American Journal of Medical Genetics 1:333-342 (1978)
Dyslexia: Search for Phenotypic and Genetic Heterogeneity Gilbert S. Omenn and Bruce A. Weber Division of Medical Genetics (Department of Medicine), Department of Speech, and Child Development and Mental Retardation Center, University of Washington, Seattle
Dyslexia, or specific reading disability, has been shown in many studies to be familial, though n o simple mode of inheritance accounts for all pedigrees. It is likely that the difficulties of genetic analysis are due t o heterogeneity within the phenotype. W e have undertaken a series of studies of normally intelligent children with dyslexia and their families in a search for phenotypic and genetic evidence of heterogeneity. Family histories with specific attention t o difficulties in learning t o read and spell were taken for 21 families. School test results were available for probands. Spelling was analyzed and anecdotal information assessed t o determine whether visual or auditory difficulties predominated. Among the probands, 1 1 had predominantly visual problems (with preference for orally presented material) and phonetic spelling errors; 7 had predominantly auditory problems (with preference for visually presented materials), mispronunciations, and dysphonetic spelling errors; and 3 had mixed features. Visual and auditory evoked responses were measured o n all the probands and some of the family members, in a search for neurophysiological evidence of abnormality or asymmetry of response. No significant differences were found between hemispheres, between those with visual- and those with auditorypredominant dyslexia, o r between left-handed and right-handed individuals. Both anecdotal family histories and spelling performances provide suggestive evidence that dyslexic patients may be delineated into subgroups with predominantly visual o r predominantly auditory impairment and that these subtypes may b e under separate genetic predisposition. Further neurophysiological investigation will b e required t o devise ways of identifying cases before learning disability becomes an educational problem. Key words: dyslexia, genetics, reading disability, dyslexia subtypes, family studies
INTRODUCTION
The term “dyslexia” refers to specific reading disability in children and adults who are otherwise at least average in cognitive skills, emotional and social experiences, and sensory and neurological examinations. Dyslexia is one of the most common educational
Submitted for publication June 20, 1977. Dr Omenn is an investigator for the Howard Hughes Medical Institute. Address reprint requests to Dr Gilbert S. Omenn,Division of Medical Genetics, Department of Medicine, RG-20, University of Washington, Seattle, WA 98195.
0148-7299/78/0103-0333$02.00 0 1978 Alan R. Liss, Inc
334
Omenn and Weber
problems of school children [Johnson and Myklebust, 1967; Critchley, 1970; Klasen, 1972; Satz and Ross, 19731, and several studies of families, sibs, and twins strongly point to genetic predisposition [Hallgren, 1950; Sladen, 1972; Zerbin-Rudin, 19671 . Ingenious reading tests and multivariate psychoeducational analyses have been employed in recent studies [Finucci et al, 1976; Foch and DeFries, 1975; Lewitter and DeFries, 19751. Although generation-to-generationtransmission of dyslexia is commonly observed, no single pattern of transmission can account for the many pedigrees and no underlying neurophysiologic or biochemical mechanisms have been identified. It is likely that this common phenotype is heterogeneous. Our present studies are based upon two observations: first, that the types of spelling errors that dyslexic persons make may be strikingly dysphonetic in some and clearly phonetic in others [Boder, 1970, 1971; Johnson and Mykleburst, 19671 (teachers note that some dyslexic children learn better orally, while others do much better with visually presented material); second, that in dyslexic individuals cortical evoked-potential recordings after visual stimuli may show attenuated amplitude over the left parietal area, where incoming sensory information is processed [Conners, 1970; Preston et al, 1974, 19771. We have combined educational and spelling test results with individual histories and evoked-potential studies to characterize probands who are dyslexic as visual-predominance or auditory-predominance subtypes. We then examined the histories and spelling difficulties of relatives of these probands to determine whether the phenotypic heterogeneity may be genetic. METHODS
