The second is to illustrate important genetic concepts of relevance to nurses who care for infants, children, or adolescents.. While it is impossible to stay current in all disordisor-de
Trang 1Cynthia A Prows, MSN, CNS, FAAN1, Robert J Hopkin, MD2, Sivia Barnoy, PhD, RN3,
& Marcia Van Riper, PhD, RN, FAAN4
1 Beta Iota, Clinical Nurse Specialist, Children’s Hospital, Cincinnati, OH, USA
2 Clinical Geneticist, Children’s Hospital, Cincinnati Ohio; Associate Professor, University of Cincinnati, Cincinnati, OH, USA
3 Delta Lambda, Head, Nursing Department, School of Health Professions, Senior lecturer, Tel-Aviv University, Tel-Aviv, Israel
4 Alpha Alpha, Associate Professor, University of North Carolina, Chapel Hill, NC, USA
Key words
Child health/pediatrics, genetics/heredity,
evidence-based practice, neonatal/infant
Correspondence
Cynthia A Prows, Divisions of Human Genetics
and Patient Services, Building E 5.259, 3333
Burnet Avenue, Cincinnati, OH, 45229-3039.
E-mail: Cindy.prows@cchmc.org
Accepted: September 16, 2012
doi: 10.1111/jnu.12003
Abstract
Purpose: Thousands of single gene, mitochondrial, and chromosomal
disor-ders have been described in children The purpose of this article is twofold The first is to increase nurses’ awareness of new developments in genetic dis-orders that are commonly seen in practice and taught in schools of nursing The second is to illustrate important genetic concepts of relevance to nurses who care for infants, children, or adolescents
Organizing Construct: This article is organized into four sections: one that
describes new developments in a well-known disorder, a second that discusses the process and potential outcomes of diagnosing a very rare disorder, and the third and fourth sections that describe select conditions caused by single gene mutations
Methods: Clinical expertise was paired with literature review to present
evidence-based current information Implications for nursing practice are highlighted throughout the article Citations of publicly available evidence-based online resources are used so nurses can continue to use these in their practices
Findings: Diagnosis and treatment strategies for children with genetic
disor-ders are rapidly changing While it is impossible to stay current in all disordisor-ders, resources are available to help nurses provide evidence-based care to children with genetic disorders
Clinical Relevance: Nurses have an important role in the early identification
of children with genetic disorders and in facilitating their access to appropri-ate services and resources Nurses can also help families understand why ge-netic testing may be necessary and assure families are informed throughout the process
Genetic disorder is the umbrella term used for diseases
or syndromes caused by variants affecting nuclear or
mi-tochondrial genes, combinations of variant genes and
environmental factors, or changes in the number or
structure of one or more chromosomes or
chromoso-mal regions The Online Mendelian Inheritance in Man
(OMIM; www.ncbi.nlm.nih.gov/omim) contains
descrip-tions of over 12,000 disorders associated with known or
suspected Mendelian or mitochondrial etiology, or
chro-mosome deletions or duplications To promote nurses’
efforts to meet genetics-genomics competencies (Con-sensus Panel on Genetic/Genomic Nursing Competen-cies, 2009), this article features a small number of genetic disorders to (a) raise awareness of new devel-opments in genetic disorders that are commonly seen
in practice and taught in schools of nursing; and (b)
to illustrate important genetic concepts of relevance to nurses who care for infants, children, or adolescents The section on Down syndrome (DS) illustrates why it
is important for nurses to stay current in commonly
Trang 2recognized genetic disorders The neonate with
hypoto-nia demonstrates the process and potential outcomes of
early evaluation by a genetics clinician (physician or
ad-vanced practice nurse with specialty training in genetics)
The autosomal dominant section reviews important
con-cepts that impact a nurse’s ability to recognize indications
for referral in children with and family members at risk
for a genetic disorder The autosomal recessive (AR)
sec-tion reviews the role of ethnicity in genetic risks and uses
cystic fibrosis as an example of advances in early
recogni-tion and targeted therapies
New Developments in a Well-Known
Disorder: Down Syndrome
DS, the most frequent genetic cause of cognitive
im-pairment, occurs in approximately 1 in 700 live births
in the United States (Parker et al., 2010) Current
estimates suggest there are over 400,000 people in
the United States with DS (National Down Syndrome
Society, 2012) and over 6 million people with DS
world-wide Life with DS in the 21st century is dramatically
dif-ferent than it was when the condition was first described
by Dr John Langdon Down in 1866 Improved health
care, the support of families and advocacy groups, and
the expansion of educational and vocational
opportuni-ties have led to improvements in quality and longevity
in the lives of individuals with DS Life expectancy has
increased from 12 years in 1929 to nearly 60 years at
