Newborn, Carrier, and Early Childhood ScreeningRecommendations for Fragile X
abstractFragile X syndrome, diagnosed by Fragile X Mental Retardation 1(FMR1) DNA testing, is the most common single-gene cause ofinherited intellectual disability. The expanded CGG mutation in theFMR1 gene, once thought to have clinical significance limited to fragileX syndrome, is now well established as the cause for other fragileX–associated disorders including fragile X–associated primary ovar-ian insufficiency and fragile X–associated tremor ataxia syndrome inindividuals with the premutation (carriers). The importance of earlydiagnostic and management issues, in conjunction with the identifi-cation of family members at risk for or affected by FMR1 mutations,has led to intense discussion about the appropriate timing for earlyidentification of FMR1 mutations. This review includes an overview ofthe fragile X–associated disorders and screening efforts to date, anddiscussion of the advantages and barriers to FMR1 screening in new-borns, during childhood, and in women of reproductive age. Compar-ison with screening programs for other common genetic conditions isdiscussed to arrive at action steps to increase the identification offamilies affected by FMR1 mutations. Pediatrics 2012;130:1–10
AUTHORS: Liane Abrams, MS,a Amy Cronister, MS,b WilliamT. Brown, MD, PhD,c Flora Tassone, PhD,d Stephanie L.Sherman, PhD,e Brenda Finucane, MS,f Allyn McConkie-Rosell, MS, PhD,g Randi Hagerman, MD,h Walter E.Kaufmann, MD,i,j Jonathan Picker, MD,k Sarah Coffey, MPH,l
Robert Miller, BA,a and Elizabeth Berry-Kravis, MD, PhDo
aNational Fragile X Foundation, Walnut Creek, California;bIntegrated Genetics, Westborough, Massachusetts; cDepartmentof Human Genetics, New York State Office for People withDevelopmental Disabilities, Institute for Basic Research inDevelopmental Disabilities, Staten Island, New York; dDepartmentof Biochemistry and Molecular Medicine, hFragile X Research,MIND Institute, and lDepartment of Neurologic Surgery, UniversityCalifornia Davis Health System, University of California, Davis,Davis, California; eDepartment of Human Genetics, EmoryUniversity School of Medicine, Atlanta, Georgia; fGenetic ServicesInstitute, Elwyn, Pennsylvania; gDepartment of Pediatrics, DukeUniversity School of Medicine, Durham, North Carolina; iRettSyndrome Program, and kFragile X Program, Boston Children’sHospital, Boston, Massachusetts; jDepartment of Neurology,Harvard Medical School, Boston, Massachusetts; mFrank PorterGraham Child Development Institute, Department ofAnthropology, University North Carolina-Chapel Hill, Chapel Hill,North Carolina; nCollege of Nursing, University of OklahomaHealth Sciences Center, Oklahoma City, Oklahoma; andoDepartment of Pediatrics, Neurologic Sciences, andBiochemistry, Rush University Medical Center, Chicago, Illinois
ABBREVIATIONSACMG—American College of Medical GeneticsACOG—American Academy of Obstetrics and GynecologyCF—cystic fibrosisFMR1—Fragile X Mental Retardation 1FMRP—fragile X mental retardation proteinFXCRC—Fragile X Clinical and Research ConsortiumFXD—fragile X–associated disorderFXPOI—fragile X–associated primary ovarian insufficiencyFXS—fragile X syndromeFXTAS—fragile X–associated tremor ataxia syndromeID—intellectual disabilityNFXF—National Fragile X FoundationNBS—newborn screeningPCR—polymerase chain reaction
www.pediatrics.org/cgi/doi/10.1542/peds.2012-0693
doi:10.1542/peds.2012-0693
Accepted for publication Aug 28, 2012
Address correspondence to Liane Abrams, MS, CGC, NationalFragile X Foundation, 1615 Bonanza St, Suite 202, Walnut Creek,CA 94596. E-mail: [email protected]
(Continued on last page)
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Fragile X syndrome (FXS) is the mostcommon single-gene cause of inheritedintellectual disability (ID) and autism.1
Caused by a trinucleotide repeat ex-pansion in the 59 untranslated regionof the Fragile X Mental Retardation 1(FMR1) gene, accurate DNA testing iswidely available for the diagnosis ofFXS and identification of individualswith FMR1 mutations.
Present screening recommendationsprimarily focus on individuals affectedwith a developmental disorder or clin-ical features of the fragile X–associateddisorders (FXDs). This strategy fails todetect many FMR1 mutation carrierswithout symptoms and those with mildor subtle effects. Furthermore, efficacyof available (eg, intensive early in-tervention) and promising (eg, neuro-biologically targeted drug treatments)therapies would be enhanced by theirearliest initiation. The importance ofearly diagnosis and intervention, inconjunction with the identification ofother family members affected by or atrisk for FMR1mutations, has promptedan intense discussion about the ap-propriate timing for identification ofFXS and screening for FMR1 carriers.With widespread general populationscreening, earlier identification of af-fected individuals and at-risk carrierscan be accomplished.
BACKGROUND
In 1943, Martin and Bell91 reported thefirst family with the FXS phenotype.In 1985, Sherman and colleagues2,3
reported unusual patterns for anX-linked disorder in fragile X familieswhich included a greater risk for FXS insubsequent generations (anticipation),affected females and identification ofunaffected male carriers. In 1991, theFMR1 gene and the expanded CGGtrinucleotide repeat, which is respon-sible for FXS, were identified.4 Im-portantly, all individuals studies withthe full mutation have inherited the full
mutation from a female carrier of anFMR1 expansion; there are no “denovo” FMR1 full mutations.5
The length of the CGG repeat regionis highly polymorphic in the generalpopulation, ranging from6 to44CGGs.6–8
The FMR1 full mutation, seen in malesand females with fragile X syndrome,contains .199 CGG repeats, and isusually hypermethylated. This leads totranscriptional silencing of the FMR1gene and absence or reduction of frag-ile X mental retardation protein (FMRP),an important protein for neural de-velopment and plasticity.9–11 The pre-mutation allele, present in carriers,contains ∼55 to 199 repeats and doesnot typically exhibit methylation.12 In-termediate alleles range from 45 to 54CGG repeats, and are not thought tohave clinical implications other than thepotential to expand to a premutation infuture generations.13
The risk for expansion from the pre-mutation to the full mutation dependson the gender of the carrier parent andthe repeat size. Premutation allelestransmitted by carrier fathers to alltheirdaughtersremainrelativelystableand no report has confirmed an ex-pansion to a full mutation. Thus,daughters of male carriers are notthought to be at risk for FXS. All off-spring of women with a premutationor full mutation inherit the FMR1mutation 50% of the time; however,the risk of the premutation to expandto the full mutation increases linearlyby maternal repeat size ranging from∼4% to 5% in women with 55 to 69CGG repeats and gradually increasingto nearly 100% for repeat alleles of.99.14 A positive family history of FXSappears to influence risk for expan-sion.15 In addition, the role of in-terspersed AGG triplets within the CGGrepeat is being investigated, as longtracts of CGG repeats without in-terspersed AGG anchors appear to beat greater risk of expansion than those
alleles where AGG anchors have beenpreserved.16
The development of the Fmr1 knockoutmouse in 199417 led to the identificationof a role for FMRP in dendritic spinematuration and synaptic plasticity andits regulation by metabotropic gluta-mate receptor signaling.18,19 Bear andcolleagues developed the mGluR the-ory of fragile X in 2002,20 based on thefinding of exaggerated group 1 mGluR-dependent depression in the FMR1knockout mouse. This proposed mech-anism opened the way for potentialtargeted treatments, specifically mGluR5antagonists21,22 and g-aminobutyricacid-B agonists currently in clinicaltrials for FXS.23
It is now appreciated that the pre-mutation leads to a significant medicalburden that has been well described inpremutation carriers. Fragile X–asso-ciated primary ovarian insufficiency(FXPOI), seen in ∼20% of premutationfemale carriers, is the most commonknown single-gene cause of ovarianinsufficiency.24 Clinical involvement inpremutation carriers also includesfragile X–associated tremor ataxiasyndrome (FXTAS), which affects olderadults.25,26 Together, FXS, FXPOI, andFXTAS are known as FXDs.
