SEARCH

SEARCH BY CITATION

Keywords:

  • intellectual disability;
  • dysmorphology;
  • clinical assessment;
  • clinical panel;
  • X-linked ID;
  • minor anomalies;
  • normal variants

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND ANALYSIS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. Appendix A
  10. REFERENCES

IDEAS (intellectual disabilities evaluation and advice system) provides the opportunity for physicians who are sending samples for the Greenwood Genetic Center (GGC) 92-gene X-linked intellectual disability (XLID) (formerly X-linked mental retardation) panel to have their male patient's clinical features reviewed by an experienced panel of six Clinical Geneticists. They were asked to obtain parental consent, complete a one-page information form, and provide A–P and lateral photographs. The panel members independently reviewed the material and forwarded comments about clinical features, possible diagnoses, and/or further testing for the patient. We present the results of the first 55 patients evaluated. In only a single case did all panelists agree on a non-XLID diagnosis, later proven by genetic testing. The XLID gene panel diagnosed an additional five (9%) cases, but in only two cases did one panelist suggest the correct gene, which was one of four they suggested. This paper examines the possible reasons for the low rate of clinical diagnosis and suggests that, while the data received were often incomplete, the most important reasons for lack of diagnoses were the source of referral and selection of patients for review. We did note that there were a number of instances where we disagreed with the submitted information as to whether the individual was dysmorphic and with the stated presence of certain physical signs, most often downslanted palpebrae and posterior ear angulation. These differences in assessment of clinical signs and the general lack of completeness and detail provided in the standard data sheet, including that regarding the extended family history, lead us to raise concerns regarding the feasibility of establishing high quality central clinical databases designed to aid in the interpretation of exomic/genomic variants. © 2014 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND ANALYSIS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. Appendix A
  10. REFERENCES

IDEAS provides a centralized format through which healthcare providers can submit information on diagnostically challenging patients and by so doing have their patient(s) reviewed by an international panel of experienced Clinical Geneticists. Rationale for offering this service included the observation that, while healthcare providers will generally recognize the common chromosome and single gene disorders, they will be challenged by the endless number of partial trisomies, microdeletions, microduplications, and the rarity and the subtle signs of most single gene disorders.

The project was instigated and coordinated through the Greenwood Genetic Center (GGC), which has had a longstanding interest and research focus on XLID. Concurrent with the initiation of IDEAS GGC had made available a panel of 92 syndromic and non-syndromic X-linked genes (XLID Next Generation Sequencing panel) for testing through its laboratory [Greenwood Genetic Center, 2013]. As part of the XLID testing clinicians were offered the services of the IDEAS panel at no additional charge.

This paper presents an analysis of the outcomes of the first 55 patients assessed by the IDEAS Clinical Panel. Included in this report are the source and completeness of data received by the Panel; variation by specialty of referral in detail and prior work-up; the nature of suggestions made by the Panel and the diagnostic outcome; the degree of success of the panel in predicting a diagnosis, both specific to the X-linked panel and generally. Finally we examine our experience in terms of the future role of clinical genetics in an age of evolving broad gene panels, exome and genome sequencing.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND ANALYSIS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. Appendix A
  10. REFERENCES

In order to receive the evaluation and advice of the IDEAS Clinical Panel as part of the testing process using the X-linked gene panel [Greenwood Genetic Center, 2013]; (Fig. 1) the following requirements were met: (1) the individual family agreed to participate by completing a standard consent form and (2) the healthcare provider(s) submitted standardized, relevant data (Appendix A). These were expected to include the family history, clinical information, good quality digital patient photographs, and prior test results. Figure 1 shows the intended flow sheet for the program. Given that a side-bar to the Panel's effort was to test patients with the X-linked gene panel, all patients were male, although a family history supporting X-linked inheritance was not required. The clinical data and Panel responses were provided electronically; the Panel members worked independently and used any resources at hand in formulating their suggestions. At the conclusion of the first 55 cases a preliminary summary was completed of: the referral data provided, the X-linked panel results, as well as any non-X-linked panel tested genes and other diagnoses suggested by the Clinical IDEAS Panel. From these data, referring physicians of specific cases were asked whether certain routine investigations had been performed prior to the referral, and/or if any of the additional Panel suggestions had been carried out, or were under way. In no instance was the Clinical Panel provided with the patient name or other identifying information. With the exception of a few cases, the identity and specialty of the referring physician was unknown to the Panel members.

image

Figure 1. Flow chart for review of cases by the clinical IDEAS panel.

Download figure to PowerPoint

The Clinical Panel consisted of JMG, AGH, GN, CR, GT, and RES; who have all had a long standing interest in the pathogenesis of intellectual disability/dysmorphology, and are further self-described as Clinical Geneticists, five with their practice largely limited to dysmorphology/intellectual disability, and having a specific research and clinical expertise in XLID. The group represents over 200 years in combined experience in clinical genetics. Case summaries were received between October 2010 and January 2012 in groups of 1–11 at a time. Generally opinions were returned to GGC within a week, with panel members working independently but sending responses to each other for later comparison and/or comment.

RESULTS AND ANALYSIS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND ANALYSIS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. Appendix A
  10. REFERENCES

The 55 samples were received from 24 individual physicians, of whom 15 submitted a single, case, one sent two cases, four sent four cases, three submitted five cases, and one sent seven, cases. The data provided for the cases submitted are summarized in Table I. There was marked variability in the detail provided on the referral form (Appendix A) ranging from only completing the left column to complete patient descriptors being given in the right hand column. The left column was completed to some degree in 41, the right column in 37, the pedigree (usually limited to nuclear family) in 38 and prior laboratory testing in 29 cases. In only 20 cases were the panel provided with specific information as to the degree of developmental/intellectual disability.

Table I. Data Provided to the IDEAS Clinical Panel by the Referring Physician
#Degree of disabilityOFC percentileStated to be dysmorphicSpecific facial signs stated presentSpecific nonfacial signs stated presentTests referring listed or “had done”
  • *

    BAV, bicuspid aortic valve.

