8
Genetic Evaluation of Intellectual Disabilities John B. Moeschler, MD, MS All children with an intellectual disability (mental retardation) or global developmental delay should have a comprehensive evaluation to establish the etiology of the disability. A specific etiologic diagnosis offers the opportunity to discuss treatment, prognosis, and genetic recurrence risk. A diagnosis also avoids unnecessary testing and can lead to opportunities for improved health and functional outcomes. The key elements of the diagnostic evaluation are the medical and developmental history, 3-generation family history, dysmorphologic examination, neurologic examination, and judicious use of the laboratory and neuroimaging. All published guidelines for the evaluation of children with intellectual disability acknowledge that there is a substantial percentage of patients who are undiagnosed after a comprehensive evaluation and who deserve ongoing follow-up for the purpose of establishing a diagnosis. Recently, studies of the clinical application of array comparative genomic hybridization (aCGH) to individuals with intellectual disability indi- cate that this approach provides a diagnosis in as much as 10% of patients and that this technique is replacing the use of fluorescent in situ hybridization for subtelomere imbal- ances now used for such patients when the standard karyotype is normal. The literature suggests that history and examination by an expert clinician will lead to a diagnosis in 2 of 3 patients in whom a diagnosis is made. Laboratory studies alone, including neuroimaging, provide a diagnosis in the remaining one third. The approach to the evaluation of the patient in whom an etiologic diagnosis is not suspected after the history and physical examinations includes a standard karyotype, Fragile X molecular genetic testing, aCGH, and neuroim- aging, based on the evidence to date. One can expect rapid changes in the microarray technology in the near future. Semin Pediatr Neurol 15:2-9 © 2008 Elsevier Inc. All rights reserved. T he child with mental retardation (or “intellectual disabil- ity”) is deserving of the best diagnostic evaluation avail- able for the specific aim of improving the health and well- being of that individual and his/her family. Shevell 1 indicated that the “etiologic diagnosis in the young child has immediate implications with respect to recurrence risks and therapeutic imperatives, possessing the potential to modify management and expected outcomes” and that “future medical challenges and the actual prognosis for the disabled child can be more accurately addressed” in a child with a known diagnosis. The family of a child with global developmental delays or an intellectual disability often experiences the feeling of a loss of control. 2 An etiologic diagnosis can contribute to the family feeling in control once more: “As physicians we have experi- ence with other children who have the same disorder, access to management programs, knowledge of the prognosis, awareness of research on understanding the disease and many other elements that when shared with the parents will give them a feeling that some control is possible.” 3 In addi- tion, a specific etiologic diagnosis will make social support and information more accessible for families and profession- als than for those without a specific diagnosis. For many diagnoses, specific management guidelines are now avail- able. 4 For primary care providers and families, there are spe- cific benefits to establishing an etiologic diagnosis including clarification of etiology, prognosis, genetic mechanism(s), re- currence risks, and treatment options; avoidance of unneces- sary tests; information regarding management or surveillance and family support; access to research and treatment proto- cols; and the opportunity for comanagement of appropriate patients in the context of a medical home to ensure the best health and social outcomes for the child. The type of developmental delay identified is an important preliminary step because typing influences the path of inves- tigation later undertaken. Global developmental delay is defined as a significant delay in 2 or more developmental domains in- cluding gross or fine motor, speech/language, cognitive, social/ personal, and activities of daily living and is thought to predict a future diagnosis of intellectual disability. 5 Such delays require From Dartmouth-Hitchcock Medical Center, Lebanon, NH. Address reprint requests to John B. Moeschler, MD, MS, Dartmouth-Hitch- cock Medical Center, Medical Genetics, One Medical Center Drive, Leb- anon, NH 03756. E-mail: [email protected] 2 1071-9091/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2008.01.002

Genetic Evaluation of Intellectual Disabilities

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Page 1: Genetic Evaluation of Intellectual Disabilities

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enetic Evaluation of Intellectual Disabilitiesohn B. Moeschler, MD, MS

