664 J Med Genet 1999;36:664–669 J Med Genet: first published as 10.1136/jmg.36.9.664 on 1 September 1999. Downloaded from Original articles

A new (DYX3) for dyslexia is located on 2

Toril Fagerheim, Peter Raeymaekers, Finn Egil Tønnessen, Marit Pedersen, Lisbeth Tranebjærg, Herbert A Lubs

Abstract skills, and adequate schooling.1 In 1950, Developmental dyslexia is a specific read- Hallgren2 reported that more than 80% of chil- ing disability aVecting children and adults dren with dyslexia in Stockholm schools had who otherwise possess normal intelli- other family members with dyslexia. Subse- gence, cognitive skills, and adequate quent studies have shown that there is both a schooling. DiYculties in spelling and physical and genetic basis for many children reading may persist through adult life. and adults with severe reading disability and Possible localisations of for dyslexia that the most frequent deficit is in phonological have been reported on 15 coding.34This is manifested by decreased abil- (DYX1), 6p21.3-23 (DYX2), and 1p over the ity to pronounce letter strings (or pseudowords) last 15 years. Only the localisation to correctly that have not been encountered previ- 6p21.3-23 has been clearly confirmed and ously. Recent studies using new methods have a genome search has not previously been provided a clearer view of the diVerence in the carried out. We have investigated a large processing of written words in dyslexics and Norwegian family in which dyslexia is non-impaired readers. In none of the studies, inherited as an autosomal dominant trait. however, were the details of the family history A genome wide search for linkage with an known, and gene localisation studies were not average 20 cM marker density was initi- carried out. Using whole brain magnetoen- ated in 36 of the 80 family members. The cephalograpy,5 it was shown that in response to linkage analysis was performed under reading lists of real and non-words normal Department of three diVerent diagnostic models. Linkage readers first activated the posterior occipital http://jmg.bmj.com/ Medical Genetics, analysis in the family identified a region in cortex in 150 ms, then activated the left tempo- University Hospital of 2p15-p16 which cosegregated with dys- roparietal area by 184 ms. Six dyslexics, Tromsø, N-9038 lexia. Maximum lod scores of 3.54, 2.92, however, failed to activate the temporoparietal Tromsø, Norway and 4.32 for the three diVerent diagnostic region in the first 200 ms and instead activated T Fagerheim M Pedersen models were obtained. These results were the right or left inferior frontal gyrus. This L Tranebjærg confirmed by a non-parametric multi- region contains Broca’s area and its activation H A Lubs point GENEHUNTER analysis in which suggests the use of guessing as an alternative on September 24, 2021 by guest. Protected copyright. the most likely placement of the gene was processing strategy. Using functional magnetic Neurogenetics ina4cMinterval between markers resonance imaging (fMR)6 and a carefully con- Laboratory, D2S2352 and D2S1337. Localisation of a Department of structed, increasingly complex series of reading Biochemistry, Born gene for dyslexia to 2p15-16, together with tests, 29 dyslexics were found to show relatively Bunge Foundation, the confirmed linkage to 6p21.3-23, con- less posterior activation (including Wernicke’s University of Antwerp stitute strong evidence for genetic area, the angular gyrus, and striate cortex), and (UIA), Belgium heterogeneity in dyslexia. Since no gene increased activation anteriorly (inferior frontal P Raeymaekers for dyslexia has been isolated, little is gyrus), compared to non-impaired readers. known about the molecular processes Center For Reading These studies show the use of a diVerent Research, Stavanger, involved. The isolation and molecular processing pathway in response to phonological Norway characterisation of this newly reported tasks and the presence of an altered temporal F E Tønnessen gene on (DYX3) and DYX1 response in dyslexics. In addition, impaired dis- will thus provide new and exciting insights crimination of both rapidly presented visual and Division of Genetics, into the processes involved in reading and Department of auditory non-verbal information have been 7–9 Pediatrics, Miami, FL, spelling. reported, and a more generalised defect in the USA (J Med Genet 1999;36:664–669) rapid processing of information may also play a H A Lubs Keywords: developmental dyslexia; reading disability; role in some or all instances of dyslexia. Many children under 2 years of age with Correspondence to: linkage analysis; chromosome 2 Dr Fagerheim. damage to the language areas of the left hemi- sphere can go on to develop satisfactory Revised version received Developmental dyslexia is a specific reading language ability. This observation implies that 28 April 1999 Accepted for publication disability aVecting children and adults who specialisation of the brain mechanism responsi- 5 May 1999 otherwise possess normal intelligence, cognitive ble for language function is not completed at A new gene for dyslexia is located on chromosome 2 665 J Med Genet: first published as 10.1136/jmg.36.9.664 on 1 September 1999. Downloaded from I ??