1Severe<3rdYesSquared, rotated ears, low columella, full lips, short philtrum, prom. chinXLR FH positive, short stature, ACC, long fingers, testes up, pectus excavatum, hip dysplasiaSNP array RSK2, FMR1, Angelmann
2IQ 45<3rdYesLow posterior hairline, long & narrow palate, dental malpostioningShort stature, obese, small penis & testes, hypotonic, skin picked 
3??NYesWidow's peak, fissures downslant, full lips, high palateChiari malformation, thin corpus callosum splenium, steep clivus, ASD, 1 testis undescended, hypotoniaSNP array, FMR1, MID1, 15q methylation, PTPN11, MAP2K1, MAP2K2, HRAS, BRAF, SOS1, KRAS, RAF1
4BorderlineNNoProminent occiputShort stature, cond. hearing loss, testes up, precocious puberty, low birth weightKaryotype, FISH 22q11.2, SNP array, del 7q11.23, subtelomere study
5??>90thYesSupraorbital narrowing, flat occiput, Eyes deep set, ears prominent, thin nasal bridge & high root, tall palate, small & wide-spaced teethUmbilicus abn. shape, proximal thumbs, cutis marmorata, dry skin patches 
6Verbal 85, PSIQ 74>95thYESCupped ears, hyperteloric, small palpebrae, small mouthXLR FH positive, Chiari I, large ventricles, 1 inverted nipple, 5th clinodactyly, prominent halluces, dysplastic toenails, febrile seizureArray CGH, MED12, FMR1 NSD1, SGB
7IQ <50>95thYESEyes “wide spaced,” ears posteriorly “rotated,” nasal bridge flat/broad, mouth downturnedShort stature, hypotonia, seizures, club foot, short neck (heart, kidney, genital NOS, visual & hearing loss not specified) 
8??, ASDNYES (mild)Eyes deep-setSeizures mostly myoclonic, asthenic habitus 
9??NNOLong face, strabismus, high palate, malpositioned teethSeizures, severe scoliosis, duplex ureters, Dandy-Walker “variant,” tethered cord, BAV*, hypomelanosis of Ito 
10? very low range test at schoolNNOFissures downslant, stellate irides, ears cupped & fleshy helices, smooth philtrum, full upper lip, diastemaSlightly wide thumbs/halluces, short squared off fingers, short nails, Ht >97% 
11??>90thYESNo descriptionASD, obese, mum spec. education 
12??NYESNarrow head, prom. glabella, full lips, epicanthus, iris heterochromia, ears underdeveloped, synophyrs, narrow palateASD, hypotonia, severe scoliosis, prominent fingertip pads, (relative macrocephaly), hallux lateral deviation, Ht <3rd% 
13Moderate<3rdCoarseDolicocephaly, low frontal hairline, low & rotated ears & prom helix, upslanting palpebrae narrow palate, large teeth, oligodontia, bifid uvulaShort stature, hypotonia, bilateral, contractures, 2–4 finger syndactyly, broad fingertips, lumbar scoliosis, short femoral heads, pectus excav.Imaging: Dandy Walker, ZEB2 sequence, SNP array
14MildNNOEyes deep setShawl scrotum, “short” fingers and toes, vascular birth mark left kneeArray CGH, FMR1, 7-dehydro chol., MRI N, EEG posterior epileptiform, Aarskog
15IQ 55–60>97thYESDolicocephaly, “hyperteloric,” nares anteverted, thick lipsShort stature,hypotonia, seizures, brachydactyly, clinodactyly 5th, mild scoliosis, reduced reflexes, ADHDIgA deficient
16Mild?NYESPalpebrae downslant, “hyperteloric with long palpebrae,” mild ptosis, “low” & fleshy ears, nose broad bridge & anteverted naresAutism SD, ADHD, hypotonia, short toes, multiple nevi, “relative” macrocephaly, thick & slightly coarse hair, groin hyperpigmented 
17??NYESSagittal synostosis, strabismus, ear pit & underdeveloped lobesHydronephrosis, hypotonia, atrial septal defect 
18??<3rdYESEpicanthus, hooded lids, nose wide bridge & broad tip, high palateShort stature, hypotonia, macrocephaly postnatal 
19??>97thNOShort uvulaAutism SD, atonic seizures, HT <3rd small feet & 2–3 syndactyly, small testes, prominent finger jointsSNP array, PTEN
20Moderate>97th, FH ofNOUplifted ear lobesAutism SD, seizures, Ht >97th%, aggressive, self stimulatesFather Asperger, M sibs autism SD, sister non verbal
21Severe>97thYESSupraorbital ridges, eyes deep set, “hypoteloric,” large ears, midface retrused, prognathicAutism SD, single palmar creases, brachydactyly, prominent fetal pads, obese 
22Severe40thYESFull lips, wide spaced teethHypotonia/spastic, intractable myoclonic/grand mal seizures, tremor, non-verbalNormal brain MRI, diagnosed Angelmann but no molecular cause found
23??<3rdYESMetopic synostosis, prominent forehead Upslanted palpebrae, midface flat, low columella, mouth “small,” high palateHypotonia, Ht <3rd, pectus excav., prominent halluces, congenital kyphoscoliosis, testes up, asthenic, tight Achilles, laryngomalaciaBrain MRI under-operculerization, thin corpus callosum PQBP1 considered
24FSIQ 58>97thYESFrontal bossing, upturned nose, prominent upper lip, wide spaced teethMild hypotonia, grand mal seizures 
25??<3rdYES“Hyperteloric,” mild micrognathia, hypo-plastic thumbs“Silly gait,” very active, limited language, desmoid tumorFH desmoids brother & maternal uncle
26?? no words @ 3yrs>97th sib/fa alsoNOFrontal bossing, “mild hypertelorism,” Rt short & upturned eyebrow, low & large ears, teeth wide-spacedAutism SD, lax joints, flat feet, infantile scoliosis, poss absence seizures 
27??NYESPalpebrae down slanting, broad nose, mouth downturned, palate highAutism SD, aggressive, 2–3 toe syndactyly 
28??NYESDuane, whorl far Rt, eyebrow up slant & medial flare, Lt Stahl ear, “hyperteloric, short palpebrae,” nose flat bridge, retrused midface, upturned upper lipAutism SD, Ht <5%, (atrial SD, MvS, CoA, subaortic membrane), behavior, short and thick fingers & toes46XY, FISH 22q11.2 N, lumbar lipoma, array CGH, FMR1
29??<3rdYES“Hypertelorism,” “mouth & palate abn,” visual lossShort stature, hypotonia, 2–3 toe syndactyly, testes up, “skeletal abn.” 
30?? SevereNNOHx esotropia, blind central, sl small distal thumbHypotoniaN NB brain CT & MRI, lysosomal enzymes, 7 dehydrochol, CBH def, transferrin, amino a, 46XY, 15q methylation, FMR1, array CGH, ARX, MECP2