All children with an intellectual disability (mental retardation) or global developmental delayshould have a comprehensive evaluation to establish the etiology of the disability. Aspecific etiologic diagnosis offers the opportunity to discuss treatment, prognosis, andgenetic recurrence risk. A diagnosis also avoids unnecessary testing and can lead toopportunities for improved health and functional outcomes. The key elements of thediagnostic evaluation are the medical and developmental history, 3-generation familyhistory, dysmorphologic examination, neurologic examination, and judicious use of thelaboratory and neuroimaging. All published guidelines for the evaluation of children withintellectual disability acknowledge that there is a substantial percentage of patients whoare undiagnosed after a comprehensive evaluation and who deserve ongoing follow-up forthe purpose of establishing a diagnosis. Recently, studies of the clinical application of arraycomparative genomic hybridization (aCGH) to individuals with intellectual disability indi-cate that this approach provides a diagnosis in as much as 10% of patients and that thistechnique is replacing the use of fluorescent in situ hybridization for subtelomere imbal-ances now used for such patients when the standard karyotype is normal. The literaturesuggests that history and examination by an expert clinician will lead to a diagnosis in 2 of3 patients in whom a diagnosis is made. Laboratory studies alone, including neuroimaging,provide a diagnosis in the remaining one third. The approach to the evaluation of the patientin whom an etiologic diagnosis is not suspected after the history and physical examinationsincludes a standard karyotype, Fragile X molecular genetic testing, aCGH, and neuroim-aging, based on the evidence to date. One can expect rapid changes in the microarraytechnology in the near future.Semin Pediatr Neurol 15:2-9 © 2008 Elsevier Inc. All rights reserved.

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he child with mental retardation (or “intellectual disabil-ity”) is deserving of the best diagnostic evaluation avail-

ble for the specific aim of improving the health and well-eing of that individual and his/her family. Shevell1 indicatedhat the “etiologic diagnosis in the young child has immediatemplications with respect to recurrence risks and therapeuticmperatives, possessing the potential to modify managementnd expected outcomes” and that “future medical challengesnd the actual prognosis for the disabled child can be moreccurately addressed” in a child with a known diagnosis. Theamily of a child with global developmental delays or anntellectual disability often experiences the feeling of a loss ofontrol.2 An etiologic diagnosis can contribute to the familyeeling in control once more: “As physicians we have experi-nce with other children who have the same disorder, accesso management programs, knowledge of the prognosis,wareness of research on understanding the disease and

rom Dartmouth-Hitchcock Medical Center, Lebanon, NH.ddress reprint requests to John B. Moeschler, MD, MS, Dartmouth-Hitch-

cock Medical Center, Medical Genetics, One Medical Center Drive, Leb-

fanon, NH 03756. E-mail: [email protected]

1071-9091/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.spen.2008.01.002

any other elements that when shared with the parents willive them a feeling that some control is possible.”3 In addi-ion, a specific etiologic diagnosis will make social supportnd information more accessible for families and profession-ls than for those without a specific diagnosis. For manyiagnoses, specific management guidelines are now avail-ble.4 For primary care providers and families, there are spe-ific benefits to establishing an etiologic diagnosis includinglarification of etiology, prognosis, genetic mechanism(s), re-urrence risks, and treatment options; avoidance of unneces-ary tests; information regarding management or surveillancend family support; access to research and treatment proto-ols; and the opportunity for comanagement of appropriateatients in the context of a medical home to ensure the bestealth and social outcomes for the child.The type of developmental delay identified is an important

reliminary step because typing influences the path of inves-igation later undertaken. Global developmental delay is defineds a significant delay in 2 or more developmental domains in-luding gross or fine motor, speech/language, cognitive, social/ersonal, and activities of daily living and is thought to predict a

uture diagnosis of intellectual disability.5 Such delays require
Page 2: Genetic Evaluation of Intellectual Disabilities

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Genetic evaluation of intellectual disabilities 3

ccurate documentation using norm-referenced and age-appro-riate standardized measures of development administered byxperienced developmental specialists.6 The term global de-elopmental delay is usually reserved for younger childrenie, typically less than 5 years of age), whereas the term intel-ectual disability (or, more appropriately, intellectual disabil-ty) is usually applied to older children when IQ testing isalid and reliable.7 Children with developmental delays arehose who present with delays in the attainment of develop-ental milestones at the expected age; this implies deficits in

earning and adaptation,5 which suggests that the delays areignificant and predict later disability. However, delays inevelopment, especially those that are mild, may be transientnd lack predictive reliability for intellectual disability orther developmental disabilities.Intellectual disability is a lifelong disability presenting in

nfancy or the early childhood years, but it cannot be diag-osed until the child is older than age 5 years when standard-