present (Bittles & Glasson, 2004) In addition, a growing
number of individuals with DS are graduating from high
school, going to college, living independently, and
find-ing employment However, the inclusion of individuals
with DS into educational, vocational, and social
oppor-tunities depends in large part on the attitudes of others,
and findings from two recent studies suggest that many
people continue to hold negative attitudes toward
indi-viduals with DS (Pace, Shin, & Rasmussen, 2010, 2011)
Nurses can play an important role in educating the
pub-lic about the potential of people with DS and participate
in policy deliberations regarding the inclusion of adults
with DS
Although clinical presentation is variable, all
individ-uals with DS have some level of cognitive impairment,
usually mild (IQ of 50–70) or moderate (IQ of 35–50)
In addition, many have distinctive facial features such as
an upward slant to the eyes, a depressed nasal bridge,
a short neck, and abnormally shaped ears Common
health concerns for individuals with DS include
hear-ing loss (75%), vision problems (60%), obstructive sleep
apnea (50%–79%), otitis media (50%–70%), eye
dis-ease (60%), and congenital heart defects (50%) A
thor-ough discussion of these, as well as other health con-cerns associated with DS, can be found in the most re-cently revised evidence-based guidelines published by the American Academy of Pediatrics (Bull, 2011) In addi-tion to including age-specific recommendaaddi-tions for health monitoring, the guidelines recommend annual assess-ment of (a) personal support available to family, (b) participation in a family-centered medical home, (c) fi-nancial and medical support programs for which the child and family may be eligible, (d) injury and abuse prevention with special consideration of developmen-tal skills, and (e) nutrition and activity to maintain fitness
Until recently, most individuals in the medical and re-search community believed it was impossible to reverse
or reduce cognitive impairment However, recent ad-vances in genomics and brain research are providing new directions for possible drug therapy designed to improve the cognitive and adaptive abilities of individuals with
DS The studies are funded in large part by foundations and institutes specifically interested in DS (e.g., Down Syndrome Research and Treatment Foundation, Re-search Down Syndrome, Linda Crnic Institute for Down Syndrome, Global Down Syndrome Foundation) and have helped researchers identify a number of unique bio-logical mechanisms associated with cognitive impairment
in DS One such mechanism is an imbalance between excitatory and inhibitory neurotransmission in the hip-pocampus, an area of the brain that is critical for learning and memory Researchers have used mouse models of DS (e.g., Ts65 Dn mice) to demonstrate that balance in the hippocampus can be restored by blocking receptors re-sponsible for inhibition (Fernandez et al., 2007) Another group of researchers have shown that memantine, a drug approved for the treatment of Alzheimer’s dementia, can reverse learning and memory deficits in Ts65 Dn mice (Costa, 2011) Clinical trials investigating the safety, tol-erability, and efficacy of potential drug therapy informed
by animal studies are underway
Recently, there have been a number of national efforts designed to address two of the major barriers facing re-searchers interested in DS: (a) lack of adequate funding and (b) lack of a national DS registry In 2011, two pieces
of legislation were introduced in the U.S Congress by the Co-Chair of the Congressional Down Syndrome Cau-cus, Representative Cathy McMorris Rodgers The first bill, H.R 2696, the Trisomy 21 Research Resource Act of
2011, authorizes current efforts already underway by na-tional patient advocacy organizations, together with the National Institute of Child Health and Human Develop-ment to establish three research databases that will pro-vide the research community with access to information that has been otherwise hard to obtain The second bill,
Trang 3H.R 2695, the Trisomy 21 Centers of Excellence Act of
2011, recognizes six centers of excellence dedicated to
conducting and coordinating translational research in DS
and requests that $6 million be allocated annually to the
National Institutes of Health (NIH) to fund these
cen-ters of excellence In September of 2011, the NIH joined
with organizations interested in DS to form a
consor-tium designed to foster the exchange of information on
biomedical and biobehavioral research on DS A central
focus of the consortium is implementation of the NIH
Re-search Plan on Down Syndrome developed by the NIH
Down Syndrome Working Group in October 2007
(Eu-nice Kennedy Shriver National Institute of Child Health
and Human Development, 2007)
There is growing excitement among families of
chil-dren with DS, advocacy groups, and DS researchers about
research designed to understand and reduce impaired
cognition in individuals with DS and research aimed at
improving the quality of life for individuals with DS
Yet, there is growing concern about research on DNA
se-quencing of maternal plasma to detect DS such as that