31??NNOPlagiocephaly (torticollis), epicanthus, Thick palate ridges, tented upper lipHypotonia, single palmar crease, reflexes 2/4, ankle clonus, shawl scrotum?, C2–C3 segment abn., inverted nipples,N cranial CT/MRI, array CGH, 46XY, echocardiogram, amino & organic acids N, VLCFA, phytanic acid, 15q methylation, CBH def transferrin studies
32??>97thNO Seizures (partial complex), Ht >97th prominent lateral & 3rd ventricle 
33??<3rdYESFlat occiput, narrow skull, coarse hair, synophoris, full upper lids, prom. anti-helix, nose wide bridge & tip, short philtrum, full everted lipHypotonia, focal seizures, initial FTT, long & slender fingers, small brown maculeon backN brain MRI/CT, 46XY, 244K oligo array CGH, MECP2, FMR1, Rett/Anglelmann 2nd tier panel, 15q methylation
34??SevereNYES“Long palpebrae,” “hyperteloric,” ears no lobe, prom antihelix, posterior rotated; nose flat root/bridge & wide tip, flat mid face, everted lower lip,Some aggression, twin not as severe, tapered fingers, narrow hands & feet, long fingers/toesArray CGH, MPS screen, ATRX
35Mild DD>97thYesBrachycephaly, high forehead, temporal narrowing, downslanting palpebrae, large central incisors, high palate, micrognathia,Hypotonia, reflexes 2/4, gait issues, single palmar ceases, pes planus, Ht >97th, ADHD self & FH, OCD, skin picking, joint laxitySotos, adv Bone Age (9yr @ 5.4 yr), array CGH, FMR1, 46XY, MPS screen,
36?? MildNNOEsotropiaAutism SD?, hypotonia, brisk reflexes, puffy feet, EMG suggests chronic active denervation, mat uncle delay ascribed to birth CDG & lysosomal screens pending46XY, array CGH N, FMR1 N, 15q, MECP2, SMA & DM1 N, mitochondria tRNA, EMG & Nerve cond. abn, MRI delayed myelination, various metabolic
37ProfoundNYESEyes deep set and nystagmoid action, upslanting palpebrae, simple helices, pinched noseAutism SD, sev hypotonia, 5th digit clinodactyly, unusual hand motion, skin doughy & redundant, IUGR 
38?? Severe<3rdYESBitemporal narrow, “telecanthus,” ear fleshy lobes, nose short & bridge low, philtrum simple, upper lip thin, xs palatal ridges,Hypotonia, sleep disorder, infantile spasms, ketogenic diet, tube fed, testes undescended, MGF increased OFC 
39FSIQ 62>97thNOLow anterior hairline, “hypertelorism,” long lashes, ears posterior rotation, nose small, teeth malalignedHypotonia, seizures, metatarsus adductus, Ht >97th, nocturnal myoclonusEEG N
40??5thYESEsotropia, nose broad bridge, high palate, “mouth wide,”Hypotonia, seizures or drop attacks, torticollis, interrupted breathing, HT 85th, mild hirsutismArray CNV gain 6p25.3 & loss Xp22.33, 7-dehydrochol, 15q methylation, FMR1, MRI, organic & amino a., MECP2
41??NYESForehead large, ears “low,” mouth “small”Seizures, syndactyly, finger 3–5 Rt, 3–4 Lt, toes 2–3 bilateral., Ht <3rd, heart VSD & PFO 
42??<3rdYESBifrontal hair whorl, tall forehead, palpebrae “sl narrow,” nose wide root, philtrum short, lips full, palate highHypotonia, Ht <3rd, fingers mild taper, toes long, drools, 
43?? MildNYESBrachycephaly, eyebrows arched & bushy, eyelashes long, “hypertelorism-IC 3.5 cm”Some FH spec ed & head trauma possible role (Mo OFC 52.6), neck sl short & wide, toes overlapArray CGH, Aarskog, Cantu, Borjeson-Forssman-Lehmann
44??NYESLong face, high forehead, epicanthus, ears stretchy & low, nose broad bridge & anteverted mild micrognathia, palate highAutism SD, hypotonia, ataxia, mouthing behavior, pectus excavatum, lax joints (FH of), flat feet; skin doughy, stretchy, capillary abn lower spine, keratosis pilarisMED12
45??NYESDeaf Rt ear, bilateral preauricular tags & 1 Lt cheek, HT 90th%, strabismus, Rt facial weakness and asymmetry,Diabetes II, Hpt since 10 years, mild scoliosis46XY, mitochondrial DNA, echocardiogram, FMR1, array CGH
46??Mod>97thYESRound face, tapering fingers, simple large uplifted earlobes, nose broad flat tipAutism SD, Ht >97th%, obese Brother similarly affected 
47??NYESStrabismus Sx, ears large & fleshy, nose flat bridge, broad tip, prognathism,Autism SD, hypotonia, sl wide thumbs, eczema, sleep disorder, non-verbal @ 5yrBrother same. MECP2, 15q methylation, UBE3A, brain MRI
48SevereNYESFrontal bossing, eyes deep set, ears “large” dysplastic, nose small, tented upper lipAutism SD, hypotonia, Kidney & heart & genital anomaly NOSStrong FH developmental disability, in X-linked pattern
49?? Moderate<3rdYESFlat occiput, tall forehead, slight retrognathia, long eyelashes, nose high root & wide flat bridge, mouth sl small, teeth wide spacedBrother affected. Hand 97th%, club foot Rx with casting46XY, array CGH, FMR1, Angelmann methylation
50?? MildN Sunken mid face & eyes, amblyopia, palpebrae “small,” prognathiaPectus excavatum, aortic dilatation, mild scoliosisFamilial FBN1 mutation not seen prior, plasma homocystine
5154NYESSl metopic prominence, facial hypotonia, epicanthus, sl ptosis, prominent lower lipAutism, seizures, sl broad halluces & some dysplastic nails, matrilineal Hx delay and seizures in M & F46XY, SNP array, FMR1, GAA, creatine, organic acids, plasma AA, acylcarnitines
52??NNO Obese, Ht >97th 
53??NYESEpicanthic folds, nose bulbous tip, optic atrophy/hypoplasia, hyperopic +7, nystagmusScoliosis from 6 mos, hypotoniaERG mild changes NOS
54??<3rd Deep set eyes, downslanting palpebrae, delayed dentition, high palateHypotonia, VSD, Ht <3rd, Father craniostenosis46XY, array CGH, plasma urine & organic acids, acyl-carnitine
55??Mild<3rd Tall & narrow cranium, Rt frontal upsweep, palpebrae sl upslant, thick eyebrows, mild synophoris & medial flare, mild epicanthus, prom & narrow nose, thin upper lipHyperextensible joints, mild clinodactyly 5th, fingers square tipped46XY, array CGH, methylation Angelman, Brain MRI/CT, NIPBL/SMCA1