zed measures of developmental skills become reliable andalid. There are many definitions of intellectual disability,ut 4 of them are the most frequently used: the AAMR 1992efinition; the Diagnostic and Statistical Manual of Mental Dis-rders, Fourth Edition 1994 definition; the International Clas-ification of Diseases, 10th Revision or 1994 definition; and themerican Psychological Association 1996 definition. Of

hese, the American Association on Mental Retardation defi-ition is the most used in the United States and the Interna-

ional Classification of Diseases, 10th Revision definition is theost used outside the United States.6 The American Associ-

tion on Intellectual and Developmental Disability definesntellectual disability using measures of 3 domains: intelli-ence (IQ), adaptive behavior, and systems of supports.hus, one cannot rely solely on the measure of IQ to define

ntellectual disability.8 More recently, the term intellectualisability has been suggested to replace “mental retarda-ion.”9 The prevalence of intellectual disability is estimated toe between 1% and 3%.10

Schaefer and Bodensteiner11 wrote that a specific diagnosiss that which “can be translated into useful clinical informa-ion for the family, including providing information aboutrognosis, recurrence risks, and preferred modes of availableherapy.” For example, agenesis of the corpus callosum isonsidered a sign and not a diagnosis, whereas the clinicaliagnosis of the autosomal recessive Acrocallosal syndrome

s. Van Karnebeek et al12 defined etiologic diagnosis as “suf-cient literature evidence . . . to make a causal relationship ofhe disorder with mental retardation likely, and if it met thechaefer-Bodensteiner definition.”

Guidelines are best when established from considerablempiric evidence on the quality, yield, and usefulness of thearious diagnostic investigations appropriate to the clinicalituation. There are 3 published guidelines regarding the di-gnostic evaluation of the patient with an intellectual disabil-ty or global developmental delays; however, the evidence isargely based on many small- or medium-size case series andn expert opinion.13-15

The diagnostic approach that should be undertaken for a

hild with an intellectual disability includes the following: t

he clinical history (including prenatal and birth histories),amily history and construction of a pedigree of 3 generationsr more, the physical and neurologic examinations empha-izing the examination for minor anomalies, and neurologicr behavioral signs that might suggest a specific recognizableyndrome or diagnosis. After the clinical genetic evaluation,udicious use of the laboratory tests, imaging, and other con-ultants may be important in establishing the diagnosis.

istory and Examinationthorough examination for minor anomalies whose pres-

nce might suggest an etiology or contribute to the recogni-ion of a particular diagnostic pattern (ie, the dysmorpho-ogic examination) should be performed.16-18 Schaefer andodensteiner11 state that the “association of intellectual dis-bility and congenital malformations has long been recog-ized” and that “a necessary component of the evaluation ofhe child with idiopathic intellectual disability is a compre-ensive dysmorphologic examination.” Several studies of thetiology of intellectual disability suggest that the dysmorpho-ogic examination and syndrome recognition by an experi-nced clinical geneticist are the critical diagnostic modalities.n early study of the co-occurrence of intellectual disabilitynd minor anomalies was performed Smith and Bostian.19

he authors examined 50 children with an intellectual dis-bility of an unknown cause for the numbers and kinds ofinor anomalies; controls consisted of 100 children without

ntellectual disability. They found that 42% of children withlobal developmental delay or an intellectual disability had 3r more minor anomalies compared with none of the con-rols. They concluded that the etiology of the intellectualisability was the abnormal development of the central ner-ous system heralded by the presence of the minor anomaliesn the surface examination. Hunter20 completed a retrospec-ive study of the diagnostic evaluation of 411 children withntellectual disability referred to a university-based geneticsenter between 1986 and 1997. He found that “physical find-ngs in the patient were the most important factors in deter-

ining whether or not a diagnosis was made . . . A diagnosisas significantly more likely when a patient was noted toave an unusual appearance and, although the numbers aremall, the presence of a major malformation did not increasehe diagnostic rate. Half the diagnoses were made on the basisf a key finding (eg, velo-pharyngeal incompetence) or theestalt of the patient.”In a prospective study of patients referred to a university

ospital clinical genetics center in Amsterdam for the diag-ostic evaluation for developmental delays or intellectual dis-bility, Van Karnebeek et al21 studied 281 children prospec-ively and made etiologic diagnoses in 150 (54%). One thirdf these diagnoses was made on the basis of the history andxamination alone; in another one third, the history and ex-mination provided essential clues to the diagnosis, later con-rmed by additional studies; and laboratory studies alonerovided diagnoses in the remaining one third. For example,