Twenty-one families having multiple members with specific dyslexia were selected through the cooperation of the Puget Sound Chapter of the Orton Society and the Shoreline School District. The protocols for study were first presented for approval to the Research and Development Committee of the School District, including parent representatives; then informed written consent was obtained from a parent at the time of testing at the University of Washington. In all cases an effort was made to help the children as well to understand the purposes of the studies. Diagnosis of dyslexia was based upon one or more of the following: school academic records, Slingerland Screening Test results from the schools, parent interviews, and type of spelling errors with a list of 25 words selected from Boder [1970] .* All IQ scores (WISC) were average or above (range 100-1 38). Probands designated as dyslexic gave test results at least two years lower than expected for chronologic age and nonverbal IQ. All had been placed in classes for reading-disabled children in a school district well-recognized for its interest and early support of these programs. Adults gave a history of similar difficulties, as well as significant impact on career choices. Historical information was particularly important in assessing older children and parents, some of whom had overcome their earlier reading disability. Criteria for Subtyping
Individual probands were classified in the auditory-predominance subtype of dyslexia if their history and test results showed dysphonetic spelling errors, striking mis*List of words: fast, farm, like, white, ready, laugh, awake, almost, guess, earth, marry, important, business, promise, wonderful, rough, position, genius, scholar, immense, tourist, doubt, across, red (color), said.
Genetic Heterogeneity of Dyslexia
335
pronunciations, greater difficulty in learning from oral presentations, and/or poorer performance on the auditory components of the Slingerland battery. Individual probands were classified in the visual-predominance subtype of dyslexia if their history and test results showed phonetic spelling errors, no tendency to mispronunciation or confusion of sounds, greater difficulty in learning from printed or visually presented materials, relative facility in learning from oral presentations, poorer performance on the visual components of the Slingerland battery, and/or persistence of reversals. A few probands were considered to have mixed subtype of dyslexia in that distinctive features of each subtype above were noted. Some of the data for subtyping were obtained from school records and from uniform spelling tests; other, often critical, information came from the anecdotal histories (some examples are given below) volunteered by the affected individual or a relative. The latter data seem to support the subtyping at a clinical and intuitive level without multivariate discriminant analyses of psychologic test batteries. Neurophysiological Testing
Averaged evoked responses to visual and auditory stimuli were recorded from at least one member of each family. As previously described [Weber and Omenn, 19771, subjects were seated in a reclining chair with recording electrodes positioned over each parietal area referenced to linked mastoid electrodes. This electrode placement provides two hemispheric readings, each referenced to the same neutral position, which conforms with Kooi’s objection [1972] to the placement in Comers’s original investigation of hemispheric asymmetry [1970]. To minimize contamination of the EEG signals by movement artifacts, the two hemispheric recordings were telemetered to an adjacent control room. There the EEG signals were recorded on magnetic tape for offline analysis. The visual stimulus was a light flash produced by a photostimulator positioned 100 cm from the subject’s nose. The auditory stimulus was a 200 millisecond burst of white noise presented through binaural earphones at a level of 7 0 dB SPL. Each subject received a randomized presentation of 64 light flashes and 64 noise bursts. To maintain a relatively stable arousal level during testing, each subject was randomly assigned to push a button for either the light flash or the noise burst. The mean duration of the variable interstimulus interval was 3.7 seconds. Four averaged evoked responses (2 stimuli X 2 hemispheres) were obtained from each subject. Amplitude measurements for the visual evoked responses (VERs) and auditory evoked responses (AERs) were obtained by measuring the difference between a negative wave with a latency of approximately 150 milliseconds and the next positive wave occurring at about 200 milliseconds (see Fig. 1). Other components, including a late positive wave, were examined as well. All response amplitudes were converted to microvolt values for statistical analyses.