FXDS: CLINICAL PHENOTYPES
FXS
FXS is characterized by a variable pat-tern of physical, behavioral, and cog-nitive features in male and femalepatients. Hallmark physical character-istics of FXS include postpubertalmacro-orchism, a long face, hyperextensiblejoints, and prominent ears.27–29 Physi-cal findings are often subtle in infantsand young children with FXS, particu-larly girls, and even at older ages, thephysical phenotype may not be readilyapparent. Therefore, the presence ofkey developmental and behavioralfeatures, such as poor eye contact,hand flapping, hand biting, attention
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deficits, anxiety, and social avoidance,should alert clinicians to the need forfragile X DNA testing, even in childrenwithout obvious physical findings.
Many infants with FXS present withhypotonia and mild to moderate motordelays that are usually noticeable by 9to 12 months.30–33 Expressive languagedelays are common and often the pri-mary reason for referral to early in-tervention services. Autism is presentin up to 30% of boys32,34,35 and 20% ofgirls with FXS.36 An additional 30% arediagnosed with an autism spectrumdisorder.35,37
Generally, all male patients with FXShave some degree of ID, ranging frommild to severe.38–40 Up to 5% of malepatients have IQs .70, typically attrib-utable to mosaicism (a mixture ofmethylated and unmethylated alleles),which results in production of FMRP ina fraction of cells.29 Approximately 30%of females with the FMR1 full mutationhave ID, and another 40% have signifi-cant learning and behavioral difficul-ties.41,42 Approximately 25% of femalepatients with the full mutation have IQsin the normal range (.85), but mayhave difficulty with executive functionand mental health issues.38,43 Womenwith mild or no apparent features ofFXS have been identified with a fullmutation after the birth of an affectedchild. Therefore, one cannot assumethat all unaffected mothers of affectedchildren have a premutation.
CLINICAL PHENOTYPESASSOCIATED WITH THE FMR1PREMUTATION
FXTAS
Characterized by progressive neuro-logic, cognitive, and psychiatric fea-tures, FXTAS is a neurodegenerativecondition associated with the FMR1premutation.44,45 Male patients aremore commonly affected than femalepatients, with typical onset after age50.25,46 Neurologically, the disorder is
characterized by intention tremor, cer-ebellar ataxia, autonomic dysfunction,peripheral neuropathy, parkinsonism,and cognitive decline.47 Psychiatricsymptoms are common, such as anxi-ety, depression, increased irritability,and impulsive behavior.48 The diagno-sis of FXTAS is based on the presenceof key clinical and/or radiologic find-ings in adults with a premutation.49
Approximately 46% of male patientsand 8% of female patients with theFMR1 premutation develop FXTAS symp-toms after age 50,50,51 although someindividuals may experience symptomsthat do not meet full clinical criteria forthe diagnosis of FXTAS.
FXPOI
At least 20% of women with an FMR1premutation experience FXPOI,24 a con-stellation of symptoms characterizedby diminished ovarian reserve leadingto irregular menses, elevated follicle-stimulating hormone levels, reducedfertility, and at the more severe end ofthe spectrum, premature ovarian fail-ure (cessation of menses before age40). The severity and age of onset ofFXPOI are correlated nonlinearly withpremutation size, with the risk in-creasing linearly in women with 60 to100 CGG repeats and then decreasingat premutation sizes from 100 to 200CGG repeats.52 In women with ovarianinsufficiency, the prevalence of theFMR1 premutation ranges from 2% to15%, depending on family history.24
FMR1 testing is recommended forwomen with infertility or ovarian in-sufficiency.53
MOLECULAR DIAGNOSIS OF FMR1MUTATIONS
Molecular diagnostic testing of theFMR1 mutation has historically beenconducted with genomic DNA, by usingboth Southern blot analysis and poly-merase chain reaction (PCR). Recent de-velopments have led to improvements
in the molecular testing for fragile X.Tassone et al54 developed a PCR-basedmethodology that uses a CGG repeatprimer able to detect expanded allelesthroughout the premutation and fullmutation ranges in both genders, andseveral other groups have reportedon the use of this approach.15,55–58 Anumber of laboratories now offer PCR-only testing for general screening oflow-risk populations, and it is likelythat a PCR-based technology will bethe primary testing method for FMR1expansion mutations in the near fu-ture. It is important to note that wholeexome sequencing, comparative geno-mic hybridization (CGH), and chromo-somemicroarrays do not identify FMR1mutations.
PREVALENCE OF FMR1 FULLMUTATIONS
FXS has been identified in every ethnicgroup studied, although no definitivestudy has been completed to assessmutation frequencies in the pan-ethnicpopulation of the United States. Generalpopulation-based studies suggest afull mutation prevalence of ∼1/4000 inwhite males.59 Seven newborn screen-ing (NBS) studies have been carriedout, including a recent study amonga racially diverse group of 36 124newborns from Georgia that identified1 in 5161 male newborns with the fullmutation (95% confidence interval of1/2500–1/10 653). There was no sig-nificant difference in prevalence esti-mates among the 3 major ethnic/racialgroups in the United States (white,African American, and Hispanic), al-though once stratification was done,numbers were small. NBS studiescompleted in other countries includea study of 5267 male newborns innorthwest Spain, which found a prev-alence of 1 of 2633 with a full muta-tion, although confidence limits werewide,60 and a study in Taiwan of 10 046male newborns that identified only 1
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newborn with the full mutation. Thislower frequency may reflect true pop-ulation differences or it may be a func-tion of sample size.