n patients with Fragile X syndrome, these authors believed

hat the history and examination were contributory to the
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4 John B. Moeschler

iagnosis and the molecular genetic analysis was essential forhe diagnosis. By using these definitions, they found that theysmorphology examination was contributory to the diagno-is in 79% of those diagnosed and essential in 62%. Thistudy found that based on clinical history alone a diagnosisould be established in 1 of 20 patients, and based on phys-cal examination alone 1 in 30 patients could be diagnosed.ased on the combination of history and examination to-ether, 1 in 3 patients were diagnosed. Furthermore, thelinical history and examination provided essential guidanceo the clinician regarding which additional investigationshould be performed. The additional investigations (labora-ory and consultation) allowed for diagnosis in another onehird of the patients in the study. Battaglia and coworkers22

ound that a “pathogenetic diagnosis” could be identified in0% of all patients; of these, half were diagnosed by historynd physical examination alone. Majnemer and Shevell6

ound that a diagnosis was made in 63.3% of patients withlobal developmental delays; of this total, the diagnosis wasade by history and physical examination alone in 18.4%.

hevell et al23 studied 99 children with global developmentalelays prospectively, and in 44 an etiology was determined.f these 44, 15 (38.6%) had diagnoses made by history andhysical examination alone.There are several studies that addressed the neurologic

xamination in the evaluation of the child with an intellectualisability,20,21,24-26 which reported a total yield of etiologiciagnoses in all studies of 42.9%. This represents those pa-ients presenting with global developmental delay or intellec-ual disability and with cerebral palsy, muscle weakness,pasticity, paresis, epilepsy, and microcephaly. Such abnor-alities on neurologic examination assisted in determining

dditional studies such as electroencephalography, neuroim-ging or molecular genetic testing, or referral to other spe-ialists. This figure (42.9%) does not include the value ofeurologic examinations in providing indications for otheriagnostic studies such as electroencephalography and neu-oimaging.

ytogenetic Analysisytogenetic studies in the evaluation of children with an

ntellectual disability are to be expected in all whose etiologys not clinically evident. The reported frequency of chromo-ome anomalies detected by high-resolution karyotyping (ie,550 bands) in patients evaluated for intellectual disability

r developmental delays varies between 9% and 36%.27 In aecent review of the frequency of cytogenetic abnormalities inhe evaluation of patients with intellectual disability, Vanarnebeek et al21 found that the median frequency of de-

ected chromosome abnormalities was 10%, ranging from% to 50% depending on the variation in the study designmong published reports. They found that chromosome ab-ormalities were present in all categories of intellectual dis-bility, mild to profound, and in both sexes. The authorsoncluded that routine karyotype (with resolution �550ands) are a “valuable diagnostic technique” in the evaluation

f children with developmental delay or intellectual disabil- s

ty. In a prospective study of the etiology of intellectual dis-bility in Amsterdam21 of 266 children karyotyped, 218.3%) had abnormalities (8 numeric and 13 structural).hese authors found that there was a relationship between

he number of minor anomalies and the likelihood of a chro-osome abnormality; a higher number of anomalies (�6)

ndicated a significantly higher likelihood to find a chromo-ome abnormality. They concluded that all patients with nonown cause for the developmental delay or intellectual dis-bility have chromosome analysis. Likewise, a review byhevell et al23 found the range of chromosomal abnormalitiesound on routine cytogenetic analysis to be from 2.93% to1.6%, with a median of 3.7%. Shevell et al concluded thatroutine cytogenetic testing is indicated in the evaluation ofhe child with developmental delay even in the absence ofysmorphic features or clinical features suggestive of a syn-rome.” Curry et al13 stated that “chromosome analysis in the

ndividual with intellectual disability is generally regarded asmainstay in the overall evaluation process.” It is key that theytogenetic study be reviewed by the clinical geneticist dur-ng the evaluation of a particular child.