RESULTS Subtyping of Dyslexia in the 21 Probands
Using the historical, spelling, and school test criteria outlined under Methods, 11 probands were classified as visual-predominant, 7 as auditory-predominant, and 3 as mixed subtypes of dyslexia. These individuals are identified by arrows in the pedigrees for these families, grouped according to subtypes of the probands in Figures 2-4. Since handedness is sometimes thought to be an important element in dyslexia, handedness was recorded
336
Omenn and Weber
P Visual
,Auditory Auditory
-1
1opv
I I
Fig. 1. Example of auditory and visual averaged evoked responses from a single individual
for all of the probands. Among the 21 children only two were left-handed and one ambidextrous. Some of the distinctive historical features in these children will be given below in the accounts of their families. Evoked-Potential Recordings
Visual inspection of the AERs and VERs from each subject revealed no consistent evidence of flattening of the responses over the left hemisphere. There were children who demonstrated smaller evoked responses over the left than the right, but other children showed the opposite asymmetry. A comparison of the left/right amplitude differences revealed no significant differences for either the AER or the VER. Dividing the children according to subtypes of sensory processing predominantly affected, by handedness, or by types of spelling errors produced no evidence of hemispheric asymmetry within any subgroup. In three large families, 11 affected and 9 unaffected members were tested, also showing no consistent differences [Weber and Omenn, 19771. Thus, the deviations from symmetry observed in some of our subjects and in previous reports may well be attributable to random variability in measurement, at least when nonlinguistic stimuli are employed. Subtyping of Dyslexia in the Relatives of Dyslexic Probands
As much information as possible was obtained about sibs of the children tested and about parents and other relatives. Evoked-potential studies on relatives were abandoned after the analyses summarized above were completed on the many members of three families and all of the other probands. Spelling tests on all first-degree relatives were obtained later in nine of the families. In many cases, highly distinctive information about school difficulties and persistent problems of visual or auditory functioning was obtained.
Genetic Heterogeneity of Dyslexia
337
However, in other cases the available information was simply insufficient to warrant classification by subtype; these individuals are marked “uncharacterized” in the pedigrees. Relatives beyond first-degree relatives are indicated only when sufficient information was obtained to assess whether they were dyslexic. Families With Auditory-Predominant Dyslexia (Fig. 2)
The 15-year-old proband in family A-1 made frequent mispronunciations, substituted similar-sounding words for the intended word often with embarrassing results, kept her vocabulary limited to avoid errors, and had predominantly auditory-component errors on the Slingerland battery; she copied well, however, Her youngest sister, father, and paternal grandfather were all predisposed to misprounciations and all had difficulty reading. On spelling, the three sisters and the father all made numerous errors, including strikingly dysphonetic errors. The mother’s spelling and handwriting were perfect. The 11-year-old proband in family A-2 had both visual and auditory difficulties on the Slingerland tests, but was poorer on the auditory components; in addition, he commonly confused sounds and made what were considered by classmates and family to be comical word substitutions. His older brother, though a good student at the university, still mispells easy words and mispronounces, reversing syllables. The middle brother had reading difficulties in school but was unavailable for testing and no distinctive historical information was volunteered; he was uncharacterized as to subtype. The mother and
21
20911
cb6cIO36
7 13
12
10
5
3
r n i 3 7 I 12
10
7
3
Fig 2. Pedigrees of 7 families in which the proband had the auditory-predominant type of dyslexia. Auditory-type dyslexia; Visual-type dyslexia; Mixed-type dyslexia; @ Dyslexia uncharac ter ized.