81 79 79 70 77 76 76 74 70 64 II 1 2 43 65 7 8 91415

41 12 46 11 11 11 42 12 12 21 53 34 51 51 55 23 53 64 18 12 22 18 18 66 32 12 46 22 24 21 22 22 24 14 24 21 38 36 33 38 38 33 38 36 34 21 21 43 21 21 13 11 21 42 23 22 32 23 23 32 13 22 32

53 55 36 43 38 35 49 5047 39 44 47 41 36 35 34 32 30 III 1 34567 8 9 10 12 15 16 17 18 21 23 24 30 31 32

11 41 14 11 11 51 11 14 24 11 11 11 25 21 11 22 12 24 53 55 53 53 13 55 41 15 15 55 35 36 56 34 83 18 12 28 13 32 83 13 78 86 86 16 85 24 14 26 24 22 22 42 24 13 24 21 41 22 22 24 44 42 22 41 86 36 33 16 35 48 85 37 23 83 83 33 13 63 33 64 14 22 14 42 24 43 14 22 43 11 11 23 33 14 24 12 33 23 23 23 21 33 31 23 32 33 33 22 33 23 23 22

25 21 11 13 19 18 16 17 15 9 13 11

5 6 7 9 11 12 13 20 21 23 32 33 Marker order: 11 11 36 11 11 15 11 42 12 12 15 Telomere 54 54 54 55 33 35 53 54 54 53 53 38 38 32 18 32 13 12 37 17 18 68 D2S1352 IV 12 12 11 22 43 21 23 14 24 24 44 36 36 43 36 58 34 38 72 32 31 31 D2S2352 42 42 13 12 43 24 23 24 24 23 33 D2S378 33 33 32 23 13 23 23 33 23 23 23 D2S2279 D2S2183 Positive on tests for dyslexia + history of reading problems D2S1337 D2S393 Positive tests only Positive history only Centromere Figure 1 Pedigree showing only family members who were included in the linkage analysis. Pedigree numbers from the complete pedigree are retained. The numbers given above the symbol are the ages at the time the study was initiated. The proband (III.9) is indicated by an arrow. Boxed haplotypes indicate the haplotype cosegregating with dyslexia. Two critical recombinants were observed in adult patients (II.1, III.7) and their oVspring (III.3,IV.9) establishing the DYX3 candidate between markers D2S2352 and D2S1337. In generation IV,IV.7to IV.33,who were below the age of 20, were excluded from the model 3 linkage analysis. Chromosome analysis of III.31 was normal. that age and that the plasticity of these complex genes may be involved. In order to identify neural networks permits their adaptive reor- possible additional genes predisposing to ganisation. In contrast, the majority of teenag- dyslexia, we have carried out a genome search ers who experience comparable brain damage and performed linkage analysis in a large Nor- http://jmg.bmj.com/ never recover normal language function.10 A wegian family in which dyslexia is clearly molecular test, or tests, for dyslexia, which inherited. The pedigree is shown in fig 1. would result from cloning genes for dyslexia, would allow earlier diagnosis of children at Methods high risk for dyslexia. This in turn would TESTS FOR DYSLEXIA permit institution of therapy while the lan- The test instrument used to test for dyslexia in guage areas were at an earlier, more plastic the Norwegian population was developed at