described by Palomaki et al (2011) At the time of this
writing, noninvasive diagnostic testing for DS was
be-ing commercially offered in many major cities in the
United States One of the main concerns voiced about
this new type of testing is that it may lead to a
reduc-tion in the number of individuals with DS being born,
which could ultimately lead to a reduction in services for
individuals with DS and funding for DS research (Greely,
2011; Leach, 2011; Van Riper & Choi, 2011) A recent
report by the Council for Responsible Genetics
(Hay-mon, 2011) thoroughly discusses some of the complex
ethical and social implications of noninvasive
diagnos-tic testing for DS (e.g., freedom of choice in
reproduc-tive decision making, justice and access to care,
stigma-tization, and disability rights) It is critical that families
are given the information needed to make informed
deci-sions about both genetic testing and involvement in
clini-cal trials Informed nurses and other healthcare providers
can advocate for and facilitate dialogue between pregnant
women, expectant families, healthcare providers,
fami-lies of individuals with DS, disability advocates, and DS
researchers about genetic testing options for DS as well
as available trials for improving cognition and quality of
life
Hypotonia in the Newborn: Rare
Disorders
Nurses have an important role in recognizing
hypoto-nia in the newborn and making or facilitating a genetics
referral when caring for a newborn commonly described
as “floppy.” On physical examination, a hypotonic new-born has limited voluntary movement, reduced strength, and joints that have increased range of movement and di-minished resistance when manipulated Hypotonia is one
of the most common reasons for considering a genetic dis-order in a newborn However, many neonates with hypo-tonia do not have a disorder as widely recognizable as DS
A genetics clinician must conduct a comprehensive eval-uation to narrow down the diagnostic possibilities from many hundred genetic and nongenetic conditions that may present with hypotonia Even when a medication
or other treatment that specifically targets a condition is not available, an accurate diagnosis can inform progno-sis and guide management to maximize developmental and health potential as well as prevent secondary com-plications For example, hypotonia due to Zellweger syn-drome (Steinberg, Raymond, Braverman, & Moser, 2003, update 2011) is very different from hypotonia associated with Prader-Willi syndrome (Cassidy & Schwartz, 1998, update 2009) or congenital myasthenia gravis (Abicht & Lochmuller, 2003, update 2012) The first of these condi-tions is lethal; the second is compatible with long-term survival but is associated with lifelong challenges and disability; the last can be serious and even life threat-ening at birth, but if due to transplacental transmis-sion of antibodies, it can resolve in the first few months
of life
Depending on the setting or country of practice, nurses
at the bedside may facilitate access to a genetics con-sult All nurses can prepare families for the evaluation and assure that their subsequent questions and service needs are met Nurses can describe that during a genet-ics consultation a patient with hypotonia may be exam-ined by a clinical geneticist or, in a few settings, a genetics advanced practice nurse These clinicians or a genetic counselor will obtain prenatal and perinatal histories to identify exposures, infections, or other events that can lead to fetal damage Existing family history data in the medical record will be reviewed Because pedigrees are seldom documented, a three- to four-generation fam-ily history with specific questions aimed at features of potential inherited disorders that present with neonatal hypotonia will be obtained A genetic clinician’s phys-ical examination always includes a dysmorphology as-sessment to identify patterns of phenotypic variations that can be found in specific disorders Nurses who want
to learn more about dysmorphology are referred to the
2009 American Journal of Medical Genetics Part A special
is-sue, “Elements of Morphology: Standard Terminology,” which provides descriptions, definitions, and pictures of common and variant phenotypic features Findings from the clinician’s comprehensive genetics evaluation inform the testing approach
Trang 4Tests to evaluate a neonate with hypotonia may
in-clude (a) measuring metabolic analytes if a condition
such as Zellweger syndrome (Steinberg et al., 2003,
up-date 2011) is suspected; (b) interrogating chromosomes
by high-resolution karyotyping if a recognizable
chromo-some disorder such as DS is suspected; (c) testing for
ab-normal methylation patterns when a condition due to
im-printing such as Prader Willi syndrome is suspected; (d)
analyzing specific genes when a condition such as
con-genital myasthenia gravis (Abicht & Lochmuller, 2003,
update 2012) is suspected When the genetic history
and examination does not uncover a readily recognizable
pattern, a chromosomal single nucleotide polymorphism
(SNP)-based microarray test may be performed (Conley,
Biesecker, Gonsalves, Merkle, Kirk, & Aouizerat, 2013;