Among the referring group were 16 pediatric geneticists, two metabolic/biochemical geneticists, one general medical geneticist, one neurologist/geneticist, one family medicine/geneticist, and in addition one each of neurologist, hematopathologist, and unknown practice. There was no correlation between the specialty/subspecialty and the number of cases referred, the degree to which the referral form was complete, including provision of information on what, if any, diagnostic tests had been carried out on the patient prior to referral (28 cases). However, among those physicians referring more than two patients, some were consistent in providing these data while others either never or rarely provided that information. In 15 cases the referral included clinical data in the form of redacted chart notes; in seven cases this was in addition to the referral form, while in eight it was the sole information. Again there was a trend among multi-referrers as to whether or not this type of information was provided.

Referrals were to include good antero-posterior (A–P) and lateral facial photographs of the patient. Of the 55 sets of photographs received, 30 were judged good or better, in that they provided the required views of good or better quality. Twenty-two were considered adequate, generally because they provided an A–P but not lateral view, and three were considered inadequate as the photograph(s) did not allow any reasonable assessment of the patient's appearance. Among the more frequent difficulties experienced by the Panel were the lack of provision of measurements (e.g., for hypertelorism), and statements regarding the ears being low-set or posteriorly angulated where no independent assessment could be made due to the quality/orientation or lack of photographs. Clearly clinical staff should be instructed as to how to photograph patients so as to obtain appropriate views of good quality, so as to allow meaningful assessment of the patient through photographic review.

It is germane to consider whether incomplete data were part of the reason for the low clinical diagnostic rate. In general, for reasons to be discussed in more detail below, we think that is not the case, although the lack of any history for the patient with iduronate-2-sulfatase deficiency might have been an exception as we were told only that the patient was obese, “dysmorphic,” had an OFC >90%, and that his mother required special education.

In several cases the Panel member(s) disagreed with a referral statement that the palpebral fissures were downslanting as the inner and outer canthi were on the same plane. The illusion of downslanting fissures was due to a fullness of the lateral supra palpebral region causing a narrowing of the lateral aspect of the fissure (Fig. 2). It was not uncommon that a photograph suffered movement blur, suggesting need for a more rapidly responsive camera, and/or a higher ISO setting and/or better light. It was also apparent that many photographs were taken by an adult looking down toward the child, thus not providing a true A–P view and compromising assessment. The frequent absence of the lateral view, problems with angle, or obscuring by hair, often compromised any assessment of ear position and angulation—not infrequently stated as abnormal.

image

Figure 2. a,b: Ears from the same patient at different ages. In 2a the position complicates assessment. The ear was described as “posteriorly rotated” and it is not. c,d: These ears were reported as abnormally shaped. c shows some uplifting and forward facing of the lobe and some slight prominence of the upper 1/3rd, but the more A–P view demonstrated all parts were essentially normal. d is a normal ear with the mild lobe position variants. e,f: These are examples where palpebral fissures are called downslanting, but where it is an impression cause by the upper, lateral fullness. Indeed the fissures in f have a very slight upslant.

Download figure to PowerPoint

Of the patients, 40 were either the only affected member in the family or no family history was provided. Five probands had an affected sibling with no further affected family; three were stated to be equivalent, one to have ADHD and one was an affected twin (zygosity not provided). One additional patient had an affected maternal half brother and two had affected fathers. Seven propositi with no affected sibling had other affected family members. In five the connection was matrilineal; three with male, one with a female, and one with both sexes of relation affected. An additional patient had delay on both sides of the family and in another the parental line was not stated. In no case did the Panel receive detailed data or photographs of affected relatives and it is possible that in some cases these data might have been helpful.

In 25 of the 55 referrals one or more Panel member spontaneously commented that the patient was non-dysmorphic; in five the referral form was checked non-dysmorphic, in seven the form was either not used or the relevant box was unmarked, leaving 13 referred as “dysmorphic” where one or more Panel member disagreed. It is not possible to assess the degree of agreement between the panelists as to whether the child was dysmorphic because they were not asked to specifically assess the question and simply chose, periodically, to comment, although an occasional disagreement can be noted (e.g., Patient 4, Table II). The reason for this significantly different interpretation in these patients' appearance is not clear but one possible explanation is the loss of depth of field that occurs with a photograph. However, perhaps it should also be kept in mind that the child/adult with intellectual disability is subject to far more scrutiny regarding their appearance than is the average person, and it may be of value to ask oneself, but for their disability would this individual be noticed among the general population? It seems that in many cases what are being called dysmorphic signs are simply part of the range of normal variation—frequent features in the general population and commonly found to cluster within the family when additional members are examined. The panel did not see the parents of the patients, and it is possible that a perceived lack of familial resemblance could have made a call of “dysmorphic” more likely.

Table II. Responses as Provided by the IDEAS Clinical Panel
CaseGeneral group comments on findings if either disagree or add observation (#)Gray: gene tested in panel; Red: panel diagnosisBlue are tests laboratory called positiveOther tests suggested by panel that had already been done but result was not included with historyResults of additional suggested tests and/or others carried out once panel was negative
Tests suggested by group (#) differences with classic cases often pointed out with suggestions92 gene XLID Panel result
  1. *NAD, panel no significant findings.