stage of development. the National Center for Reading Research. The on September 24, 2021 by guest. Protected copyright. The localisation of a susceptibility locus for assessments of both orthographic and phono- dyslexia to 6p21.311 has been confirmed in logical abilities are very similar to those used in three independent studies.12–14 Localisation to the genetic studies of Olson et al23 and the 6p, however, was not found in a large sib pair Woodcock Reading Mastery Tests.24 However, study,15 or in the large family studied by Sawyer a measure of reaction time was also included in et al.16 The linkage with chromosome 15p three of the tests. markers reported in 198317 was not initially The present dyslexia test battery was based confirmed,11 18 19 but two recent reports suggest on selected subtests from a series of tests given a localisation to D15S143, with lod scores of to Norwegian school children with possible 3.1512 and 1.38.20 This marker, however, is 49 reading problems to test their reading level and cM distal to the centromere and thus does not ability (KOAS25 and KOAP26). Tests were pre- confirm the earlier localisation with 15p mark- sented in a standardised form from a compu- ers. A locus on 1p has also been considered ter. The most informative five subtests from because of a suggestive lod score at 1p34-3621 KOAS and KOAP were selected and supple- and the identification of a family in which dys- mented with a standardised spelling test. Three lexia segregated together with a tests were scored both by time of response and 46,XY,t(1;2)(p22;q22) translocation.22 By percentage correct (table 1). analogy to many other common inherited Any history of reading and spelling problems disorders, genetic heterogeneity is likely and in school was also recorded for the family could provide some explanation for the high members. In generations I and II, since the frequency of dyslexia, but has not yet been school system at that time was often not aware clearly shown. Furthermore, the complexity of of dyslexia, family members were considered as the reading process also suggests that many aVected when two tests were abnormal in the 666 Fagerheim, Raeymaekers, Tønnessen, et al

absence of a history of reading problems. There show bimodality. Cut oV points defining J Med Genet: first published as 10.1136/jmg.36.9.664 on 1 September 1999. Downloaded from was no history of recognised dyslexia in aVected status were selected to include these generation I. Only family members above the extreme values and to minimise overlapping age of 8 years were tested. The tests derived values. Using these cut oV points only four of from the KOAS and KOAP test battery were as 198 scores in the overall study were scored as follows. positive in the 27 unaVected family members (1) KOAS 1 is a test of how well the subject or spouses. The known distributions of test can read words in isolation when given a scores in older school children (14-15 years) generous amount of time; 72 common words were also helpful in determining these cut oV are presented one at a time on the computer points. Because of this conservative definition screen. The subject is asked to read the word of the cut oV points, only two of nine test scores aloud into a microphone as quickly as possible. were required to be abnormal to establish an The computer registers the amount of time the aVected status. One, however, had to be a non- subject takes. The results are recorded both as word test, since non-word tests are generally percentage pronounced correctly and response accepted as the most discriminate. Thus, the time. The remaining tests are similarly admin- cut oV points in adults were established istered and scored. empirically and the determination of aVected (2) KOAS 2.1 tests how well the subject can status was primarily based upon non- read when given a very short amount of time; 72 overlapping, outlying scores. common words, diVerent from KOAS 1, are Too few (aVected or unaVected) children flashed on the screen one at a time, each were available to establish comparable cut oV presentation lasting only 100 msec. Otherwise points in children. Inspection of the distribu- this test is administered in the same way as tions of scores in Norwegian school children KOAS 1. did not show obvious cut oV points, and there (3) KOAS 3.1 tests the subject’s ability to was no basis for comparing a group of those “read” non-words (experimentally designed children with familial dyslexia with other letter strings such as “wug” or “mape” that are children, since no family history or genetic data orthographically acceptable, but semantically were available. Therefore, it was necessary to empty); 36 non-words are presented. use the adult cut oV points even though it was (4) KOAP 9A measures the subject’s ability known that the test means in children changed to form words on the basis of individually pre- significantly from grades 2 to 10. Conse- sented phonemes. The test giver pronounces a quently, it was anticipated that both false posi- series of sounds, for example, /b/, /æ/, and /g/, tive and negative results might occur in with 0.5 second pauses between the sounds. children. The cut oV points for the tests are The subject is then asked to blend the sounds shown in table 1. into a familiar word (“bag”). The test consists of 16 sequences of phonemes which are from GENOTYPING three to nine phonemes long. (Reaction time is The family was ascertained through the Norwe-