In South Carolina,61 families of 1459newborns were offered screening forFXS. Two full mutations and 2 pre-mutations were identified (1:730), arather high frequency, suggesting astatistical fluctuation owing to a smallsample size.
PREVALENCE OF FMR1PREMUTATION AND INTERMEDIATEALLELES
Broad-based general population studyprevalence figures for intermediateand premutation alleles vary signifi-cantly because of study design (eg,repeat range definition, small samplesize, various exclusion criteria, andrace/ethnicity). In unselected popula-tions, a large Canadian study reporteda premutation (defined as 55–199repeats) frequency of 1 in 259 in femaleindividuals.62 Cronister et al63 founda similar prevalence among women ofreproductive age with no family historysuggestive of FXS (1 in 257). This com-pares to 1 in 158 reported in a largeIsraeli study of women with no relevantfamily history,64 and suggests variationamong different ethnic/racial groups.
Studies of the premutation frequencyin male individuals are limited. A Ca-nadian study of 10 572 male individualsfound 1 in 813 with the premutation.65
A Spanish NBS study of 5267 maleblood spots reported a premutationfrequency of 1 in 251.60 A recent studyof a cohort of 6747 Wisconsin highschool graduates from 1957, primarilywhite, found a premutation prevalenceof 1 of 468 male individuals and 1 of151 female individuals.13,66
Studies of intermediate allele frequen-cy are difficult to compare because ofinclusion criteria. By using the currentdefinition of intermediate alleles of 45to 54 repeats,67 Brown et al68 identified
43 intermediate alleles (45–54) among2500 controls (1 in 58). Among 9538women with no family history of IDs,using the same allele range, Cronisteret al63 found 1 in 53 women were in-termediate allele carriers.
A collaborative NBS pilot study designed,in part, to assess full, premutation, andintermediate allele prevalence in thegeneral population in the United Statesis ongoing.69
POTENTIAL FOR GENERALPOPULATION SCREENING FORFMR1 PREMUTATIONS AND FULLMUTATIONS
Widespread population screeningprograms for FMR1 mutations couldbe established among 2 groups:preconception/pregnant women of re-productive age and newborns. Pre-natal and preconception settingswould primarily identify premutationcarriers. Screening for carriers wouldalert families to the possibility of hav-ing a child with FXS, allowing themprenatal testing and family planningoptions. In addition, screening thesegroups would alert carriers to theirrisk for FXPOI and potential fertilityproblems.
SCREENING IN THE OBSTETRICSETTING
Musci et al70 concluded that a pop-ulation-based FMR1 carrier screeningprogram is clinically desirable andcost-effective. Others have examinedfeasibility and decision-making by pre-mutation carriers. Four studies re-ported that women made changes inreproductive decisions as a result ofFMR1 testing. One study that screenedwomen with ovarian dysfunction foundthat most (15/20) reported it wouldhave been important for them to haveknown sooner that they were pre-mutation carriers.71 Furthermore, womenin the general population have been
quite positive about prenatal FMR1 test-ing and considered FXS a very seriouscondition with severe consequences fortheir children.72
Basedonsuccessfulprenatal screeningclinical trials in Israel, a recommenda-tion was made, from both a human andcost perspective, for consideration offull population screening. Currently,the American Academy of Obstetricsand Gynecology (ACOG) recommendsscreening for women with a positivefamily history of FXS or develop-mental disabilities, or elevated follicle-stimulating hormone levels of unknowncause, and considers general pop-ulation screening an option for in-terested women.
SCREENING IN THE NEWBORNPOPULATION
The average age of FXS diagnosis isstill quite delayed, averaging about 35to 37 months in boys and 41 monthsin girls, making the burden and the“diagnostic odyssey” encountered bythe families, overwhelming. A surveyof parents of children diagnosed withFXS found that 37.6% reported that theyunderwent more than 10 symptom-related visits to their health care pro-fessional before a diagnostic DNA testfor FXS was ordered; additionally,55.5% of the parents studied alreadyhad another child before the first childwas diagnosed.72
In 2005, the American College of Med-ical Genetics (ACMG) task force formedto evaluate and recommend condi-tions for inclusion in state newbornscreening panels, considered and re-jected FXS for universal NBS. This wasprimarily because of lack of medicaltreatment or data on the benefits ofearly intervention and absence ofa cost-effective screening test. Sincethat decision, advances have beenmade in both pharmacological andnonpharmacological treatment, devel-opment of cost-effective molecular
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tests for FMR1 mutations, and identifi-cation of other benefits to screeningfor FXS. In addressing presumptivebenefit, Bailey et al73 concluded thatexisting evidence is sufficient to sup-port NBS for conditions associatedwith ID.73 Van der Schuit et al74 foundthat children in an early interventiongroup showed greater progress thanthose in a control group on all mea-sures related to language develop-ment. Importantly, in 2006, Alexanderand Van Dyck92 challenged the dogmathat NBS applies only to conditionswitheffective treatments and broadenedthe concept to include benefits for thefamily, including reproductive decision-making, potential to participate in re-search or innovative therapies, andavoiding the diagnostic odyssey.75 Addi-tionally, the substantial progress in PCRtechnology has raised the possibility ofuniversal testing for FXS.
The arguments in favor of an FMR1 NBSprogram are based on the high preva-lence in the general population, accu-rate, quick and specific DNA testing, thehigh risk for recurrence and risk in ex-tended family members, the clinicalsignificance of FXS, opportunities forearlier intervention and participation inresearch, and the emotional and eco-nomic burden of the diagnostic odysseyfor families and, ultimately, society.
Concerns have been raised related toNBS and identification of premutationsthat are not fully expressed and aretypically late onset and fullmutations infemale individuals that may be in-completely penetrant. There are alsoconcerns related to the incidental de-tection of other genetic disorders, suchas sex chromosome abnormalities.76
Finally, in considering NBS for FXS, it isimportant to provide resources forgenetic counseling and early inter-vention programs to the families thatare identified.
The possibility of developing symptomsrelated to the premutation, particularly
FXTAS and FXPOI, must be explained tothe family and is an ethical issue.Screening tests that would identify onlythe fullmutationavoid thisdilemma,butlose the potential to identify the vastmajority of FMR1 mutation carrierswho define at-risk families.