Miller et al., 2010) Please see Gene Tests or Genetic
Home Reference listed in Clinical Resources for more
in-formation about specific tests
An example of a condition that can present with
new-born hypotonia and was once thought to be very rare
be-fore chromosomal microarrays became available is 1p36
deletion (Battaglia & Shaffer, 2003, update 2008) This
deletion was first described in 1981, but the phenotype
was not clearly delineated until the late 1990s With the
advent of microarray technology, the incidence of 1p36
deletion has been found to be 1 in 5,000 to 10,000
chil-dren (Battaglia et al., 2008) Several case series have been
published (Battaglia, et al., 2008; Battaglia & Shaffer,
2003, update 2008; Gajecka, Mackay, & Shaffer, 2007)
that provide insight into knowing when to consider 1p36
deletion and what problems to anticipate for the newly
diagnosed child The presenting features are nonspecific
but consist of hypotonia and feeding problems in the
neonatal period This is often accompanied by
recogniz-able but minor abnormalities in facial features and less
frequently by major malformations like heart defects,
cleft lip, or cleft palate As the children with deletion 1p36
grow older, they are often slower to master
developmen-tal skills than other children the same age This is
par-ticularly true for language and communication, but also
impacts motor skills and global development The
devel-opmental outcomes are varied, and children are usually
more severely impaired than children with DS The
af-fected children may also have other health problems like
slow growth, seizures, and chronic aspiration of oral
con-tents into the trachea However, this condition has been
widely recognized for only a few years, so information on
long-term outcomes is limited
The juxtaposition of rapidly advancing genetics
tech-nology and information techtech-nology has provided the
op-portunity for parents of children newly diagnosed with
very rare disorders to interact regardless of where they
live Families living with rare diseases have used social
networking resources to connect with one another and
to share ideas and information When families of patients
of the second author initially looked for information on 1p36 deletion, they were dismayed to find little was avail-able One family responded to this by raising money to support production of a brochure for families that was nationally distributed and is still in use (personal obser-vation, second author) Another family used social net-working to sponsor a site for discussion that has led to
a national support group The 1p36 support group now sponsors an annual family meeting and is working with physicians and scientists to increase not only awareness but scientific and medical understanding of the disor-der affecting their families (1p36 Deletion Support and Awareness, 2012) Similar online networking and ad-vocacy groups have been developed for many rare ge-netic disorders Social media can bring together families, healthcare providers, and scientists so that management plans and research studies focus on priorities that impact the health and quality of life for their children (Landy
et al., 2012) This networking is expected to have an in-creasing impact on healthcare delivery and research, es-pecially for rare disorders
Conditions Caused by Single Gene Mutations: Autosomal Dominant Disorders
An autosomal dominant disorder is recognizable in the heterozygous state, which has classically referred to a pair
of genes at a specific locus in which one of the genes has a mutation that changes the function of the pro-tein in a deleterious manner Autosomal dominant dis-orders may occur due to a de novo mutation (new mu-tation that spontaneously occurred in a gene carried by
an individual germ cell) or can be inherited Improved technology can now detect chromosome deletions and duplications too small to detect with routine some analysis (categorized as submicroscopic chromo-some imbalances) Most of these imbalances occur spon-taneously and are thus unique to the individual with the associated disorder However, when a submicroscopic chromosome imbalance is contained on an autosome (chromosomes 1–22) and the resulting disorder does not prevent reproduction in the affected adult, then it is possible for the de novo submicroscopic chromosome imbalance to be transmitted to subsequent generations
in an autosomal dominant pattern A good example is velo-cardio-facial syndrome, which is due to a submi-croscopic deletion in chromosome 22 that is usually de novo but can be transmitted to subsequent generations (McDonald-McGinn, Emanuel, & Zackai, 1999, update
Trang 52005) When the submicroscopic imbalance is on an X
chromosome and the adult is able to reproduce, then
the imbalance can be transmitted in an X-linked
pat-tern Clinical recognition of these disorders can be
con-founded by reduced penetrance, variable expressivity,
and pleiotropy Each of these concepts will be explained
and clinical examples given in the following section
Reduced penetrance is a population-based concept It
refers to the proportion of people with a causative gene
mutation who have observable or measurable