not measured.) gian Dyslexia Association in response to our http://jmg.bmj.com/ (5.) KOAP 9B is the same as KOAP 9A, but request for large families for linkage analysis. presents 16 sequences of phonemes that make Candidate regions were first screened using 12 up non-words. markers on 1p, 11 markers on 6p, and 11 mark- (6) Spelling from dictation. This is a ers on 15q. A total of 307 highly informative di-, standard list of 50 Norwegian words, both tri-, and tetranucleotide repeat markers were regular and irregular, scored as percentage cor- selected for an (average) 20 cM genome screen, rectly spelled. used in all aspects of the genome wide screening

study. PCR primers were labelled with either on September 24, 2021 by guest. Protected copyright. ESTABLISHMENT OF CUT OFF POINTS 6-FAM, TET, or HEX phosphoramidites, and The distributions of the initial scores in family pooled PCR products were run on a 377 members who had a clearly positive history sequencer (Applied Biosystems). The runs were were compared with spouses and family mem- followed by analysis with GENESCAN™ (ver- bers having a clearly negative history. Although sion 2.0), and the results were entered in the majority of scores overlapped in these two CYRILLIC (version 2.1) for generation of link- sets of test results, the distribution of scores age files and haplotype analysis. among those with strongly positive histories were clearly skewed in the direction of a lower LINKAGE ANALYSIS percentage correct or prolonged response Parametric linkage analysis times. The number of family members in- Since there was no single reliable diagnostic cluded in this comparison was too small (20) to test available, it was decided to carry out a cat- egorical linkage analysis assuming an auto- Table 1 Test results somal dominant inheritance pattern with reduced penetrance rather than a quantitative Cut oV scores trait locus model. This seemed reasonable Test % correct Milliseconds (ms) since an autosomal dominant model was com- patible with the segregation of the trait in this KS1- ordinary words <90 >900 family. It should be noted, however, that the KS2.1- ordinary words <96 >625 KS3.1- non-words <91 >1925 inheritance of dyslexia is complex and that the KP9A- phonemes to words <70 eVects of sex diVerences in penetrance, KP9B- phonemes to non-words <56 heterogeneity, absence of a definitive diagnos- Dictation (spelling) <86 tic test, and age compensation all complicate A new gene for dyslexia is located on chromosome 2 667 J Med Genet: first published as 10.1136/jmg.36.9.664 on 1 September 1999. Downloaded from 0.0001 normal cases and dyslexic cases with both positive history and tests; penetrance and phe- nocopy values were as in model 1. Cases with more uncertain diagnosis were considered p = 0.0009 0.001 unknown. Model 3 is essentially the same as model 1, but excluded all subjects under the age of 20. To correct for multiple testing in our linkage analysis we used the 3 + log(n) 0.01 p = 0.016 formula, where n is the number of models used. This gives a lod score of 3.47 as a thresh- p = 0.023 Model 3 old for claiming significant linkage in our two Model 2 point parametric analysis. NPL associated p value 0.1 Model 1 Non-parametric linkage analysis Non-parametric multipoint linkage analysis was employed using the GENEHUNTER pro- 1 29 01520015 gram. NPL Zall scores were calculated for all cM three models and the associated p values are presented in fig 2. The whole pedigree could not be analysed in GENEHUNTER, so less in-