luorescent in Situybridization Testing

bout half of all structural chromosome abnormalities (“seg-ental aneusomies”) include the telomere of the chromo-

ome. A test for the absence of the functional end of thehromosome (subtelomere region) effectively evaluatesany potential abnormalities of that chromosome and, thus,

he cause of the global developmental delay or intellectualisability. Many deletions of the telomeres are visible by stan-ard techniques, and the syndromes caused by such dele-ions are often clinically recognizable (eg, cri du chat syn-rome, which is caused by the deletion of the telomere of thehort [p] arm of chromosome 5). However, deletions of otherubtelomeric regions lead to a phenotype that is not recog-ized easily, and the deletions often go undetected by routinearyotype. Fluorescent in situ hybridization (FISH) tech-iques have been applied to examine the subtelomeric re-ions of each chromosome for abnormalities that are knowno cause intellectual disability.22 Since the clinical availabilityf a complete set of FISH probes, the utility of these probesas been shown by the numerous reports of patients with

ntellectual disability who have had a previously normal rou-ine karyotype suggesting that subtelomeric abnormalitiesdeletions or duplications of chromosome regions) are sec-nd only to Down syndrome as the most common cause ofntellectual disability.28,29 Some deletions and duplications oflinically significant chromosome material at the telomeresre not visible by standard karyotype analytic techniques;hese are often referred to as “cryptic” subtelomeric chromo-ome anomalies (ie, not detectable by routine cytogeneticesting). These FISH techniques have allowed more sensitivenalysis of the telomeres for clinically significant abnormali-ies. The application of the FISH technique to examine the

ubtelomere region of each chromosome has led to the rec-
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Genetic evaluation of intellectual disabilities 5

gnition that approximately 7.4% of children with a moder-te to severe intellectual disability who have had normal rou-ine chromosome analysis have an abnormality detectedeither a deletion or duplication, sometimes both) by theISH technique to explain their intellectual disability. Also,.5% of children with a mild intellectual disability of un-nown etiology have been found to have cryptic telomereearrangements as the etiology. Biesecker29 reviewed 14 stud-es involving 1,718 subjects who were selected on the basis ofntellectual disability, growth retardation, major and minornomalies, exclusion of known diagnosis, and familial versusporadic occurrence. Notably, even with the variation fromtudy to study of subject selection criteria, there was a rela-ively constant yield for subtelomere abnormalities detectedy FISH of about 6%. The presence of major and minorhysical anomalies did not affect the yield; however, the yieldas higher among familial cases compared with sporadic.eVries et al30 have proposed a 5-item checklist designed to

ncrease the yield of FISH subtelomere studies; using a scoref �3 as a cutoff for subtelomere testing, the authors notehat �20% of cases could be excluded from testing withoutissing a subtelomeric case.

omparativeenomic Hybridization

owever, it now appears that subtelomere FISH investiga-ions are quickly becoming obsolete as a first-line diagnosticnvestigation by the newer chromosome microarray or com-arative genomic hybridization techniques (aCGH).31 aCGHompares DNA content from 2 differentially labeled ge-omes: the patient and the control. The 2 genomes are cohy-ridized usually onto a glass microscope slide on whichloned or synthesized DNA fragments have been immobi-ized. Arrays have been built with a variety of DNA substrateshat may include oligonucleotides, complementary DNAs,nd bacterial artificial chromosomes (BACs). The arraysight be whole-genome arrays, which are designed to cover

he entire genome, or targeted arrays, which target knownathologic loci, the telomeres (similar to the use of FISHubtelomere probes), and pericentromeric regions. The pri-ary advantage of aCGH over FISH is the array’s ability toetect DNA copy changes simultaneously at multiple loci in aenome in 1 “experiment” or test. These copy numberhanges may include deletions, duplications, or amplifica-ions at any locus as long as that region is represented on therray. aCGH might be thought of as a coordinated and con-urrent FISH test over hundreds or even thousands of loci intest sample. aCGH, independent of whether it is “whole

enome” or “targeted” and what type of DNA substrate (oli-onucleotides, complementary DNAs, or BACs), identify de-etions and/or duplications of chromosome material with aigh degree of sensitivity in a more efficient manner thanISH techniques. Furthermore, the FISH test is predomi-antly used to confirm a clinical diagnosis, whereas theCGH does not require an expert clinician to suspect a spe-

ific diagnosis. The resolution of aCGH is defined by 2 main r

actors: (1) the size of the nucleic acid targets and (2) theensity of coverage over the genome; the smaller the size ofhe nucleic acid targets and the more contiguous the targetsn the native chromosome, the higher the resolution of therray. There are several recent clinical studies that supporthe use of aCGH in the diagnostic evaluation. Recently, Shaf-er et al32 reported their experience in 1,500 consecutiveases that were submitted to 1 laboratory for array evaluation.he targeted array used detected genomic abnormalities in9% of patients referred for a multitude of problems that