Informing families of a positive FMR1screening result would likely fall on thechild’s pediatrician, genetic counselor,or other health professional. Access toessential information on FXS and FXDsmust be available for informing pe-diatricians and genetic counselors.Additional education, use of the Na-tional Fragile X Foundation (NFXF) Website, and consultation with FragileX Clinical and Research Consortium(FXCRC) specialists can provide pedia-tricians and genetic counselors withappropriate education and supportregarding FXDs. This has also provenfeasible for many disorders currentlyscreened using the ACTion (ACT) Sheetsdeveloped by the American College ofMedical Genetics.
FXS SCREENING OUTSIDE OF THEHEALTH CARE SYSTEM
Special educators; behavior, speech,and occupational specialists; and otherprofessionals have direct involvementwith children with ID over extendedperiods of time, allowing them to po-tentially recognize cognitive and be-havioral symptoms of FXS. Because oftheir frequent contact with families,they are in an excellent position toinitiate and follow-up on referralsmadeforgenetic evaluation.With involvementof educators and therapists, the uni-versally implemented Part C, specialeducation preschool program (age 3–5years) could be an important setting togenerate referrals for FXS screening.
IDENTIFIED POTENTIAL BARRIERSTO SCREENING
FXSchallengescurrent criteria forNBS.76
Social scientists and bioethicists
question whether identifying new-borns as having an “untreatable”condition could negatively affect theparent-child bond, and increase pa-rental anxiety. Because screening forFXS has the potential to raise issuesthat other NBS core conditions donot, including identifying individualsat risk for FXPOI and FXTAS, initially itcould be conducted voluntarily withinformed consent. All efforts wouldneed to be made to ensure that aconsent process would not tax hos-pital staff, overwhelm parents, orreduce participation in the standardNBS program. NBS for FXS would alsoincrease the need for genetic coun-seling, early intervention, and familysupport programs. These and otherissues are currently being exploredin a pilot research study of NBS forFXS.77
In a recent survey of genetic health careprofessionals’ (medical geneticistsand genetic counselors) attitudes re-garding FXS screening, most the re-spondents were in favor of newbornand prenatal screening.78 The mostcommonly endorsed time for screen-ing was for women before pregnancy.An important component in FMR1population screening is the time re-quired for genetic counseling becauseof the multigenerational mutationalprocess and the variable phenotypesassociated with each genotype.79 Afurther issue is the relative frequencyof, and limited knowledge regarding,the implications of an intermediate-size allele, that if reported as abnor-mal, may lead to increased anxiety ina significant number of individualsbeing screened. Genetic counselingstrategies and educational informationhave been developed and are availablefor families and professionals (www.fragilex.org).80
There are also socioeconomic barriersto population screening that need to beidentified and addressed. Research is
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limited on the interrelated role thatcultural, racial, educational, and othersocioeconomic factors play in the ac-cess and availability of genetic testing.However, some prior studies addressfactors that affect access to geneticservices. In a study exploring access togenetic counseling services for chil-dren with IDs, including autism andDown syndrome, investigators foundthat the single most important vari-able determining referral was to havea consistent medical provider as wellas having the child covered by eitherprivate or public insurance.81 Accesswas also influenced by how parentsperceived the severity of the disorder.Access issues related to socioeco-nomic factors would be predicted topotentially delay the diagnosis of FXSeven longer in medically underservedpopulations.
Studies of other genetic disorders canhelp with identification of barriers toFMR1 testing. Such studies have sug-gested that the level of genetics liter-acy, trust in medical providers, andtailored culturally sensitive recruit-ment strategies are major factors inAfrican American and other racial/ethnic minorities’ decisions to par-ticipate in genetics research and clin-ical testing.82 Additionally, Johnsonet al83 found that like-ancestry of theparticipant-researcher/recruiter is keyto successful recruitment and reten-tion of racial/ethnic minorities in ge-netics research. Genetic counselingeducational materials that are cultur-ally sensitive need to be developed, asthese materials have been shown toreduce concerns about genetic test-ing (Barlow-Stewart, Yeo et al 2006;Baty, Dudley et al 2006; Charles, Kessleret al 2006).93–95 In line with many otherhuman services organizations, the Cen-ters for Disease Control and Prevention,March of Dimes, and NFXF have recog-nized this need and have initiated theprocess of incorporating culturally
sensitive photographs and other rep-resentations in their educationalmaterials.
For population-based screening pro-grams to be successful, it will be criti-cally important to address potentialbarriers and to focus on developing,implementing, and assessing geneticcounseling, educational, and thera-peutic interventions. This researchshould partner with families and otherstakeholders, such as the NFXF to helpinform best practices.
COMPARISONS WITH OTHER NBSPROGRAMS OF GENETICDISORDERS
Given the high carrier frequency ofFMR1 premutations, resulting FXDsare among the most common geneticconditions. Comparisonwith population-screening programs for other commongenetic conditions is informative andcan help initiate the discussion ofwidespread screening. Cystic fibrosis(CF), an autosomal recessive condition,with a carrier rate of 1 of 31 Cauca-sians, and a prevalence rate of 1 of3000 births, has recently been includedin newborn and prenatal screening.Years of debate preceded the intro-duction of routine CF carrier testing inprenatal care because of concerns re-garding the complexity of CFmutations,the need for education of medicalprofessionals, and the difficulty of de-fining the disease phenotype.84 In2001, however, both ACOG and ACMGrecommended that all pregnant womenbe offered CF carrier screening, withsubsequent carrier testing for part-ners on identification of a carrier.Additionally, CF is now included in themandatory NBS panel in all 50 states.85
The road to universal screening for CFfollowed a path that included strongadvocacy by the CF Foundation, theadvent of testing by inexpensive PCR-based DNA technologies, evidence ofthe benefit of early diagnosis, and
support for carrier screening frompatients and the obstetrics commu-nity.86
Similarities between FXSandCF includethe delay of diagnosis, often after thebirth of a second, affected child; vari-able phenotype in carriers (men withcongenital absenceof thevasdeferenceare often CF carriers); accurate, avail-able PCR-based DNA testing; and highcarrier rate and genetic risks to ex-tended family members.
SUGGESTIONS/PROPOSALS FORALLEVIATING BARRIERS TO EARLYIDENTIFICATION
Evaluation of screening for FMR1mutations at any level must weigh thecosts and benefits of early identifica-tion of FMR1 mutations. Some obviousbenefits include the following: oppor-tunities for enhancement of de-velopment and adaptive functioningthrough early intervention and in-tensive therapy programs, eliminationof the “diagnostic odyssey” for thefamily searching for the cause of theirchild’s difficulties, opportunities toparticipate or benefit from clinical tri-als of promising new treatments, abil-ity to provide genetic counselingregarding risk for future pregnanciesin the immediate and extended family,and identification of other familymembers with undiagnosed FXDs whocould benefit from diagnosis-basedmanagement.