manifesta-tions of the disorder When 100% of people who inherit
the mutation develop one or more features of the
disor-der, no matter how mild, the mutated gene is considered
100% penetrant
Achondroplasia (a type of short-limbed dwarfism) is an
example of an autosomal dominant disorder caused by a
mutation in the FGFR3 gene that is 100% penetrant and
recognizable during childhood and usually infancy (Pauli,
1998) Achondroplasia is due to a de novo mutation in
80% of children with the disorder Although their
par-ents do not have achondroplasia, children with the de
novo mutation have a 50% chance of transmitting the
mutation to each of their future children
Van der Woude syndrome (VWS) is a rare
autoso-mal dominant craniofacial disorder with reduced
pene-trance recognizable in childhood that is caused by
par-ticular mutations in the IRF6 gene (Durda, Schutte, &
Murray, 2003, update 2011) Most children with VWS
inherited it from a parent since de novo mutations are
not common Approximately 80% of people with a
mu-tation will demonstrate one or more features of the
con-dition The phenotype also demonstrates variable
expres-sivity even between affected family members The more
common features of VWS include lower lip fistulae (pits)
or mounds, cleft lip, cleft palate, or any combination of
the three main features VWS is a good example of
vari-able expressivity because individuals within a family may
have one or any combination of these congenital
cran-iofacial anomalies, and the degree of severity will also
vary Reduced penetrance or variable expressivity
mis-leads people to think conditions like VWS “skip
gener-ations.” When an “unaffected” adult has a parent and a
child with VWS, the unaffected adult has the gene
mu-tation; it did not skip the adult The mutation is either
not penetrant in that individual or it is possible that the
adult’s very mild expression was unrecognized, the latter
of which is an example of variable expressivity
Neurofibromatosis type 1 (NF1) is a relatively
com-mon (incidence 1 in 3,000) autosomal dominant
disor-der that demonstrates pleiotropy and variable
expressiv-ity Pleiotropy refers to findings that have the same cause
but are otherwise seemingly disconnected For example,
manifestations of the gene mutation can be found in
more than one body system Mutations in the NF1 gene
are virtually 100% penetrant Some signs of the condition may not be recognizable until after childhood (Friedman,
1998, update 2009) The NF phenotype is pleiotropic be-cause clinical manifestations can involve the skin, eyes, bones, peripheral or central nervous system, cardiovas-cular system, or any combination of these Expression of
the NF1 mutation transmitted within a family can vary
considerably, with some individuals having only specific cutaneous findings such as caf ´e au lait spots (that may be thought of as insignificant “birth marks”), while others may have aggressive tumors or malignancies that cause significant morbidity or death Since obvious signs and symptoms can be delayed until adolescence or adulthood, children with an affected parent need to be carefully
monitored A symptom-free child may have the NF1
mu-tation transmitted within a family but the features are not yet recognized earlier in life Delayed or mild mani-festations in early childhood do not necessarily predict a milder case of the disorder as he or she ages
Nurses need to consider concepts such as reduced penetrance, variable expressivity, and pleiotropy demon-strated by many dominant disorders when collecting fam-ily history and identifying individuals who may benefit from genetic information or services For example, al-though cleft lip is most often an isolated anomaly asso-ciated with a 3% to 5% recurrence risk (Bender, 2000), VWS illustrates that a congenital anomaly, like cleft lip, may actually be a manifestation of an underlying disorder with a 50% recurrence risk Each of the dominant condi-tions discussed illustrates some rate of de novo mutation However, to determine if a child’s disorder is due to a de novo or inherited mutation in conditions such as VWS
and NF1, the parents need to be carefully examined by
a professional skilled in dysmorphology and knowledge-able about the spectrum of signs and symptoms for the disorders These disorders also illustrate the importance
of nurses recording seemingly unrelated problems, signs, symptoms, or features when obtaining a three-generation family health history
Early recognition and diagnosis of a genetic disorder can inform targeted screening, early intervention, pre-vention of secondary complications, education strategies, and social connections that can improve quality of life Identification of the variant gene and subsequent under-standing of the molecular and cellular consequences of particular mutations can lead to novel treatments De-velopment of molecular targeted therapies for dominant conditions has been particularly difficult since targeted therapies for autosomal dominant conditions need to pre-vent the production of the mutated proteins that can in-terfere with the normal protein produced by the normal allele This is in contrast to AR disorders that result in
