell anemia
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have a 20-fold variation in the amounts of HbF in the red
blood cells that is genetically determined (Quinn & Miller,
2004). The three primary sources or 50% of the variance
in increased production of HbF has been explained by the
X-linked-F-cell production locus (X-FCP), the beta-globin
haplotype or cluster, and some family-specific beta-globin
mutations not relevant to the general public.
A novel approach to pharmacological management in
SCD is the attempt to reactivate genes that are active during fetal development (Buchanan et al., 2004; Steinberg &
Burgnara, 2003; Weatherall, 2003). Hydroxyurea is thought
to increase HbF by enhancing bone marrow regeneration
by its cytotoxic effects or by the nitric oxide-related increases in soluble guanylyl cyclase and cGMP that augments
the gamma-globin gene expression (Buchanan et al., 2004;
Steinberg & Burgnara, 2003; Weatherall, 2003). In infants,
children, and adolescents, the effects of hydroxyurea in increasing HbF are more robust than in adults (Quinn &
Miller, 2004; Steinberg & Burgnara, 2003). One concern in
using hydroxyurea is its potential long term affects on children that might include bone marrow suppression (Quinn
& Miller, 2004).
Beta S Gene Cluster Haplotype
The beta S gene cluster haplotype is composed of globin
genes located on chromosome 11 and a unique set of linked
polymorphisms close to HbS that are inherited. Haplotypes
are named for the geographic regions where they were first
discovered. BEN (Benin), SEN (Senegal), and CAR (Central African Republic) are the three most common African
haplotypes, with the Arab-Indian haplotype occurring in India and the Arabian peninsula (Quinn & Miller, 2004). The
phenotypic effects of the haplotypes are probably mediated
through the gamma-globin gene promoter regions that determine the amounts of HbF and hematocrit. People with
CAR seem to have the most severe disease, with a two-fold
increase in the risk of complications and early death compared with those with the BEN and SEN haplotype. The SEN
and Arab-Indian haplotypes are associated with the mildest
disease; BEN is between CAR and SEN.
Alpha-Thalassemia
Deletions of one or two of the four alpha-globin genes
on chromosome 16 are common among people of African,
Asian, and Mediterranean ancestry. Alpha-globin gene deletions modify the phenotype of sickle cell anemia by producing an unbalanced synthesis of the alpha and betaglobins that decreases HbS concentrations, and increases
hematocrit (Quinn & Miller, 2004). These gene deletions
produce both beneficial and deleterious clinical effects. A
single alpha-globin deletion decreases hemolysis, but it predisposes to more frequent painful events and aseptic vascular necrosis of the hip (Milner et al., 1991; Steinberg et
al., 1984). A full complement of four alpha-globins at birth
predicted a benign clinical course in one study (Thomas,
Promoting Children’s Health
Higgs, & Serjeant, 1997), but another study did not show
that alpha-thalassemia protected from vasoocclusive complications (Steinberg et al., 1984).
Stroke Risk
In children with sickle cell anemia, the rate of stroke and its
complications is highest in comparison with the other three
genotypes (Adams, 2000; Ohene-Frempong et al., 1998;
Vichinsky & Schlis, 2003). As many as 11% of children
with sickle cell anemia have symptoms of stroke by 20 years
of age (Ohene-Frempong et al., 1998), and about 22% have
silent cerebral infarcts by age 14 (Buchanan et al., 2004).