NEWBORN SCREENINGADVANTAGES
Parent studies indicate that mostparents are in favor of NBS for “less-treatable” conditions, the categoryunder which FXS would fall at this time.Although therapeutic interventionsare not a “cure,” they do stimulate de-velopment and address delays anddisabilities early on to maximize thepotential of the therapy and the
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individual. In a recent study of 2045parents’decision to participate in a pi-lot newborn FMR1 gene screeningproject, most parents accepted thescreening for reasons including “want-ing to know,” “benefiting research/social responsibility,” and “minimalrisk.”77 If development efforts for newFXS targeted therapeutics, includingmGluR5 antagonists, g-aminobutyricacid agonists,87 and other medicationspresently being investigated in clinicaltrials are successful, more effectivetreatment is potentially available. Withthe formation of the FXCRC, an infra-structure now exists to help coordinateclinical trials as well as medical treat-ment in the future. The recent de-velopment of rapid and inexpensivePCR technologies will further supportthe feasibility and implementation ofmass NBS for FXS. Identified familieswill have the opportunity to take part inclinical trials, research studies, andgenetic counseling, and will have theadvantage of entering into early in-tervention before symptoms arise.
PRECONCEPTION/PRENATALSCREENING ADVANTAGES
In a recent study of FXS caregivers, 83%agreed or strongly agreed that pre-conception and/or prenatal screeningshould be offered at all times.88 Pre-natal or preconception screening forFMR1 mutations has been availablethrough commercial laboratories ser-vicing the obstetrics community and isoffered on a voluntary basis to patientsin select obstetrics practices that rou-tinely offer it as part of geneticscreening. Although the ACMG andACOG do not have a policy statementregarding “low-risk” general pop-ulation screening, this is occurring invarious socioeconomic, educational,and geographic populations that in-vestigate (and request) genetic testing.At this point, as more carriers areidentified in large USmetropolitan areas
with higher income and educated pop-ulations, this is creating a stratifiedclass system of carrier testing for FMR1gene mutations. Offering all pregnantand pre-pregnant women FMR1 screen-ing would alleviate this imbalance. Afurther advantage to preconception orprenatal screening is to assist in theidentification of women with possibleovarian insufficiency. The latter is ofimportance because expensive fertilitytreatments are often undertaken byunknowing premutation carriers.
ADVANTAGES OF EARLY CHILDHOODSCREENING
In the absence of widespread prenatalscreening or NBS, every attempt shouldbemade to lower theageof diagnosis inaffected children. In this regard, thewell-child visits are a preferred settingtoevaluateearlydevelopmentandscreenfor common etiologies of developmental,speechorbehavioraldisorders.Basedonthe American Academy of Pediatricsrecommendations for developmentalevaluations at 9, 18, and 30 months,a thorough screening should be done toinclude gross motor, fine motor, social,cognitive, and language development.Clinical models for genetic screeningoutside of the newborn period havebeen suggested, primarily in the con-text of informed consent, counseling,and well-child care.89 At this time,however, mass screening for geneticconditions outside of the newborn orprenatal period does not exist, so weare forced to rely on clinical pre-sentations of symptoms to initiatechildhood testing.
In line with the American Academy ofPediatrics fragile X health supervisionguidelines,90 which recommend FMR1testing in any child with developmentaldelay, our recommendation would bethat all children with delays bescreened for FMR1 mutations as soonas delays are identified. This wouldlower the age of identification of FXS
while the issues regarding univer-sal screening (prenatal/preconceptionscreening, and NBS) are being workedthrough. One should be aware that thismethod of screening is likely to missmany affected girls and some mildlyaffected boys. On the other hand,if FMR1 screening was to be offeredfor all children, regardless of de-velopmental status, the period forearly intervention and/or familyplanning that is optimized by NBS mayhave passed by the time young chil-dren are identified.
CONCLUSION ANDRECOMMENDATIONS
To more accurately quantify and beginto ameliorate the significant publichealth burden of FMR1 mutations, wepropose the goals of increasing theidentification of families affected byFMR1 mutations and of lowering theage of identification of children withFXS. Toward that end, we propose thefollowing action steps:
1. Support and continue the pilot NBSstudies that are under way withthe goal of identifying the fullrange of costs and benefits ofNBS for FMR1 mutations.
2. Encourage the American Society ofReproductive Medicine and ACOGto address/endorse the offeringof general population FMR1 screen-ing to all preconception or prenatalpatients, regardless of family his-tory.
3. Recommend that pediatricians or-der FMR1 DNA testing for childrenwith developmental delays at theoffice visit when the delays areidentified. Pediatricians may chooseto have consultation with a medicalgeneticist or clinical staff at 1 of theFXCRC fragile X clinics (www.fragilex.org) if they have questions.
4. Increase education and awarenessof FXD in nonmedical professionals
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through use of the Part C establishednetworks providing services to chil-dren with developmental delays.
5. Increase education for health andeducation professionals serving un-derserved populations about FXDs,
by using publicly funded health andeducation agencies.
6. Use the existing FXCRC infrastruc-ture to promote greater out-reach to underserved populationswithin 100 miles of each clinic,
based on efforts that have de-monstrated success in reaching his-torically underserved populations.