338
Omenn and Weber
maternal grandfather have both overcome early difficulties to be good readers, but the grandfather mispronounces commonly (“a family joke”) while the mother relied almost entirely upon visual recall. Similar histories were obtained on the probands in families A-3 through A-6. It is likely that the 19-year-oldbrother in A-6 and possibly the father also have predominantly auditory difficulties, but they were not personally examined and spelling tests were not obtained on them, so they are considered uncharacterized. In family A-7, the proband frequently spells without vowels (dysphonetic) and her 1l-yearold brother described to the authors a “hopgrasser” he had encountered on his walk to the clinic, without recognizing the mispronunciation. The 13-year-old brother has predominant difficulty with oral instructions, while the father was said to be better with verbal instructions. A summary of the subtyping of the first-degree relatives in this group of families is given in Table I. Families With Visual-Predominant Dyslexia (Fig. 3)
The proband in family V-1 is a 16-year-old girl who still has frequent reversals, as did her brothers. All of them and their father had multiple spelling errors, all phonetic. Proband V-2 had persistent reversals, made all phonetic errors and memorized well from listening; both of her parents and all three sibs had completely phonetic multiple spelling errors and a history of reading difficulties. Similar histories and test results were obtained for the other probands and various relatives marked as visual-predominant dyslexia. In some cases comments were volunteered that the child would fail on open-book test or had great difficulty recognizing printed words used in his speech or did much better when the teacher dictated. The degree of reading difficulty varied among family members; relatives who had not been forced to repeat a year in school or who simply didn’t like to read were not counted as dyslexic. Family V-5 contains numerous cousins who had been extensively tested in Seattle-area schools and who were in Specific Learning Disability (SLD) classes. Families of Probands With Mixed Type of Dyslexia (Fig. 4)
Proband M-1 had marked reading difficulties, mispronounced, had copy reversals, inserted wrong letters in spelling, yet also made many phonetic errors. Proband M-2 was frustrated by both visually presented and orally presented materials and had marked deficiencies on all components of the Slingerland battery. Proband M-3 had a good vocabulary, but was the worst speller in his family; he was far below grade level in reading despite special efforts, still reversed numbers and also mispronounced. Designation of these three families as mixed type of dyslexia was based only on the assessment of the proband; among the family members all combinations of difficulties were noted. The father of M-3 gave a particularly revealing history for auditory-predominant dyslexia; he had been incapable of distinguishing the long and short signals necessary to master the Morse code during marine training. TABLE I. Type of Dyslexia in First-Degree Relatives Type of dyslexia in proband Verbal Auditory Mixed
N
Verbal
Auditory
Mixed
Uncharacterized
Total
11
17
1 2
1 10 3
1 0 5
5
I
24 18 12
3
I 2
Genetic Heterogeneity of Dyslexia
3 39
N&7ha 16
8
II
8
h 6 y9
3
43
44
48
49
19 17 15 14 16
d i a
9.12
10
8
mh-9
v 10
v11
F - i d m - a h3 18
16 915
I3
8
18 18 17 912
9
Fig. 3. Pedigrees of 11 families in which the proband had the visual-predominant type of dyslexia Symbols same as in Fig. 2.
Segregation Ratios for Dyslexia According to Subtype
The distribution of subtypes of dyslexia among the dyslexic first-degree relatives who could be characterized provides very suggestive support for the hypothesis that the phenotypic subtypes reflect independent familial predispositions (Table I). Visual-predominant dyslexia clustered in families of probands with that subtype, and auditorypredominant dyslexia clustered in families of probands with the auditory-predominant subtype. For all three subtypes, the ratio of affected to unaffected among sibs and parents was close to 50%; the ascertainment of families with more than one member affected certainly provided a bias that may account for the prevalence somewhat in excess of 50% (Table 11). These results and the pedigrees themselvos are consistent with transmission of autosomal dominant alleles strongly predisposing to dyslexia subtypes; however, the apparent complexity of the pedigrees, with cases of dyslexia among second- and third-degree relatives on either side in a number of families, allows other interpretations. For example, on a polygenic model, one would expect a higher prevalence of dyslexia among the relatives of probands of the less frequently affected sex, namely females. Table I1 includes analysis by sex, omitting because of small numbers the subtyping for phenotypic and genetic heterogeneity. The higher proportion affected among relatives of female than among relatives of male probands is not a significant difference (x’ = 1.5, p > 0.3).
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Omenn and Weber
M1
16
14 912
II
9
8
16
13
8
M2
n
I
I
1
M3
Fig 4. Pedigrees of 3 Pdmilies in which the proband had the mixed-type of dyslexia. Symbols same as in Fig. 2.