1Ears not rotated, await already ordered SNP first (2)Mowat-Wilson (5)ZEB2 positiveNo follow-up as diagnosis made 
2Face N (2), not obesePQBP1 (4), RSK2 (2), PHF6 (4), Vasquez et al. [1979], MRXS7, Wilson-Turner (MRXS6), ATRX (2), JARID1C, SLC6A8, MEHMO (MRXS20), MRXS9N  
3Fissures look long, mild ectropion; reminded of case with no Dx developed bilateral WilmsBrain MRI, Storage (3), Kabuki (3), GPC3, Coffin-Sirus, RAS-MAPK pathway?NBrain MRI; Chiari I, partial agenesis corpus callosumN mucopolysaccarides, lysosomal enzymes, RAS-MAPK pathway, Kabuki declined by family
4Face N (2), appears dysmorphic, SGA vs. premie?No Dx (2), partial mat isodisomy 14, array CGH?, del 17q21.31, brain MRIGRIA3 (c.1501-8T > A)Normal SNP arrayNo further testing since panel
5Macrostomia, SM cleft?, Exam & work up seem cursoryFloating Harbor (2), CGH array? (4), 22q11, FMR1?, Lujan like-MED12, BRWD3, UPF3B, skin sugg. UBE2AUPF3B (c.674_677delGAAA)  
6Narrow chest, sloping shoulders, (agreed with HEWE1)SHANK3, HUWE1(3), BRWD3, Atkin-Flaitz, CGH array?, FLNA (2) missense, dup GP3C, UPF3B, MED12N but dup HEWE1/HSD17B10 would not be R/O by testing  
7Arched brows, epicanthus, paranasal folds, lateral orbital fullness; broad tipped nose; ears large?, not rotated, forward & uplifted lobes, prominent antihelix; philtrum long; jaw small, mouth not downturned, looks chromosomal, need more info re heart, renal, genital anomalies, etc. (4)No Dx, Atkin-Flaitz, CGH array?(4)DMD (p.I1225T) Unreported  
8Face NNo Dx(2), SCN1A, CGH array (3), RPL10, NLG3, NLG4ATRX, FANCB, unreported missense  
9Clearly dysmorphic (2), no fit with XLMR with cerebellar abn.R/O mosaic (4), RSK2 or Aitkin-Flaitz (face only), array CGH (4), CDG screen, ECHO parents, Ritscher-Schinzel, MIM 304340, MED12, SMS?Intronic in BRWD3 & PAK3,likely non-pathogenicBrain MRI Dandy-Walker variant, N methylation for Angelman, UBE3A, Fragile X, transferrin isofocusing re CDG, plasma & organic acids, biotinidase 
10Face N (2), ear not abnormal, palpebrae not down slanting, thumb wide? Not Rubenstein-TaybiCGH array (4), GPC3UPF3B intronic 12bp dup, possibly pathogenicN karyotype, Fragile XN array CGH, GPC3 pending follow-up
11Inadequate info given (2), eyes deep set?, nose tip flat, Not dysmorphicPrader Willi (2)?, PHF6?, SNP array re del NFIX, PTEN, Clark-BaraitserIDS consensus splice change, Abn Iduronate-2-sulphatase  
12Hypotonic facer/o DM1 (3), RSK2 (2), Aitkin-Flaitz, brain MRI (2), CGH array, ATRX?, FG “spectrum” not MED12, SMSCULB4B missense, not pathogenic, in unaffected brotherN brain MRI, EEG, CGH array, TCF4 sequencing/MLPA 
13Looks syndromic, not straightening, pterygium?KBG (2), FGD1 but severe, HRAS-MAPK type (2), Juberg-Marsidi vs. ProudNXF5 nonsense mutation in 1,000 Genomes DB, no point mutations reported in NXF5- not thought causitive  
14Non dysmorphic (3), not Aarskog 4),short terminal phalanges?Chrom X array, FGD1, array, brain imagingARX 24 bp dup, abnormal  
15Hands look thick & wrinkledR/O RSK2 (3), Aitkin-Flaitz, HRAS-MAPK pathway?, cardiac ECHO, array CGHIL1RAPL1-missenseBrain MRI, Chiari I & cervical syrinx, N SNP array and Fragile XN cardiac echo, no further testing, family studies for IL1RAPL1 variant discussed
16Non Dysmorphic (3)Array CGH (3), Legius?BCOR (p.T1610I) missense, NLGN4X??N brain MRI, CGH array, Fragile X, Noonan chip, amino acid screen 
17 Array CGH (4), R/O del 22q13, Angelman (2)?, EEG, brain MRILAMP2 (IVS1-4G > C) likely non pathogenic  
18 Array CGH (2), Dubowitz (3), brain MRI, atypical Retts?NXF5 missense, CASK intronic changeN brain MRI, array CGH, Fragile X, PWS methylation 
19Non-dysmorphic (2)Not CLS or BFL, PTEN (2), Brain MRI, MRXS6, check pituitary-gonadal axis, Atkin-Flaitz?, array CGHLAMP2 missenseBrain MRIN array CGH, PTEN
20Sparse eyebrows, unruly hair, Non dysmorphic (2), Non-verbal & dyslexic?? (2)Array CGH (5), 16p11.3 dup/del, R/O pili torti, Smith-Magenis, Brain MRI, MRXS6, check pituitary-gonadal axis, NLGN3, NLGN4, and RPL10 but likely just macrocephaly-autismNBrain MRI and array declined, N Fragile X, subtelomeric FISH, karyotype., plasma amino acidsN array CGH, no RAI1 sequencing
21Ears normal,Array CGH (4), Smith-Magenis (2)? (RA1), FMR1, Brain MRI (2), 22q13?OPHN1 & PORCN missenseNormal SNP array, Fragile X, PWS methylation, acylcarnitines, plasma amino acidsNo further testing since panel
22Not dysmorphic (2), hands always in midlineFOXG1 (3), TCF4 (2), SLC9A6 (3), SLC16A2 (3), Array CGH (2), STXBP1, ARX, SCN1A, ATRX, RSK2, SLC9A6Normal  
23Striking but?Say-Meyer?, array CGH (5), OFD or OFP? FLNA?, HEWE1 > MECP2 dup > PQBP1 > ATRXPQBP1 missense- believed to be pathogenic  
24Not dysmorphic, hypotonic face, stop at array, many macrocephaly-hypotonia syndromes [RIGHTWARDS ARROW] panelDel 22q13, array CGH (4), FMR1 (4), RSK2?, FLNAACSL4 missense and IDS missense  
25More signs noted on photosr/o FANCB (2), X-array, brain MRI (2), PQBP1?NormalBrain MRI; microcephaly, sl prominent lateral ventricles; CGH array dup 1q25.1 & dup 2q36.3 (both maternal); N plasma amino & urine organic acids, Fragile X 