ncluded developmental delay, dysmorphic features, and aariety of birth defects; 134 (8.9%) showed a genomic abnor-ality, 36 (2.4%) showed polymorphisms or familial vari-

nts, 14 (0.9%) showed alterations of unknown clinical sig-ificance, and 84 (5.6%) showed clinically relevant genomiclterations. These included subtelomeric deletions and un-alanced rearrangements, microdeletions and reciprocal du-lications, rare abnormalities, and low-level trisomy mosa-

cism. Shaw-Smith et al33 investigated 50 patients withental retardation and dysmorphic features using a whole-

enome complementary DNA aCGH and identified 12 (24%f the total sample) patients with deletions or duplications ofhich 5 were seen in phenotypically normal parents. Thus,

he aCGH led to diagnosis in 5 cases or 14% of the sample.ikewise, Vissers et al34 evaluated 20 patients with mentaletardation who had had a normal standard karyotype usingwhole-genome aCGH and identified 4 patients (20%) withdeletion or duplication causal of the disability (and one

rom a phenotypically normal parent). Shoumans et al35 eval-ated 41 children with “idiopathic mental retardation andysmorphic features” by using a commercially available ge-ome-wide aGCH using BAC clones. From this sample, 4hildren were diagnosed with pathologic deletions (9.8%).yson et al36 evaluated 22 individuals with a mild to moder-te intellectual disability using a commercially availablehole-genome aCGH and identified 2 patients with abnor-alities, one with a duplication and one deletion. deVries et

l37 evaluated 100 individuals with intellectual disability byhole-genome aCGH to find 7 with deletions and 3 duplica-

ions (10% of sample) that were diagnostic. In a group of 30ndividuals with mental retardation and dysmorphic fea-ures, Miyake et al38 found 5 aCGH abnormalities using ahole-genome BAC clone approach. Two of the 5 were sub-

elomeric in location. In the largest study to date of a well-haracterized sample of individuals with idiopathic mentaletardation, Menten et al39 reported on a sample of 140 pa-ients of whom 28 (20%) had abnormal aCGH using a whole-enome BAC array. Of these, 17 (12.1%) had abnormalitiesetected, and, of the 17, 11 had had prior FISH subtelomereesting that was normal. Hoyer et al40 used a single nucleotideolymorphism genome-wide array on 104 unselected indi-iduals with mental retardation of whom 10 (9/1%) patientsad abnormalities detected. Engels et al41 reported on a seriesf 60 individuals with unexplained mental retardation usinggenome-wide oligonucleotide aCGH. Of those, 6 abnormal

mbalances were found (10%), all of whom had dysmorphicacial features. Thus, it appears from these studies that the

ole of aCCH is important in the evaluation of the child with
Page 5: Genetic Evaluation of Intellectual Disabilities

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6 John B. Moeschler

developmental delay or intellectual disability. It may be thatn the future aCGH will actually replace the standard karyo-ype (as it has the FISH subtelomere testing) in the evaluationf the child with an intellectual disability. This, of course, willequire systematic study of the application of aCGH com-ared with the standard karyotype.

ragile Xolecular Genetic Testing

ragile X syndrome is said to be the most common geneticause of a developmental delay or intellectual disability,14

nd yet reviews suggest that only about 2.0% of patients withn intellectual disability (both sexes) will be found to have autation in this gene (with prevalence ranging from 0% to

8.6%). In their comprehensive review of the literature, Vanarnebeek et al21 found that those with a more significant

ntellectual disability are more likely to be positive for Fragiletesting (4.1%) as compared with those with milder delays

r borderline intelligence testing results (1.0%). In a largetudy of unselected school-age patients with intellectual dis-bility, deVries et al42,43 reported the prevalence of Fragile Xiagnosis by molecular genetic testing to be 0.7% with higherrevalence among boys (1.0% for boys and 0.3% for girls).here have been a number of studies using clinical checklistsith the aim to improve patient selection for whom Fragile X

esting is warranted. For example, de Vries et al43 found that7-item clinical checklist increased the molecular genetic

iagnostic yield to 7.6% without the loss of cases identified.his checklist included a positive family history of MR, long