DISCUSSION
Genetic analyses of dyslexia as a single phenotypic entity have been unsuccessful in identifying any uniform pattern of transmission. In part, the high prevalence of dyslexia in the population may be responsible, in that many unlikely pedigrees may occur by chance. However, the present results, together with many earlier observations, strongly point to phenotypic and genetic heterogeneity of dyslexia. Delineation of visualpredominant and auditory-predominant subtypes of dyslexia, if confirmed in systematic investigations, may prove valuable for application of reading stress tests to asymptomatic relatives (Finucci et al, 1976), for discriminant analysis of multiple psychoeducational batteries (Foch and DeFries, 1975), and for neurophysiologic (Comers, 1970; Preston et al, 1974,1977; Weber and Omenn, 1977) and eventually biochemical elucidation of the mechanisms of the genetic predispositions. As in many other phenotypes in medical genetics, recognition of heterogeneity may be essential both for investigation of underlying mechanisms and for design of more effective preventive and therapeutic educational regimens.
Genetic Heterogeneity of Dyslexia
341
TABLE 11. Prevalence of Dyslexia in First-Degree Relatives Type of dyslexia in proband
Sibs (> 7 years old)
N
Male
Verbal Auditory Mixed
11
3
619 7/10 518
Total
21
All females All males
8 13
7
Female
Parents Father
Mother
8/13 217 314
6/11 617 313
4/11 317 113
24/44 18/31 12/18
18/27
13/24
15/21
8/21
54/93
9113 9/14
8/10 511 4
618
418 4/13
27/39 27/54
9/13
Total
Our phenotypic categories of visual-predominant, auditory-predominant , and mixed subtypes of dyslexia probably are related to the subtypes classified by Boder from spelling patterns as dyseidetic (phonetic), dysphonetic, and mixed (1970, 1971). In an effort to determine whether the Boder phenotypes run true to form within families, we gave the partial list of 25 words (above) to many of the families reported here, in which phonetic and dysphonetic errors segregated according to type of errors in the proband, and to another I 4 cooperative families, among whom those with dysphonetic errors clustered in 6 of the families. The observations upon which the present classification is based include admittedly subjective data gained from the clinical history. However, distinctive features were often volunteered, and the auditory/visual dichotomization was supported in most affected persons by test results in school and/or by spelling performances with standardized word lists. The lack of usefulness of evoked responses in identifying individuals as dyslexic and in localizing brain regions as dysfunctional was disappointing, since such tests might have been applicable to younger sibs before they enter school. Those identified as affected by neurophysiological criteria could be started on compensatory educational programs before encountering grave difficulties in school. It is possible that more meaningful stimuli than light flash and auditory click would be more revealing. Preston et a1 (1977) have compared elements of the visual evoked responses after three-letter words to those after light flashes and found a group difference between dyslexics and normals over the left parietal area; however, individual variation in these measures produced considerable overlap between the two groups. ACKNOWLEDGMENTS
We gratefully acknowledge the assistance of Dorothy Revelle and the teachers and families of the Shoreline School District and the Puget Sound Orton Society. REFERENCES Boder E (1970). Developmental dyslexia: a new diagnostic approach based o n the identification of three subtypes. J School Health 40:289-290. Boder E (197 1). Developmental dyslexia-prevailing diagnostic concepts and a new diagnostic approach. In Myklebust, RH (ed): “Progress in Learning Disabilities.” New York: Grune and Stratton, vol 2, 293-321.