D2S2294 D2S119 D2S2295 D2S2240 D2S2378 D2S1352 D2S2352 D2S378 D2S2279 D2S2183 D2S1337 D2S393 D2S357 D2S337 D2S134 formative healthy subjects who did not have Figure 2 Non-parametric multipoint mapping results of aVected descendants were excluded. In model 1, the DYX3 locus for three diagnostic models. The 15 markers the pedigree had to be split into two parts, which in 2p15-p16 are presented in order on the x axis. NPL Zall probably led to some loss of information. scores were calculated using the GENEHUNTER program and the associated p values are presented. The DYX3 gene is mapped between the same flanking markers (D2S2352 Results and D2S1337) found by inspection of the marker A genome wide search beginning with the three haplotypes in fig 1. reported possible loci for dyslexia (see Meth- an exact analysis of the mode of inheritance. ods) was initiated in 36 members of the family, Two point lod scores were calculated using the using a total of 307 microsatellite markers MLINK program of the LINKAGE package (Fagerheim et al, in preparation). This screen- (version 5.1).27 In all analyses, the gene ing did not show significant linkage, but marker frequency for dyslexia was set to 1% and D2S1356 at 2p15-p16 showed a slightly marker allele frequencies were estimated from positive lod score of 0.8. Analysis of 17 the family. In model 1, the penetrance and additional microsatellite markers in the region phenocopy rates for males and females who gave strong evidence in favour of linkage (table were scored as positive on the test battery and 2).30 The parametric linkage analysis was who had a positive history of reading impair- calculated under three diVerent models. Model

ment were set to 0.99 and 0.04, and 0.85 and 1 included all adults and children depicted in http://jmg.bmj.com/ 0.01, respectively. These figures correspond to fig 1. This model assumes sex dependent pen- a population prevalence in the Norwegian etrance and phenocopy values and diVerential population of 5.9% in males and 2.7% in diagnostic weight factors as described in the females. These penetrance and phenocopy Methods section. Model 2 included all normal values were similar to results obtained in earlier readers and only the aVected family members segregation studies.3 Cases with either a with both a history of reading problems and positive test result or a positive history, but not positive testing. Because of concern about the both, were given a diagnostic weight of 75% of accuracy of the test results in classifying school on September 24, 2021 by guest. Protected copyright. the clearly dyslexic cases.28 Model 2 used only children, as discussed above, a third analysis model excluded all persons under the age of 20 Table 2 Maximum lod scores for two point linkage analysis of dyslexia with 2p15-p16 (IV.7 to IV.33). As indicated in table 1, markers maximum lod scores were obtained for the Model 1* Model 2 Model 3 three models with markers D2S2183 (Z=3.53, Distance è=0.00), D2S393 (Z=2.93, è=0.0), and Marker Zmax èmax Zmax èmax Zmax èmax in cM† D2S378 (Z=4.32, è=0.0), which are within a 3 D2S177 0.058 0.22 0.009 0.23 1.363 0.03 63 cM region. Most importantly, the “Lander- D2S1356 0.818 0.20 0.652 0.21 1.856 0.05 65 Kruglyak” criteria of 3.3 for genome wide sig- D2S2328 2.565 0.00 2.234 0.04 2.005 0.06 65 nificance were exceeded in two of the three D2S2294 0.415 0.19 0.258 0.20 1.439 0.06 68.2 31 D2S119 0.915 0.17 0.381 0.22 1.949 0.00 69 analysis models. In addition, correcting for D2S2298 1.195 0.18 0.835 0.19 2.147 0.06 70 multiple testing in our analysis calculated the D2S2240 0.689 0.19 0.238 0.24 1.458 0.09 73.3 threshold for reporting significant linkage as D2S2378 0.697 0.20 0.484 0.20 1.771 0.06 74 D2S1352 1.440 0.08 1.162 0.07 1.153 0.07 76 3.47, and this was obtained for both models 1 D2S2352 2.860 0.03 2.920 0.00 2.674 0.03 80 and 3. Furthermore, lod scores in excess of 3 D2S378 2.668 0.09 2.055 0.11 4.323 0.00 81 D2S2279 0.614 0.18 0.429 0.19 2.160 0.00 81 were obtained in models 1 and 3 with other D2S2183 3.525 0.00 2.789 0.00 2.860 0.00 81 markers from the 2p15-p16 region as well D2S1337 1.152 0.17 0.762 0.19 2.393 0.03 82 (D2S393 for model 1 and D2S357, D2S393, D2S393 3.467 0.00 2.929 0.00 3.051 0.00 84 D2S357 1.550 0.15 0.965 0.18 3.010 0.02 84 D2S337 for model 3). Parametric high density D2S337 1.766 0.15 1.170 0.17 3.010 0.02 84 multipoint linkage analysis greatly increases D2S134 0.257 0.26 0.026 0.41 0.011 0.32 88 the number of false negative mapping results in *Models 1–3 are defined in the text. cases where the exact mode of inheritance of †Distances from p telomere according to the Généthon linkage map. the disorder is unknown.32 Therefore, we 668 Fagerheim, Raeymaekers, Tønnessen, et al