26Macrocephaly just familial (3), facial asymmetry (2)Array CGH, OAV spectrum?, brain MRI, predict N panel, RAS-MAPK?, UPF3B, HEWE1DMD synonymous change (mat. Inherited)Brain MRI; Chiari 1 & decompression, N CGH array, PTEN VUS (Paternal) 
27Not dysmorphic (3), palpebrae not downslantedArray CGH (2), FMR1 (2), Smith-Magenis?, if NSXLMR panel negative [RIGHTWARDS ARROW] FLNA & NLGN3&4Normal No further testing since panel
28Not dysmorphic (2) Stahl ear, some Hispanic-Oriental features? Too many acronyms! (2)Array was pending (3), NLGN3&4, RPL10Normal  
29Report insufficientSmith-Magenis?, RA1?, Kabuki?, array CGH, r/o Smith-Lemli-Opitz if syndactyly extends/not familial?, MECP2, ATRXFLNA missense (mat. Inherited) N array CGH, 7-dehydrocholesterol
30Perinatal origin? Late prenatal insult?, fungiform papillae tongue/melanotic macules? Mother diabetic?Mowat-Wilson?, repeat MRI nowNLGN4, OPHN1, AFF2, DMD, SYN1, NHS all with missense changes (all inherited) Repeat MRI under consideration as is exome sequencing.
31Not dysmorphic (2), palate 2ary to hypotonia & <tongue thrustarray CGH, FLNA??, not AarskogNormal N array CGH
32Report insufficient (2) need recent photosYoung RAS-MAPK pathway?, HUWE1 (2)??, FLNA re FG syndrome? Array CGH re 22q13.3 etc., R/O Sotos, Clark-BaraitserNormal  
33Not dysmorphic, ethnicity?TCF4??, ATRX (4)?,RSK2?, SCN1A?, R/O San Filipo (MPS)2NHS and SOX3 missense changes  
34Need recent photosARX, ATRX (2)??, Brain MRI, R/O Angelman incl'd variantsNormal Brain MRI “needed,” consider Angelman clinically R/O
35Little beyond familial traits (2), not Sotos (2), palpebrae horizontal, looks Sotos (2)Brain MRI, PTEN (2), NFIX, GDF6 (not delayed), CDG, investigate clonus-spine, array CGH (2), HUWE1CASK-noncoding Brain MRI; diffusely thick calvarium with heterogeneous marrow signal
36Not dysmorphicRepeat EMG, repeat MRI at >2 years, Pallister-Killian??, NSD1ATRX-missense Laboratory does not consider pathogenic; no further family studies no other studies (see text)
37Description several inaccuracies, not dysmorphicArray CGH (2), Angelman (2), brain MRI (2), ARX?, CASK (2)?,PLP1,SLC16A2MID1 synonomous and AP1S2 intronic  
38 CASK, PQBP1, ARX, STBP1, CDKL5, SLC25A22, CGH array, SPTANI, PEHO, brain MRI (2), ATRX, MEHMO (MRXS20), Norrie??, HUWE1 > PLP1NormalMRI white matter <volume, N MRS, array CGH; CDKL5, ARX, MSCP2, SLC9A6, ATRX seq & MLPA, plasma & organic acids, lysosomal studies, mitochondrial DNA 
39Big but not dysmorphic (3)Array CGH (4) Kabuki if panel negativeNormal N array CGH, Kabuki not done
40 SLC9A6, TCF4 (2) (was done), RSK2 (2), mild CDLS, ATRXSHROOM4 synonomous and L1CAM intronic  
41 Array CGH (3), R/O diploid/triploid mosaic, FLNAKIAA2022 synonomous N array CGH, karyotype
42 Array CGH (3), brain MRI, Cohen-funduscopic, SMS versus SLC16A2Normal  
43 FGD1 (3)??, PHF6, Cantu, ATRX (2)?, not FGD1 (2), array CGH, Kang syndrome?PHF8 missense Array CGH “equivocal” del 11p15.1, Referral MD consider PHF8 missense likely causal as pt & mum resemble Siderius XLMR; panel does not agree-remains a question
44Not dysmorphic (2) (hypotonic)ALDH18A1, brain MRITSPAN7 missense (SNP# and HGMD) and SHROOM4 missense and GPC3 intronic  
45Some facial asymmetryBrain MRI & Rt ear, spine radiographs, infant of diabetic mother + x-linked? (2), array CGH, SMS > Lujan (MED12)Normal  
46 some hints of PHF6 (3), r/o translocation (3), array CGH (3), FMR1-(PWS-phenotype),not CLS, HUWE1? (2),Clarke-Baraitser (2)?, not Aitkin-Flaitz or SGB, Aitkin-Flaitz or GPC3ATP7A missense  
47Not dysmorphic (2), slight midface retrusion, OFC?Family genome sequencing, PHF6?; NLGN3&4 > RPL10 > RAB39B. del PTCHD1 > MED12Normal  
48Need specifics of malformations (3), ears cupped only, telecanthus, anterior upsweepATRX? (2), Smith-Magenis?, GPC3 (2), FGD1, FLNA, UPF3BFLNA missenseCGH array, acylcarnitines, urine organic and plasma amino acids 
49Not very dysmorphic (3)Array CGH, HEWE1 > AP1S2PQBP1 nonsense-pathogenic N array CGH
50Not dysmorphic, cannot match photo to description, head disparity @ different agesSort out Marfan history (3), predict N (1)-(do) array CGH, Lujan-Fryns (MED12), Not Lujan-Fryns (2), r/o homocystinuria, oligosaccarides,DMD missense N homocystinuria; considering array, oligosaccarides, FBN1 VUS segregating in N mother & MGM
51Not dysmorphic (2)ARX, SYN1, non-specific heredofamilialIGBP1 noncoding  
52Inadequate information (2), blurred photo, not dysmorphic (2) NHS missense  
53Not dysmorphic (2), nose tip not bullbousBrain MRI, array CGH not likely, PLP1, CASK (2), array CGH, HEWE1 > AGTR2, Schimke > PLP1SRPX2 (SNP# and HGMD)  
54Lacking FH detailsATRX (4), RSK2, PWS?Normal N SNP array FRAXA, biochemistry including acylcarnitines, PWS
55BDLS unlikelyRubinstein-Taybi(4) but not typical?, array CGH (2), Not CDLS (NIPBL & SCMCA1 N?); Smith-Fineman-Myers (ATRX) > PQBP1 > Schimke > AP1S2Not complete N array CGH, Rubinstein-Taybi not done