Routine screening of children with transcranial doppler ultrasound is recommended to detect cerebral artery narrowing (Fullerton, Adams, Zhao, & Johnston, 2004). However,
recent work on genetic interactions and stroke risk might
hold promise for identifying these at-risk children (Adams
et al., 2003; Hoppe, Klitz, Virgil, Vichinsky, & Sty, 2004;
Hoppe, Klitz, Vigil, Vichinsky, & Styles, 2003). For instance,
an association was found between specific HLA alleles and
either increased or decreased risk of stroke (Styles et al.,
2000; Hoppe et al., 2003), and specific polymorphisms in
genes were found to be independently associated with small
(i.e., VCAM1, LDLR) and large vessel (i.e., IL4R, TNF,
ADRB2) strokes, and a combination of TNF and IL4R variant was associated with a strong predisposition to largevessel stroke in children with sickle cell anemia (Hoppe
et al., 2004). Polymorphisms of genes associated with adhesion, thrombophilia, inflammation, and regulation of blood
pressure have been associated with risk of stroke, and a polymorphism in vascular cell adhesion molecule-1 (VCAM1)
might protect against stroke in patients with SCD (Hoppe
et al., 2004; Taylor et al., 2002). In a recent study, 31 polymorphisms in 12 genes were found to interact with fetal
hemoglobin to modulate the risk of stroke (Sebastiani, Ramoni, Nolan, Baldwin, & Steinberg, 2005). In the future,
genetic testing for risk-modifying genes might prove better
than transcranial doppler ultrasound to predict risk of stroke
earlier and before silent strokes occur (Meschia, & Pankratz,
2005).
Sickle Cell Disease: A Complex Single
Gene Condition
The overall mortality for children with sickle cell disease
has decreased over the years, the mean age at death is increasing, and a smaller proportion of deaths are from infection
(Quinn et al., 2004). Improvements are most likely the result
of environmental factors such as early diagnosis by newborn
screening, patient and family education, and better medical care including aggressive management with prophylactic
penicillin and conjugated pneumococcal vaccine to prevent
fatal pneumococcal sepsis (Ashley-Koch et al., 2000). As future research indicates the genotype-phenotype variability
of sickle cell disease, the potential is great for understanding
more fully the biology of sickle cell disease and the develop-
ment of more effective treatments and preventive strategies,
and, more importantly, how the disease effects might vary
depending on a child’s level of risk (Kirkham, 2003; Schatz,
Finke, & Roberts, 2004).
Although sickle cell disease is still described as a monogenic, single gene condition, many genetic and environmental factors likely modify its phenotype (Chui & Dover, 2001;
Quinn & Miller, 2004). As the knowledge of genomics increases, the molecular genetic context in which to understand sickle cell disease will evolve (Buchanan et al., 2004),
and the interaction of genes and the environment will most
likely be considered more complex than a Mendelian or single gene inheritance pattern (Nadeau, 2005).
Understanding the Complexity of Genetic Conditions
The Human Genome Project is the foundation of a new
frontier in health care. Gradually, scientists are identifying
what genes are related to what diseases and where they are
located in the human genome. Health education will be different if genetic risk factors coupled in some instances with
environmental exposures are known and reframe how disease management is implemented. If a child or family is considered high risk for a certain condition, or if a screening test
is positive while the person remains in the presymptomatic
phase, then more expanded definitive testing is necessary
and follow-up is tailored to the test results and the risk profile. For example, testing for cystic fibrosis can include an
expanded 25-mutation panel that has the capacity to distinguish among 47 different mutations (Gilbert, 2001). The
specificity of identification of the type CF an individual is
at risk for or has will assist in getting a more individualized
plan of care. For example, Fragile X that can be detected by
karyotyping or use of the Southern Blot Test. To identify the
exact mutation, polymerase chain reaction assay is needed
(Houdayer et al., 2002).
Conclusions
The overarching clinical implications of current genetic
knowledge center on the health professional’s ability to integrate genetic breakthroughs and knowledge into practice.
This is accomplished through making appropriate genetic
referral resources for screening, testing, and follow-up, as
the examples of Usher syndrome and sickle cell disease
indicate.
The National Coalition for Health Professional Education in Genetics (2004) has developed core competencies
for health professional’s education. In the case of child and
family care these guiding principles pertain to the need to
understand the genetic risk factors for common pediatric
conditions, know what the effect of the course of screening,
diagnosis, and treatment has on the child and family, and recognize when a referral should be made for genetic counseling
and specialized follow-up. None of this can happen without
a working knowledge of genetics and genomics.
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