decided to perform a non-parametric multi- B, a calmodulin dependent J Med Genet: first published as 10.1136/jmg.36.9.664 on 1 September 1999. Downloaded from point linkage analysis (NPL) using the pro- phosphatase, which constitutes 1% of the total gram GENEHUNTER.29 Although not en- brain protein, was roughly mapped to the tirely meeting the levels of genome wide region by in situ hybridisation.34 It was significance, this independent method essen- therefore an obvious candidate gene, but tially confirmed the two point lod score results sequencing of the whole coding region did not (fig 2). The lower lod score may have resulted detect any changes in the sequence in two from loss of information owing to exclusion of aVected family members. Recent mapping normal family members. NPL associated p information, however, has placed calcineurin B values of 0.023 (model 1), 0.016 (model 2), centromeric to the candidate region.35 and 0.0009 (model 3) were obtained in the The finding of linkage to 2p15-p16 in this region between D2S2352 and D2S1337. The family and the confirmed linkage to 6p21.3 distance between these markers is approxi- indicate that dyslexia is heterogeneous. Clon- mately 4 cM according to the latest Généthon ing of the DYX3 gene will provide important linkage map.33 This localisation was confirmed insight into the nature and frequency of at least by inspection of marker haplotypes, which one gene that is involved in reading and identified two critical recombinants (II.1 and spelling. Furthermore, it represents an oppor- III.7) in adult patients. These placed the DYX3 tunity to study the phenotypic variation associ- locus centromeric to D2S2352 and telomeric ated with one gene, and to develop better rou- to D2S1337 (fig 1). tine testing by correlating test results with specific genotypes. It will also be of great inter- Discussion est to determine whether magnetoencephalo- The present family is one of the few large, well graphy or fMR will provide evidence of clinical studied kindreds in which dyslexia is inherited subtypes when combined with a precise genetic as an autosomal dominant trait (fig 1). The diagnosis. Specific remedial plans and a more dyslexia was generally mild to moderate in this predictable long term outcome may also be family, and most of the 11 aVected adults important benefits. responded well to minimal therapy or compen- sated over time. A computer administered test We are deeply indebted to all members of the family who made battery was used for the diagnosis of dyslexia. In this research project possible. We thank Dr Wadelius and the Nordic Genome Initiative for providing us with the genetic order to classify a family member as dyslexic, markers and a special thanks to Dr Gotthold SchaVner and two of the nine test scores had to be positive coworkers at the Service Department at IMP, Vienna, for excel- lent help and service to TF at a critical stage of the project. This (see Methods). A broader version of this test research project was funded in part by the Norwegian National system is used throughout Norway to evaluate Research Council to FET, HL, and TF (grant no 107367/330). The study was approved by the Research Ethical Committee of children with possible reading problems. Cut Health Region 3, Norway. oV points for this study were developed empiri- cally by comparing results in clearly aVected 1 Critchley M, Critchley E. Dyslexia defined. London: and clearly normal adults after 20 subjects had Heinemann Medical Books, 1978. 2 Hallgren B. Specific dyslexia. Acta Psych Neurol 1950;suppl