7. Support additional studies todetermine/establish the true prev-alence of FMR1 mutations.
REFERENCES
1. Belmonte MK, Bourgeron T. Fragile X syn-drome and autism at the intersection ofgenetic and neural networks. Nat Neurosci.2006;9(10):1221–1225
2. Sherman SL, Morton NE, Jacobs PA, TurnerG. The marker (X) syndrome: a cytogeneticand genetic analysis. Ann Hum Genet. 1984;48(pt 1):21–37
3. Sherman SL, Jacobs PA, Morton NE, et al.Further segregation analysis of the fragileX syndrome with special reference totransmitting males. Hum Genet. 1985;69(4):289–299
4. Verkerk AJ, Pieretti M, Sutcliffe JS, et al.Identification of a gene (FMR-1) containinga CGG repeat coincident with a breakpointcluster region exhibiting length variation infragile X syndrome. Cell. 1991;65(5):905–914
5. Smits AP, Dreesen JC, Post JG, et al. Thefragile X syndrome: no evidence for anyrecent mutations. J Med Genet. 1993;30(2):94–96
6. Fu YH, Kuhl DP, Pizzuti A, et al. Variation ofthe CGG repeat at the fragile X site resultsin genetic instability: resolution of theSherman paradox. Cell. 1991;67(6):1047–1058
7. Brown WT, Houck GE Jr, Jeziorowska A,et al. Rapid fragile X carrier screening andprenatal diagnosis using a nonradioactivePCR test. JAMA. 1993;270(13):1569–1575
8. Snow K, Doud LK, Hagerman R, PergolizziRG, Erster SH, Thibodeau SN. Analysis ofa CGG sequence at the FMR-1 locus infragile X families and in the general pop-ulation. Am J Hum Genet. 1993;53(6):1217–1228
9. Bassell GJ, Warren ST. Fragile X syndrome:loss of local mRNA regulation alters syn-aptic development and function. Neuron.2008;60(2):201–214
10. Waung MW, Huber KM. Protein translationin synaptic plasticity: mGluR-LTD, Fragile X.Curr Opin Neurobiol. 2009;19(3):319–326
11. Zukin RS, Richter JD, Bagni C. Signals,synapses, and synthesis: how new proteinscontrol plasticity. Front Neural Circuits.2009;3:14
12. Maddalena A, Richards CS, McGinniss MJ,et al; Quality Assurance Subcommittee ofthe Laboratory Practice Committee. Tech-nical standards and guidelines for fragileX: the first of a series of disease-specificsupplements to the Standards and Guide-lines for Clinical Genetics Laboratories ofthe American College of Medical Genetics.Genet Med. 2001;3(3):200–205
13. Finucane B, Abrams L, Cronister A, ArchibaldAD, Bennett RL, McConkie-Rosell A. GeneticCounseling and Testing for FMR1 GeneMutations: Practice Guidelines of the Na-tional Society of Genetic Counselors [pub-lished online ahead of print July 14, 2012].J Genet Couns. doi. 1007/s 10897-012-9524-8
14. Nolin SL, Brown WT, Glicksman A, et al. Ex-pansion of the fragile X CGG repeat infemales with premutation or intermediatealleles. Am J Hum Genet. 2003;72(2):454–464
15. Nolin SL, Glicksman A, Ding X, et al. FragileX analysis of 1112 prenatal samples from1991 to 2010. Prenat Diagn. 2011;31(10):925–931
16. Yrigollen CM, Durbin-Johnson B, et al. Therole of AGG interruptions in the FMR1 CGGrepeat during transmission in a clinicalsample. Paper presented at: 12th In-ternational Congress of Human Genetics/61st Annual Meeting of the American So-ciety of Human Genetics; October, 13, 2011;Montreal, Canada
17. The Dutch-Belgian Fragile X Consortium.Fmr1 knockout mice: a model to studyfragile X mental retardation. Cell. 1994;78(1):23–33
18. Comery TA, Harris JB, Willems PJ, et al.Abnormal dendritic spines in fragile Xknockout mice: maturation and pruningdeficits. Proc Natl Acad Sci U S A. 1997;94(10):5401–5404
19. Irwin SA, Galvez R, Greenough WT. Dendriticspine structural anomalies in fragile-Xmental retardation syndrome. Cereb Cor-tex. 2000;10(10):1038–1044
20. Bear MF, Huber KM, Warren ST. The mGluRtheory of fragile X mental retardation.Trends Neurosci. 2004;27(7):370–377
21. Yan QJ, Rammal M, Tranfaglia M, BauchwitzRP. Suppression of two major Fragile XSyndrome mouse model phenotypes by themGluR5 antagonist MPEP. Neuropharma-cology. 2005;49(7):1053–1066
22. de Vrij FM, Levenga J, van der Linde HC,et al. Rescue of behavioral phenotype andneuronal protrusion morphology in Fmr1KO mice. Neurobiol Dis. 2008;31(1):127–132
23. Berry-Kravis E, Knox A, Hervey C. Targetedtreatments for fragile X syndrome. J Neu-rodev Disord. 2011;3(3):193–210
24. Sherman SL. Premature ovarian failureamong fragile X premutation carriers:parent-of-origin effect? Am J Hum Genet.2000;67(1):11–13
25. Hagerman RJ, Leehey M, Heinrichs W, et al.Intention tremor, parkinsonism, and gen-eralized brain atrophy in male carriers offragile X. Neurology. 2001;57(1):127–130
26. Jacquemont S, Hagerman RJ, Leehey M,et al. Fragile X premutation tremor/ataxiasyndrome: molecular, clinical, and neuro-imaging correlates. Am J Hum Genet. 2003;72(4):869–878
27. Merenstein SA, Sobesky WE, Taylor AK,Riddle JE, Tran HX, Hagerman RJ.Molecular-clinical correlations in maleswith an expanded FMR1 mutation. Am JMed Genet. 1996;64(2):388–394
28. Hagerman RJ. Physical and behavioral phe-notype. In: Hagerman RJ, Hagerman PJ, eds.Fragile X Syndrome: Diagnosis, Treatmentand Research. 3rd ed. Baltimore, MD: TheJohns Hopkins University Press; 2002:3–109
29. Loesch DZ, Huggins RM, Hagerman RJ.Phenotypic variation and FMRP levels infragile X. Ment Retard Dev Disabil Res Rev.2004;10(1):31–41
30. Mirrett PL, Bailey DB Jr, Roberts JE, HattonDD. Developmental screening and detectionof developmental delays in infants andtoddlers with fragile X syndrome. J DevBehav Pediatr. 2004;25(1):21–27
31. Baranek GT, Roberts JE, David FJ, et al.Developmental trajectories and correlatesof sensory processing in young boys withfragile X syndrome. Phys Occup TherPediatr. 2008;28(1):79–98
8 ABRAMS et al at Asoc Espanola De Pediatria on November 8, 2012pediatrics.aappublications.orgDownloaded from
32. Roberts JE, Mankowski JB, Sideris J, et al.Trajectories and predictors of the de-velopment of very young boys with fragile Xsyndrome. J Pediatr Psychol. 2009;34(8):827–836
33. Zingerevich C, Greiss-Hess L, Lemons-Chitwood K, et al. Motor abilities of chil-dren diagnosed with fragile X syndromewith and without autism. J Intellect DisabilRes. 2009;53(1):11–18
34. Kaufmann WE, Cortell R, Kau AS, et al. Au-tism spectrum disorder in fragile X syn-drome: communication, social interaction,and specific behaviors. Am J Med Genet A.2004;129A(3):225–234