Trang 6deficient or absent protein for which protein replacement
therapy may be an option Targeted therapies in
auto-somal dominant conditions are being studied which use
specially designed probes that cause naturally occurring
cellular mechanisms to degrade the messenger RNA of
the mutated gene, thus preventing the abnormal
pro-tein from being produced This then allows the wild-type
(normal) gene’s protein to function However, there are
several significant problems to overcome, such as rapid
degradation of probes and getting probes to specific
tar-get tissues Comprehensive reviews of animal and human
research using this technology were recently published
by Davidson and McCray (2011) and Kole, Krainer, and
Altman (2012) The use of genetic testing prior to such
therapies can be compared with the use of antibiotic
sen-sitivities to pick the best antibiotic for the “same
infec-tion” in different people Genetic testing prior to targeted
therapies is particularly important for disorders in which
a single disorder can be caused by a mutation in one of
several possible genes
Autosomal Recessive Disorders
AR disorders result when both alleles of a gene contain
a mutation that contributes to the disorder Children who
have one functional allele and one disease-associated
al-lele are called carriers and do not develop signs and
symp-toms of the disorder When these children reach
repro-ductive age, if their partner is also a carrier of a mutation
in the same gene, they are at 25% risk with each
preg-nancy of having a child with the disorder
Mutant alleles responsible for AR diseases are
gener-ally rare; these alleles may be transmitted in families
for many generations without their awareness Unlike
dominant mutations that interfere with the functional
allele’s protein, recessive mutations typically result in
reduced or nonfunctional protein product, and the
re-maining wild-type allele’s functional protein is adequate
for its intended purpose It has been estimated that
ev-ery person is a carrier of 8 to 10 recessive mutant alleles
However, analysis of whole exome and whole genome
sequencing has revealed that the genome from healthy
individuals contains approximately 100 loss-of-function
variants, most of which are expected to be in
nonessen-tial genes (MacArthur et al., 2012)
The chance that both parents are carriers for the same
mutation increases in genetic isolates (a community
iso-lated from the general population due to geography,
eth-nicity, or other factors) and in consanguinity (both
par-ents share a biologic relative in common) Both raise
the prevalence of rare AR disorders In genetic isolates,
since these populations cohabited within themselves for
many generations, the frequency of specific AR diseases
is high Typically a distinct mutation shared by all indi-viduals with the rare AR disease reveals a founder effect (Peltonen, 2005) An example of genetic isolates is the Finnish disease heritage, a group in which about 30 AR diseases occur more frequently than in the general pop-ulation Each of the 30 diseases has a major founder mutation (Pastinen et al., 2001) Consanguinity is com-mon in some ethnic groups such as Arab communities
in the Middle East (El Mouzan, Al Salloum, Al Herbish, Qurachi, & Al Omar, 2008), yet low in many Western countries as it may carry a social stigma, causing pa-tients to avoid sharing this information with their care providers (Mensink & Hand, 2006) Nurses need to estab-lish an open and honest relationship with their patients
in order to obtain an accurate family history that may re-veal consanguinity
Until recently, carriers were detected only after an af-fected child was born However, carrier screening for rel-atively common AR diseases such as cystic fibrosis (CF) and sickle cell disease now makes it possible to detect healthy carriers before conceiving an affected pregnancy Some tests are recommended to all, while others are of-fered according to ethnic origin (Borry et al., 2011) The test panel may change in response to findings from epi-demiologic or genetic studies or new genetic technolo-gies These tests may examine common mutations in a given population, and accordingly the mutation panel might be updated when new mutations are identified For this reason, nurses need to be aware that in some cases
a person who was previously tested and found to not be
a carrier for any of the analyzed mutations might benefit from being retested in the future after new mutations are identified and added to the panel CF is a good example
of a disorder for which the carrier panel was specifically designed to detect mutations commonly found in differ-ent racial and ethnic populations In those cases when targeted mutation screening does not capture the muta-tions in a given ethnic group, additional steps might be required, such as gene sequencing It is important that nurses who work in women’s health or perinatal settings keep current knowledge about available testing panels and help their patients obtain the information they need