been tested. No unaVected and only three 65:1-273. http://jmg.bmj.com/ aVected young children were initially available 3 Pennington BF, Gilger JW, Pauls D, Smith SA, Smith SD, DeFries JC. Evidence for major gene transmission of in the family, so that comparable empirical developmental dyslexia. JAMA 1991;18:1527-34. norms in children could not be developed. As 4 Pennington BF. Using genetics to dissect cognition. Am J Hum Genet 1997;60:13-16. anticipated, these norms worked well in adults 5 Salmelin R, Service E, Kiesila P, Uutela K, Salonen O. but were less accurate in school children Impaired visual word processing in dyslexia revealed with magnetoencephalography. Ann Neurol 1996;40:157-62. because the continuous development of reading 6 Shaywitz SE, Shaywitz BA, Pugh KR, et al. Functional dis- ability during the school years results in both ruption in the organization of the brain for reading in dys- lexia. Proc Natl Acad Sci USA 1998;95:2636-41. year specific means and wide standard devia- 7 Livingston MS, Rosen GD, Drislane FW, Galaburda AM. on September 24, 2021 by guest. Protected copyright. tions. A retrospective review of the haplotype/ Physiological and anatomical evidence for a magnocellular defect in developmental dyslexia. Proc Natl Acad Sci USA phenotype correlation in children showed 1991;88:7943-7. several discrepancies (IV.7, IV.11, IV.32, and 8 Tallal P, Miller S, Holly Fitch R. Neurobiological basis of speech: a case for preeminence of temporal processing. Ann IV.33). IV.33, who had a strongly positive NY Acad Sci 1993;682:27-47. history of reading problems and possible atten- 9 Gross-Glenn K, Skottun BC, Glenn W, et al. Contrast sen- sitivity in dyslexia. Neuroscience 1995;12:153-63. tion deficit hyperactivity disorder (ADHD), 10 Fisher KW,Lazerson A. Human development.From conception tested positively on all tests for dyslexia, but did through adolescence. New York: Freeman: 1984. 11 Cardon LR, Smith SD, Fulkner DW, Kimberling WJ, Pennig- not have the aVected haplotype. On the other ton BF, DeFries JC. Quantitative trait locus for reading dis- hand, her brother, IV.32, had no history of ability on chromosome 6. Science 1994;266:276-8. 12 Grigorenko EL, Wood FB, Meyer MS, et al. Susceptibility reading disability and fell in the dyslexia range loci for distinct components of developmental dyslexia on on only one test, a non-word test, but had the chromosome 6 and 15. Am J Hum Genet 1997;60:27-39. 13 Gayán J, Smith SD, Cherny SS, et al. Quantitative-trait disease haplotype. He was classified as normal locus for specific language and reading deficits on chromo- in the linkage analysis, but may represent an some 6p. Am J Hum Genet 1999;64:157-64. 14 Fisher SE, Marlow AJ, Lamb J, et al. A quantitative-trait instance of non-penetrance. These and other locus on chromosome 6p influences diVerent aspects of discrepancies clearly indicate the need for better developmental dyslexia. Am J Hum Genet 1999;64:146-56. 15 Field LL, Kaplan BJ. Absence of linkage of phonological tests in children. Since most of the study coding dyslexia to chromosome 6p23-p21.3 in a large fam- subjects were adults, however, the diagnostic ily data set. Am J Hum Genet 1998;63:1448-56. 16 Sawyer DL, Krishnamani RS, Hannig VL, et al. Genetic classification system still allowed the detection analysis of phonologic core deficit dyslexia (PCDD). Am J of the present linkage. These discrepancies low- Hum Genet 1998;63:A307. 17 Smith SD, Kimberling WJ, Pennington BF, Lubs HA. Spe- ered the lod scores for models 1 and 2. cific reading disability: identification of an inherited form Few genes have been identified in 2p15-p16 through linkage analysis. Science 1983;21:1345-8. 18 Bisgaard ML, Eiberg H, Møller N, Niebuhr E, Mohr J. Dys- (http://www.ncbi.nlm.nih.gov/genemap) and lexia and chromosome 15 heteromorphism: negative lod none is an obvious candidate gene for dyslexia. score in a Danish material. Clin Genet 1987;32:118-19. A new gene for dyslexia is located on chromosome 2 669

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