35. Harris SW, Hessl D, Goodlin-Jones B, et al.Autism profiles of males with fragile Xsyndrome. Am J Ment Retard. 2008;113(6):427–438
36. Clifford S, Dissanayake C, Bui QM, HugginsR, Taylor AK, Loesch DZ. Autism spectrumphenotype in males and females withfragile X full mutation and premutation. JAutism Dev Disord. 2007;37(4):738–747
37. Hall SS, Lightbody AA, Reiss AL. Compulsive,self-injurious, and autistic behavior inchildren and adolescents with fragile Xsyndrome. Am J Ment Retard. 2008;113(1):44–53
39. Hall SS, Burns DD, Lightbody AA, Reiss AL.Longitudinal changes in intellectual de-velopment in children with Fragile X syn-drome. J Abnorm Child Psychol. 2008;36(6):927–939
40. Hessl D, Nguyen DV, Green C, et al. A solu-tion to limitations of cognitive testing inchildren with intellectual disabilities: thecase of fragile X syndrome. J NeurodevDisord. 2009;1(1):33–45
41. de Vries BB, Wiegers AM, Smits AP, et al.Mental status of females with an FMR1gene full mutation. Am J Hum Genet. 1996;58(5):1025–1032
42. Hatton DD, Wheeler A, Sideris J, et al. De-velopmental trajectories of young girls withfragile x syndrome. Am J Intellect Dev Disabil.2009;114(3):161–171
43. Cordeiro L, Ballinger E, Hagerman R, HesslD. Clinical assessment of DSM-IV anxietydisorders in fragile X syndrome: preva-lence and characterization. J NeurodevDisord. 2011;3(1):57–67
44. Hagerman PJ, Hagerman RJ. The fragile-Xpremutation: a maturing perspective. Am JHum Genet. 2004;74(5):805–816
45. Tassone F, Berry-Kravis E. The Fragile X-Associated Tremor Ataxia Syndrome(FXTAS). New York: Springer; 2011
47. Seritan AL, Nguyen DV, Farias ST, et al. De-mentia in fragile X-associated tremor/ataxiasyndrome (FXTAS): comparison with Alz-heimer’s disease. Am J Med Genet B Neuro-psychiatr Genet. 2008;147B(7):1138–1144
48. Bourgeois JA, Coffey SM, Rivera SM, et al. Areview of fragile X premutation disorders:expanding the psychiatric perspective.J Clin Psychiatry. 2009;70(6):852–862
49. Jacquemont S, Farzin F, Hall D, et al. Agingin individuals with the FMR1 mutation. Am JMent Retard. 2004;109(2):154–164
50. Jacquemont S, Hagerman RJ, Leehey MA,et al. Penetrance of the fragile X-associatedtremor/ataxia syndrome in a premutationcarrier population. JAMA. 2004;291(4):460–469
51. Coffey SM, Cook K, Tartaglia N, et al. Ex-panded clinical phenotype of women withthe FMR1 premutation. Am J Med Genet A.2008;146A(8):1009–1016
52. Allen EG, Sullivan AK, Marcus M, et al. Ex-amination of reproductive aging mile-stones among women who carry the FMR1premutation. Hum Reprod. 2007;22(8):2142–2152
53. Sherman S, Pletcher BA, Driscoll DA. FragileX syndrome: diagnostic and carrier testing.Genet Med. 2005;7(8):584–587
54. Tassone F, Pan R, Amiri K, Taylor AK,Hagerman PJ. A rapid polymerase chainreaction-based screening method foridentification of all expanded alleles of thefragile X (FMR1) gene in newborn and high-risk populations. J Mol Diagn. 2008;10(1):43–49
55. Filipovic-Sadic S, Sah S, Chen L, et al. Anovel FMR1 PCR method for the routinedetection of low abundance expandedalleles and full mutations in fragile X syn-drome. Clin Chem. 2010;56(3):399–408
56. Hantash FM, Goos DG, Tsao D, et al. Quali-tative assessment of FMR1 (CGG)n tripletrepeat status in normal, intermediate,premutation, full mutation, and mosaiccarriers in both sexes: implications forfragile X syndrome carrier and newbornscreening. Genet Med. 2010;12(3):162–173
57. Lyon E, Laver T, Yu P, et al. A simple, high-throughput assay for Fragile X expandedalleles using triple repeat primed PCR andcapillary electrophoresis. J Mol Diagn.2010;12(4):505–511
58. Chen L, Hadd AG, Sah S, et al. High-resolution methylation polymerase chainreaction for fragile X analysis: evidence fornovel FMR1 methylation patterns un-detected in Southern blot analyses. GenetMed. 2011;13(6):528–538
59. Crawford DC, Acuña JM, Sherman SL. FMR1and the fragile X syndrome: human genomeepidemiology review. Genet Med. 2001;3(5):359–371
60. Fernandez-Carvajal I, Walichiewicz P, XiaosenX, Pan R, Hagerman PJ, Tassone F. Screeningfor expanded alleles of the FMR1 gene inblood spots from newborn males in a Span-ish population. J Mol Diagn. 2009;11(4):324–329
61. Saul RA, Friez M, Eaves K, et al. Fragile Xsyndrome detection in newborns-pilotstudy. Genet Med. 2008;10(10):714–719
62. Rousseau F, Rouillard P, Morel ML, KhandjianEW, Morgan K. Prevalence of carriers ofpremutation-size alleles of the FMRI gene—and implications for the population geneticsof the fragile X syndrome. Am J Hum Genet.1995;57(5):1006–1018
63. Cronister A, Teicher J, Rohlfs EM, DonnenfeldA, Hallam S. Prevalence and instability offragile X alleles: implications for offeringfragile X prenatal diagnosis. Obstet Gynecol.2008;111(3):596–601
64. Berkenstadt M, Ries-Levavi L, Cuckle H,Peleg L, Barkai G. Preconceptional andprenatal screening for fragile X syndrome:experience with 40,000 tests. Prenat Diagn.2007;27(11):991–994
65. Dombrowski C, Lévesque S, Morel ML,Rouillard P, Morgan K, Rousseau F. Pre-mutation and intermediate-size FMR1alleles in 10572 males from the generalpopulation: loss of an AGG interruption isa late event in the generation of fragile Xsyndrome alleles. Hum Mol Genet. 2002;11(4):371–378
66. Seltzer MM, Baker MW, Hong J, Maenner M,Greenberg J, Mandel D. Prevalence of CGGexpansions of the FMR1 gene in a USpopulation-based sample. Am J Med GenetB Neuropsychiatr Genet. 2012;159B(5):589–597
67. Kronquist KE, Sherman SL, Spector EB.Clinical significance of tri-nucleotiderepeats in Fragile X testing: a clarificationof American College of Medical Geneticsguidelines. Genet Med. 2008;10(11):845–847
68. Brown WT, Nolin S, Houck G Jr, et al. Prenataldiagnosis and carrier screening for fragile Xby PCR. Am J Med Genet. 1996;64(1):191–195
69. Long KP, Tong T, Gane L, et al. Newbornscreening in fragile X syndrome: preva-lence and allele distribution of the FMR1gene. Paper presented at: American College
STATE-OF-THE-ART REVIEW ARTICLE
PEDIATRICS Volume 130, Number 6, December 2012 9 at Asoc Espanola De Pediatria on November 8, 2012pediatrics.aappublications.orgDownloaded from
of Medical Genetics Annual Clinical Genet-ics Meeting; March 16–20, 2011; Vancouver,Canada.