to make informed decisions regarding testing This can be achieved by being involved in related professional orga-nizations, developing collaborations with genetics profes-sionals, or keeping in close contact with a genetics clinic Traditionally, the reproductive choices available to two carriers were either to avoid having biologic children or
to have prenatal testing after conception When a fetus was diagnosed with a disorder, the couple had to decide
to either terminate the affected pregnancy or prepare for the delivery and care of a child with the disorder (Harper
Trang 7& Sengupta, 2012) When the mutation in each carrier
parent is known, preimplantation genetic diagnosis
(PGD) is now an additional option Couples using PGD
undergo in vitro fertilization (IVF), let the embryos
de-velop for 3 to 5 days, and then remove one or two cells
for genetic testing, allowing selection of the embryos that
are not at risk for the AR disorder and for transfer to
the uterus (Harper & Sengupta, 2012) The most
fre-quent AR diseases tested in PGD are CF, beta-thalassemia,
and sickle cell disease (Demko, Rabinowitz, & Johnson,
2010) PGD has lately been expanded to test over 200
dominant, recessive, and X-linked as well as some
chro-mosomal disorders PGD can also be used for sex selection
when an X-linked disorder is known to run in the family
but the causative gene mutation is not known PGD does
have disadvantages, including the risks and stress
associ-ated with the IVF procedure (Harper & Sengupta, 2012)
and the fact that IVF and PGD are expensive and often
not covered by insurance, which leads to unequal access
to available options
While knowing the mutated genes in different
dis-eases enables identification of carriers, it also stimulates
advances in the development of new therapies CF is
such an example Approximately 1,500 different
func-tionally significant mutations have been described in the
CF transmembrane conductance regulator (CFTR) gene.
The common functional CFTR allele produces a
pro-tein that is an adenosine triphosphate–dependent
chlo-ride channel Most of the variant CFTR alleles are
pri-vate (when a specific mutation is reported in only one
family) or rare, and appear with different prevalence
ac-cording to race and ethnicity The exception isF508, a
three–base pair deletion causing a frameshift mutation at
codon 508 that accounts for 70% of the CF-associated
mutations worldwide (Becq, Mall, Sheppard, Conese, &
Zegarra-Moran, 2011) Developing drugs for 1,500
dif-ferent mutations in a rare disease is not feasible
Classify-ing CFTR mutations into five categories accordClassify-ing to the
mechanism of altered CFTR (protein) function improved
the feasibility of developing mutation targeted therapy
For example, F508 produces a protein with abnormal
folding that prevents the protein from leaving the
endo-plasmic reticulum However, the abnormally folded
pro-tein has been shown to have partial function if able to
reach the cell membrane Studies to discover or develop
compounds that can rescue the variant CFTR and
es-cort it to the cell membrane are being conducted (Becq
et al., 2011) Another category of mutations creates
pro-teins that are successfully transported to the cell
mem-brane but do not function, yet may function when
patients with these types of mutations are given a CFTR
potentiator medication (Ramsey et al., 2011) that was
re-cently approved by the Food and Drug Administration
(Davis, Yasothan, & Kirkpatrick, 2012) However, the medication is not effective in people who carry two copies
of the commonF508 allele (Flume et al., 2012) Nurses
will need to help patients understand why different med-ications are being prescribed for patients that share the same clinical diagnosis
Summary
The genetic disorders featured in this article demon-strate that recognition, diagnosis, and treatment demon-strategies for children with genetic disorders are rapidly changing
It cannot be expected that nurses remain current in all genetic disorders or genetic tests It is important, how-ever, to be familiar with expert, peer-reviewed, regularly updated resources that are freely accessible on the In-ternet and have been described or cited in this article Nurses have an important role in assessing and identify-ing patients who may benefit from a genetics evaluation; preparing families for a genetics consultation; coordinat-ing related testcoordinat-ing, procedures, and care; and helpcoordinat-ing families process the information they learned from the consultation process Informed nurses can assure that pa-tients and families are aware of available support groups and clinical trials that may benefit them Development of drugs tailored to specific mutations or categories of mu-tations require nurses to anticipate the need to explain to families why children with the same diagnosis are receiv-ing different treatments
Clinical Resources
r Clinical trials: http://clinicaltrials.gov/
r Genetics home reference: http://ghr.nlm.nih.gov/
r Gene reviews: http://www.ncbi.nlm.nih.gov/sites/ GeneTests/
r Genetic Alliance: http://www.geneticalliance.org/
r Genetics education: http://www.geneticseducation nhs.uk/
r National Coalition for Health Professional Educa-tion in Genetics: http://www.nchpeg.org
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