Table II contains the comments and descriptors, suggested diagnoses and diagnostic tests, offered by the Panel, as well as the results of the XLID gene testing. In only the first patient did all Panel members suggest a single correct diagnosis; Mowat–Wilson syndrome was confirmed by ZEB2 testing [Garavelli et al., 2009] and the gene panel was not performed. A diagnosis was provided in an additional five cases by the XLID gene panel (Fig. 1). In two of those (Patients 5 and 23) the correct XLID gene was suggested by a single Panel member as one of four genes they suggested. The three remaining genes (Patients 11, 14, and 49) were not suggested by any panel member.

An important question is whether there are characteristics that single out the patients who had positive laboratory studies. Positive family histories of the five XLID-panel diagnosed cases were the mother of patient 11 who required special education, and a brother of patient 49 that was stated to be affected (no further information given). While both family histories are compatible with X-linked inheritance, neither is incompatible with other mode(s) of inheritance, nor would they be unusual in a typical clinical setting. Of the five cases only patient 23 was striking in appearance. Patient 14 had minimal (1 to 2 degrees) downslant to his palpebrae and some lateral orbital fullness (not dysmorphic). Patient 11 was obese and not dysmorphic. Patient 5 had macrostomia and wide-spaced teeth, and three of the panel spontaneously commented that patient 49 was not dysmorphic; based on the photographs, neither patient would stand out if of normal intelligence. Unfortunately, it has not proven possible, working back through third parties, to obtain consent to publish the photographs; indeed the patient with the UPF3B mutation had not returned to receive the positive laboratory result. Thus physical findings generally were not helpful in identifying those who carried an X-linked gene mutation, and helping to decide to whom the XLID-gene panel should be offered ($5,500).

Clearly at first glance the IDEAS Clinical Panel's efforts were not impressive in terms of recognizing specific non-XLID (vide infra) or in suggesting specific XLID conditions but the majority of those affected due to mutations causing XLID are not dysmorphic. We consider it unlikely that deficient referral data were the major reason for the low clinical diagnostic rate. It seems more likely that the answer lies in the referral source and type of patient being referred. The great majority of patients had been referred by various subtypes of Clinical Geneticist, who undoubtedly were experienced in evaluating individuals with intellectual disability, and so most readily recognizable syndromes were excluded from IDEAS, with only the most challenging examples referred for the 92 gene XLID panel and the clinical assessment. Indeed for many in Genetics practice today, their experience suggests that the many readily recognizable syndromes are diagnosed before the patient is referred to Genetics. This opinion is supported by the fact that, in addition to the 25 cases discussed above as non-dysmorphic, a further 12 were noted as non-dysmorphic on the referral sheet, which left only 18 patients with an appearance that might have suggested a syndrome diagnosis—one of which was diagnosed. Our conclusion that patient selection is important is further supported by the outcomes of the first 200 cases evaluated by the 26 centers participating in the European DYSCERNE project. This program had a somewhat broader spectrum of type of referring physician and also had a gate-keeping process that assured adequate data and photographs, and selected patients considered suitable for review [Douzgou et al., 2013]. A consensus diagnosis was suggested for 22.5% of the patients and follow-up of 40 of these cases at the time of publication reported confirmation of the diagnosis in 17 (including one “new” syndrome by exome sequencing), and negative testing in 10 with tests pending in five others.

Panel members often made one or more suggestions regarding specific XLID genes (Table II, column 5, highlighted in gray), as well as for other diagnoses, for some of which gene testing is available. Suggestions for more general investigations such as MRI or array CGH were often made when this information had not been provided. Suggestions were forwarded to the referring physician for cases where the XLID gene panel was uninformative. The mean number of specific genes suggested for all panel members per case was 0.88 and ranged from 0 to 2.17 for individual cases. Panel members differed in the mean number of suggestions they made per case with the range from 0.51 to 1.62. The six clinical panelists provided a total of 324 individual responses for the 55 cases; each response providing an opportunity to suggest one or more genes. There were 164 (50.6%) of replies where no specific gene was suggested, 94 (29%) with one, 38 (11.7%) with two, eight with three, seven with four, four with five, and three with six genes suggested. Generally more XLID genes were suggested by those most closely associated with the Greenwood Genetic Center, undoubtedly reflecting their greater familiarity with those genes.

There were 29 of 55 patients where no information was provided as to prior testing (Table I, column 9). Letters requesting whether tests of specific interest to one or more of the panel members (e.g., brain MRI, microarray) had been carried out were sent to the referring physician and responses obtained from 12 (41%). Those tests are shown in Table II, column 6. Specific, non X-linked panel, testing was suggested in 45 cases and requested follow up data were obtained for 20 (44%). The replies included normal arrays in 10 patients and specific suggested genes tested in five. Many had not had further testing with respect to specific genes/diagnoses suggested. Likely in many cases the patient is yet to be seen again and/or the clinicians are awaiting further consensus on the role of whole genome/exome sequencing.

Novel missense mutations were found in two patients. Case 36 had an ATRX missense change and further testing showed his mother was heterozygous, a developmentally disabled maternal uncle was hemizygous, and unaffected brother hemizygous normal. The uncle had a questionable history of birth trauma as a cause for his delays. The referring physician and clinical panel did not consider the patient dysmorphic. The laboratory continues to consider this a variant of unproven significance. Case 43 had a novel PHF8 missense change. The referring physician considers the mutation and the patient's physical findings are compatible with Siderius syndrome, which has been associated with this gene [Siderius et al., 1999; Laumonnier et al., 2005]. No further family laboratory studies have been carried out to date, and the Panel, while agreeing the child is dysmorphic, does not think the findings characteristic of Siderius syndrome.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND ANALYSIS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. Appendix A
  10. REFERENCES

Is there anything to be learned from our experience? Likely it adds credence to what many have come to realize as we have experienced the generalization into practice of microarrays and as we enter the exome/genome era—the role of the clinical geneticist/dysmorphologist has changed and will continue to do so. Already we spend considerable time explaining variants of unknown significance (VUS) to families and are frustrated by the lack of any significant and useful clinical data for many/most of these variants. Exome and genome sequencing can be expected, at least initially, to magnify this problem and it has been suggested that clinical dysmorphologists must increase the skill with which they assess the patient's phenotype. In many cases this will occur post hoc, when test results are reported, and this suggests the need for a centralized clinical database [Hennekam and Biesecker, 2012; Robinson, 2012]. The Clinical IDEAS Panel did not have test results at the time they reviewed the patients. There have been recent major efforts to clearly define the descriptive terminology in dysmorphology [Allanson et al., 2009] but our experience is that there was quite frequent difference of opinion between the Panel and the referral data regarding the presence or absence of a finding and whether a child was truly “dysmorphic.” Thus before there can be a meaningful database there needs to be a standardization of clinical assessments. Furthermore, it was apparent that a significant percentage of physicians were not willing, perhaps related to available time and resources, to fully complete a simple, one-page, form regarding a patient for which they sought diagnostic help. One must wonder if they would be any more willing to commit to a detailed and standardized assessment for a standardized database.