70. Musci TJ, Caughey AB. Cost-effectivenessanalysis of prenatal population-basedfragile X carrier screening. Am J ObstetGynecol. 2005;192(6):1905–1912; discussion1912–1915
71. Pastore LM, Morris WL, Karns LB. Emotionalreaction to fragile X premutation carriertests among infertile women. J GenetCouns. 2008;17(1):84–91
72. Bailey DB Jr, Skinner D, Sparkman KL. Dis-covering fragile X syndrome: family expe-riences and perceptions. Pediatrics. 2003;111(2):407–416
73. Bailey DB Jr, Skinner D, Warren SF. New-born screening for developmental dis-abilities: reframing presumptive benefit.Am J Public Health. 2005;95(11):1889–1893
74. van der Schuit M, Segers E, van Balkom H,Verhoeven L. Early language interventionfor children with intellectual disabilities:a neurocognitive perspective. Res Dev Dis-abil. 2011;32(2):705–712
75. Alexander D. Medicaid reform: an oppor-tunity to focus on the real challenges forchildren. Pediatrics. 2006;117(3):949–950
76. Bailey DB Jr, Skinner D, Davis AM,Whitmarsh I, Powell C. Ethical, legal, andsocial concerns about expanded newbornscreening: fragile X syndrome as a pro-totype for emerging issues. Pediatrics.2008;121(3). Available at: www.pediatrics.org/cgi/content/full/121/3/e693
77. Skinner D, Choudhury S, Sideris J, et al.Parents’ decisions to screen newborns forFMR1 gene expansions in a pilot researchproject. Pediatrics. 2011;127(6). Available at:
www.pediatrics.org/cgi/content/full/127/6/e1455
78. Acharya K, Ross LF. Fragile X screening:attitudes of genetic health professionals.Am J Med Genet A. 2009;149A(4):626–632
79. Musci TJ, Moyer K. Prenatal carrier testingfor fragile X: counseling issues and chal-lenges. Obstet Gynecol Clin North Am. 2010;37(1):61–70
80. McConkie-Rosell A, Abrams L, Finucane B,et al. Recommendations from multi-disciplinary focus groups on cascade test-ing and genetic counseling for fragileX-associated disorders. J Genet Couns.2007;16(5):593–606
81. McGrath RJ, Laflamme DJ, Schwartz AP,Stransky M, Moeschler JB. Access to geneticcounseling for children with autism, Downsyndrome, and intellectual disabilities. Pe-diatrics. 2009;124(suppl 4):S443–S449
82. Rajakumar K, Thomas SB, Musa D, Almario D,Garza MA. Racial differences in parents’ dis-trust of medicine and research. Arch PediatrAdolesc Med. 2009;163(2):108–114
83. Johnson VA, Powell-Young YM, Torres ER,et al. A systematic review of strategies thatincrease the recruitment and retention ofAfrican American adults in genetic and ge-nomic studies. Association of Black NursingFaculty Journal. 2011;Winter 22(4):84–88
84. Dungan JS. Carrier screening for cystic fi-brosis. Obstet Gynecol Clin North Am. 2010;37(1):47–59 [Table of Contents.]
85. Sanak M. [Newborn screening for cysticfibrosis, a clinical geneticist perspective].Przegl Lek. 2011;68(1):14–16
86. Petros M. Revisiting the Wilson-Jungnercriteria: How can supplemental criteriaguide public health in the era of genetic
screening? Genet Med. 2012;14(1):129–134
87. Wang LW, Berry-Kravis E, Hagerman RJ.Fragile X: leading the way for targetedtreatments in autism. Neurotherapeutics.2010;7(3):264–274
88. Bailey DB Jr, Bishop E, Raspa M, Skinner D.Caregiver opinions about fragile X pop-ulation screening. Genet Med. 2012;14(1):115–121
89. Botkin JR. Newborn screening for fragile xsyndrome: do we care what parents think?Pediatrics. 2011;127(6). Available at: www.pediatrics.org/cgi/content/full/126/6/e1593
90. Hersh JH, Saul RA; Committee on Genetics.Health supervision for children with fragileX syndrome. Pediatrics. 2011;127(5):994–1006
91. Martin JP, Bell J. A pedigree of mental de-fect showing sex-linkage. J Neurol Psychiat.1943;6(3–4):154–157
92. Alexander D, van Dyck PC. A vision of thefuture of newborn screening. Pediatrics.2006;117(Supp 3): S350–S354
93. Barlow-Stewart K, Yeo SS, Meiser B, GoldsteinD, Tucker K, Eisenbruch M. Towards culturalcompetence in cancer genetic counselingand genetics education: lessons learnt fromChinese-Australians. Genetics in Medicine.2006;8:24–32
94. Baty BJ, Dudley WN, Musters A, Kinney AY.Uncertainty in BRCA1 cancer susceptibilitytesting. Am J Med Genet Part C Semin MedGenet. 2006;142C:241–250
95. Charles S, Kessler L, Stopfer J. Satisfactionwith genetic counseling for BRCA1 andBRCA2 mutations among African AmericanWomen. Patient Educ Couns. 2006;63(1):196–204
FINANCIAL DISCLOSURE: Dr Hagerman has received funding to carry out clinical trials in fragile X syndrome or autism from Novartis, Roche, SeasideTherapeutics, Curemark, and Forest, and is on the Advisory Committee for fragile X treatment with Novartis. Dr Picker is on a Novartis-funded clinical trial and isa member of the Roche DSM committee for their fragile X trial. Ms Cronister is employed by LabCorp and holds stocks in LabCorp. Integrated Genetics is part ofLabCorp. These institutions provide genetic testing and genetic counseling services. The other authors have indicated they have no financial relationships relevantto this article to disclose.
FUNDING: This article was supported by Cooperative Agreement U01DD000231 from the Centers for Disease Control and Prevention to the Association of UniversityCenters on Disabilities and RTOI 2008-999-03 from Association of University Centers on Disabilities to W.T. Brown in support of the National Fragile X Clinical andResearch Consortium.
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DOI: 10.1542/peds.2012-0693; originally published online November 5, 2012;Pediatrics
Miller and Elizabeth Berry-KravisKaufmann, Jonathan Picker, Sarah Coffey, Debra Skinner, Vanessa Johnson, Robert
Sherman, Brenda Finucane, Allyn McConkie-Rosell, Randi Hagerman, Walter E. Liane Abrams, Amy Cronister, William T. Brown, Flora Tassone, Stephanie L.
XNewborn, Carrier, and Early Childhood Screening Recommendations for Fragile
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