aw or high forehead, large and/or protuberant ears, hyper-xtensible joints, soft and velvety palmar skin with redun-ancy on the dorsum of the hands, testicular enlargement,nd behaviors of initial shyness and lack of eye contact fol-owed by friendliness and verbosity. Other checklists de-igned to increase the efficiency of Fragile X genetic testingave been used with results that are generally positive. Gen-rally, they included male sex, a positive family history forntellectual disability, and the absence of microcephaly. Theonsensus Conference convened by the American College ofedical Genetics13 recommends that Fragile X testing be

strongly considered in both males and females with unex-lained intellectual disability especially in the presence of aositive family history, a consistent physical and behavioralhenotype and absence of major structural abnormalities.”ikewise, Shevell et al14 in the Practice Parameter for thehild Neurology Society and American Academy of Neurol-gy advise that Fragile X testing be “considered in the evalu-tion of the child with global developmental delay” and thatclinical preselection may narrow the focus of who can beested without sacrificing diagnostic yield.” Van Karnebeek etl21 recommend that all boys with an unexplained intellectualisability have molecular genetic testing for Fragile X syn-rome but that routine testing of girls is not warranted unlesshere are indications of increased risk (eg, a positive family

istory). s

olecular Geneticiagnostic Testing

here are situations in which the clinical geneticist or otherxpert clinician may establish a clinical diagnosis and useenetic testing to confirm the clinical diagnosis (much in theame way that the clinical diagnosis of Down syndrome isonfirmed by the karyotype). In addition to confirming thelinical diagnosis, such genetic testing may be important forescribing the genetic mechanism for the diagnosis and for

mproving the precision of genetic counseling. For example,ngelman syndrome might be caused by one of several ge-etic mechanisms including interstitial deletion of the criticalegion of chromosome 15q, uniparental disomy, an imprint-ng mutation, or a mutation in the gene UBE3A, the knowl-dge of which becomes important for genetic counseling andonfirming the clinical diagnosis.44 In other situations, oneay use molecular genetic testing for the patient who mayresent with “atypical features” of a known syndrome as ishe case for those suspected to have a mutation in the MECP2ene that causes Rett syndrome in patients who do not fulfillhe diagnostic criteria. There are now case reports of girlsith a milder disability who have mutations in MECP245 andales with X-linked intellectual disability syndromes.46

hus, in certain circumstances, one might suggest testing forECP2 mutations when the patient does not fulfill the clin-

cal diagnostic criteria for the syndrome in question (in thisxample, Rett syndrome) but when deemed appropriate toddress the question of an “atypical presentation” of thenown clinical syndrome. This serves as an example of a

ikely trend in clinical genetics (ie, testing for genetic muta-ions for known conditions being suggested for potentialtypical cases causing the intellectual disability).

euroimagingarly studies of the use of computed tomography (CT) scans

n the evaluation of patients with an idiopathic intellectualisability47,48 indicated a low diagnostic yield or the nonspe-ific finding of “cerebral atrophy” that did not contribute tolarifying the cause of the intellectual disability. Later studieshat used magnetic resonance imaging (MRI) for central ner-ous system abnormalities have established that MRI is moreensitive than CT scans with increased yield10,49 and is nowhe appropriate imaging technique for those patients withossible central nervous system malformations associatedith intellectual disabilities. The frequency of a detected im-

ge abnormality varies widely in the literature based on fac-ors such as the study subject selection criteria and theethod of imaging (CT scans, MRI, quantitative methods oro, and so on). Schaefer and Bodensteiner50 in their literatureeview found reported ranges of abnormalities from 9% to0% of those patients studied. Shevell et al10 reported a sim-

lar range of findings in their review. For example, in 3 stud-es totaling 329 children with global developmental delay,sing CT scans in almost all patients and MRI in a small

ample, found a specific cause in 31.4%, 27%, and 30% of
Page 6: Genetic Evaluation of Intellectual Disabilities

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Genetic evaluation of intellectual disabilities 7

hildren.6,23,51 In their systematic review of the literature, Vanarnebeek et al21 reported on 9 studies in which magnetic

esonance brain imaging was used. The mean rate of abnor-ality found was 30% (range, 6.2%-48.7%), with more ab-ormalities found in children with a moderate to profound

ntellectual disability versus a borderline to mild disabilitymeans of 30% v 21.2%, respectively). These authors alsooted that none of the studies reported on the value of thebsence of any neuroradiologic abnormality for a diagnosticorkup and concluded that the “value for finding abnormal-

ties or the absence of abnormalities must be higher” than the0% mean rate implies.If the neuroimaging was performed in only selected cases