Clearly many patients present significant diagnostic challenges and although early results with exome/whole genome sequencing are impressive, the patients tested to date tend to have been selected for moderate to severe delay, with or without dysmorphic signs, and/or sensory disabilities [Brunner, 2013]. They do not represent the more common mildly delayed child that often has a parent or parents with a learning disability, and it is clear that in many cases patients will continue to lack a causative diagnosis/explanation for their developmental delay into the foreseeable future. It is reasonable to consider the logic as to why, and how far, we pursue diagnostic testing in patients with DD/ID, because, notwithstanding current and anticipated reductions in cost, the total health care spending for genetic testing has increased dramatically, and this is being scrutinized by governments that provide universal health care and by private insurers. An example of how costly it can be to find a diagnosis was provided by Barge-Schaapveld et al. [2013]. They investigated a 25-year-old woman with moderate ID and essentially normal appearance. They found a 298 kb deletion that included the gene GPD2. Sequencing uncovered a variant in the patient's single GPD2 copy; also present in her mother and sister. Functional studies showed 0% activity in the patient and 50% in mother and sister. The authors considered this circumstantial evidence for a role for this gene in the patient's disability, and provided the total cost of investigating this single patient—US$27,029. The high costs that can be involved in genetic diagnoses have also been reported recently by Shashi et al. [2014]. To provide such service in a health care setting requires due consideration that there should be significant realizable benefit to the patient and family. We must also keep in mind that there is potential for our testing to “do harm,” be it with results of uncertain or of known significance, or provision of information beyond what was sought. We must also be certain of the cause and effect relationship of a new genetic change in a known gene where a patient's findings are outside the characteristic changes generally associated with mutations in that gene, or where the clinical expression of the gene is non-syndromic.

Providing an answer to “Why did this happen?” for families whose child has unexplained developmental delay is a justifiable indication for genetic testing. Included here is the concern that the cause was somehow their fault. However, not uncommonly, this reason has a limited lifespan and once a few years have gone by and the parents have come to know, understand, and love their child, the focus changes from why to, how do we help our child and provide the best opportunities for the future? If the question is asked of patients arriving at their genetics appointment, “do you know why you are here?” the answer very often is “we have no idea” or is completely misinformed. Quite often it is the referring physician, not the family, who wants a causative diagnosis. If the pros and cons of testing are fully discussed it is not uncommon to have parents decline further studies because it will not change anything for them or their child. There is sometimes an important exception to the frequent lack of direct benefit of a diagnosis for the child, and that is when the absence of a diagnosis is inhibiting the provision of developmental services. In that case a diagnosis, even a variant of unknown significance, can be used to open the door for needed support.

Family planning, trying to obtain a specific recurrence risk for parents, or occurrence risk for the extended family, is a sound reason to pursue a diagnosis. The question of cause may also reemerge regarding reproductive implications for normal sibs. However, it is incumbent on us to consider whether the parents plan further children and/or whether there is a close relative likely to have children in the foreseeable future. Clearly discussion must be tempered with particular caution where a family history strongly suggests an increased risk in the extended family. If the answer is no in the latter instance, it may make sense to wait, hopefully for a future with better and less costly testing. It is important to ensure the family understands that present testing does not exclude a genetic cause even if all results are negative and that a review by genetic services, especially for patients with moderate and greater delays and/or physical signs, remains important, particularly when siblings are starting to consider having their own families. It will be of interest to see if further experience with exome sequencing confirms the finding that a large proportion of sporadic patients with ID, born to nonconsanguineous parents, represent de novo mutations and that autosomal recessive inheritance is not common [Brunner, 2013]. It will be important to maintain an active dialogue between professionals as to the most appropriate and effective approach to evaluating patients with intellectual disability.

Most clinical geneticists/dysmorphologists would admit that an aspect of their work that gives great satisfaction is when they make a diagnosis for a referred patient. However, in a service setting this should not be a prominent reason for ordering expensive tests that are not of direct benefit to the patient/family, and could potentially have negative consequences. If there is not a clear clinical indication surely testing belongs in the research setting with its separate funding and safeguards for the patient.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND ANALYSIS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. Appendix A
  10. REFERENCES

Our experience has been that the likelihood of further clinical assessment of a patient already seen in genetics leading to a diagnosis is low, unless the time since the initial visit has allowed the development of new diagnostic tests. Well-recognized conditions with a distinct pattern of signs and/or routine diagnostic test have already been diagnosed. Many of the patients we were asked to assess fell in a spectrum where what is called dysmorphic is really often on the basis of normal variations in appearance that would not really draw attention but for the developmental delay. A major role of a clinical geneticist will be not only to document the variability of dysmorphic signs but also the variability of clinical expression of intellectual disability in the extended family. A new role for clinical geneticists in the future will be to assess, describe and forward to a database specific clinical data regarding new genes and/or their variants, if we are ever to provide secure and helpful interpretation of results to families. From our experience, we can say it is not enough to use the correct terminology for dysmorphic signs; we must also assess the presence or absence and level of expression of those signs in an objective and as standardized a way as possible.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND ANALYSIS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. Appendix A
  10. REFERENCES

We would like to thank the referring physicians who participated by forwarding summary information regarding their patients. This work would not have been possible without the dedicated work of staff at GGC who assembled the information for distribution, reviewed and summarized results and sent the letters of enquiry regarding prior and later laboratory studies.

Appendix A

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND ANALYSIS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. Appendix A
  10. REFERENCES

Patient Referral Information Form. Patient name was substituted by a case number before transmission to panel.

ajmga36456-gra-0001

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND ANALYSIS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. Appendix A
  10. REFERENCES