ith a head circumference size or a focal neurologic finding,he results increased. Shevell et al23 reported that the percent-ge of abnormalities was 13.9% if performed on a “screeningasis” but increased to 41.2% if performed on an “indicatedasis.” In the CNS Practice Parameter,10 the authors dis-ussed other studies on a smaller number of patients thathowed similar results that led to the recommendation thatneuro-imaging is a recommended part of the diagnosticvaluation” particularly should there be findings on exami-ation (microcephaly and focal motor findings) and that MRI

s preferable to a CT scan. However, in the American Collegef Medical Genetics Consensus Conference report,13 the au-hors state that neuroimaging by a CT scan or MRI in theormocephalic patient without focal neurologic signs shouldot be considered the “standard of practice” or mandatory.hese authors believed that the decisions regarding “cranial

maging will need to follow (NOT precede) a thorough as-essment of the patient and the clinical presentation.”13

In contrast, Van Karnebeek et al21 find that MRI alone leadso an etiologic diagnosis in a much lower percentage of pa-ients studied. They cite Kjos et al52 who reported 3.9% di-gnoses in patients who had no known cause for their intel-ectual disability and followed no progressive or degenerativeourse. Bouhadiba et al53 found 0.9% diagnoses in patientsith neurologic symptoms, and 4 additional studies20,48,51,54

ound no etiologic or syndrome diagnosis on the basis of theeuroimaging alone. Three studies reported the results ofnselected patients: Majnemer and Shevell6 found a diagno-is by this type of investigation in 0.2% of patients,tromme25 in 1.4%, and Van Karnebeek et al12 in 2.2% ofatients.Abnormal findings on MRI are observed in approximately

0% of patients with developmental delays or intellectualisability. However, MRI leads to an etiologic or syndromeiagnosis in 0% to 3.9% of patients studied. The value of aegative MRI in leading to a diagnosis has not been studied.hus, MRI is often useful in the evaluation of the child with aevelopmental delay or intellectual disability; it is not be-

ieved to be a mandatory study and has a higher yield whenndications exist (eg, microcephaly and focal motor findingsn neurologic examination).

etabolic Studiesnborn errors of metabolism appear to be a rare cause of

evelopmental delay or intellectual disability and routine

etabolic evaluation of all patients with developmental delayr intellectual disability does not appear to be warranted. Anyetabolic evaluation should be targeted on the basis of theistory and examination. Shevell et al10 found that “routineetabolic screening” of patients with a developmental delay

r intellectual disability has a yield of �1% and that a step-ise evaluation (based on clinical indicators) will increase

he diagnostic yield. Curry et al13 reported an “extremely lowield for unselected metabolic screening” and that metabolicesting be selective and “targeted at the suspected category ofisorder” on the basis of the history and examination. In their

iterature review, Van Karnebeek et al21 found few studies ofutpatients with a developmental delay or intellectual dis-bility and found that comparisons between studies was notossible given the lack of uniformity of metabolic testingtudy to study. These authors suggest that any metabolictudies be determined by the history and examination find-ngs and that, in an effort to standardize and study the ap-roach, that checklists be used to guide the metabolic evalu-tion of patients with a developmental delay or intellectualisability. Thus, routine metabolic screening of all patientsith a developmental delay or intellectual disability is not

onsidered optimal; targeted metabolic studies are expectedn some patients on the basis of findings in the history orxamination. Although there is no standard checklist for met-bolic evaluation supported by the literature, Curry et al13

ave listed selected clinical findings or laboratory abnormal-ties that may indicate the need for further metabolic inves-igations.

onclusionn summary, the best approach to the genetic evaluation ofhe child with an intellectual disability is to do a carefulistory, 3-generation family history, dysmorphologic exam-

nation, and neurologic examination. The expert clinical ge-eticist will suspect or establish a diagnosis based on theselone in as many as two thirds of those diagnosed. If noiagnosis is established or suspected, it is appropriate to ar-ange for Fragile X molecular genetic testing, aCGH, andtandard karyotype. Brain imaging is of most utility if it iserformed based on selective criteria (eg, microcephaly andbnormal neurologic examination), although it can be con-idered in any patient with no established diagnosis. Meta-olic screening is best reserved for those patients with symp-oms or signs to suggest that an underlying metabolicisorder is present. It is likely that there will be rapid im-rovements in aCGH that will improve the diagnosis of indi-iduals with intellectual disabilities.

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