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Conners CK (1970). Cortical visual evoked response in children with learning disorders. Psychophysiol 7:418-428. Critchley M (1970). The Dyslexic Child.” London: Heineman. Finucci JM, Guthrie JT, Childs AL, Abbey H, Childs B (1976). The genetics of specific reading disability. Ann Hum Genet (London)40: 1-23. Foch TT, DeFries JC (1976): Specific reading disability: Discrimination among affected and1 control index cases and their relatives. Behavior Genetics 6: 106. Hallgren B (1950). Specific dislexia (“congenital word-blindness”): A clinical and genetic study. Acta Psychiat Scand Suppl65. Johnson D, Myklebust H (1967). “Learning Disabilities: Educational Principles and Practices.” New York: Grune and Stratton. Klasen EL (1972). “The Syndrome of Specific Dyslexia.” Baltimore: University Park Press. Kooi KA (1972): Letter to Ed. Psychophysiol9:154. Lewitter F , DeFries JC, (1976). Parent-offspring resemblance in reading ability. Behavior Genetics 6: 111. Preston MS, Guthrie JT, Childs B (1974). Visual evoked responses (VERs) in normal and disabled readers. Psychophysiol 11:452-458. Preston MS, Guthrie JT, Kirsch I, Gertman D, Childs B (1977). VERs in normal and disabled adult readers. Psychophysiol 14:8- 14. Staz P, Ross JJ (eds) (1973). “The Disabled Learner. Modern Approaches to the Diagnosis and Instruction of Multi-Handicapped Children.” Rotterdam: Rotterdam University Press. Sladen BK (1972). Some genetic aspects of dyslexia. Bull Orton SOC22:41-53. Weber BA, Omenn GS (1977). Auditory and visual evoked responses in children with familial reading disabilities. J Learn Disab 10:153-158. Zerbin-Rudin E (1967). Congenital word blindness. Bull Orton SOC17:47-54, 1967 E d i t e d by Judith G . Hall
Dyslexia: Search for Phenotypic and Genetic Heterogeneity Gilbert S. Omenn and Bruce A. Weber Division of Medical Genetics (Department of Medicine), Department of Speech, and Child Development and Mental Retardation Center, University of Washington, Seattle
Dyslexia, or specific reading disability, has been shown in many studies to be familial, though n o simple mode of inheritance accounts for all pedigrees. It is likely that the difficulties of genetic analysis are due t o heterogeneity within the phenotype. W e have undertaken a series of studies of normally intelligent children with dyslexia and their families in a search for phenotypic and genetic evidence of heterogeneity. Family histories with specific attention t o difficulties in learning t o read and spell were taken for 21 families. School test results were available for probands. Spelling was analyzed and anecdotal information assessed t o determine whether visual or auditory difficulties predominated. Among the probands, 1 1 had predominantly visual problems (with preference for orally presented material) and phonetic spelling errors; 7 had predominantly auditory problems (with preference for visually presented materials), mispronunciations, and dysphonetic spelling errors; and 3 had mixed features. Visual and auditory evoked responses were measured o n all the probands and some of the family members, in a search for neurophysiological evidence of abnormality or asymmetry of response. No significant differences were found between hemispheres, between those with visual- and those with auditorypredominant dyslexia, o r between left-handed and right-handed individuals. Both anecdotal family histories and spelling performances provide suggestive evidence that dyslexic patients may be delineated into subgroups with predominantly visual o r predominantly auditory impairment and that these subtypes may b e under separate genetic predisposition. Further neurophysiological investigation will b e required t o devise ways of identifying cases before learning disability becomes an educational problem. Key words: dyslexia, genetics, reading disability, dyslexia subtypes, family studies
INTRODUCTION
The term “dyslexia” refers to specific reading disability in children and adults who are otherwise at least average in cognitive skills, emotional and social experiences, and sensory and neurological examinations. Dyslexia is one of the most common educational
Submitted for publication June 20, 1977. Dr Omenn is an investigator for the Howard Hughes Medical Institute. Address reprint requests to Dr Gilbert S. Omenn,Division of Medical Genetics, Department of Medicine, RG-20, University of Washington, Seattle, WA 98195.
0148-7299/78/0103-0333$02.00 0 1978 Alan R. Liss, Inc
334
Omenn and Weber
problems of school children [Johnson and Myklebust, 1967; Critchley, 1970; Klasen, 1972; Satz and Ross, 19731, and several studies of families, sibs, and twins strongly point to genetic predisposition [Hallgren, 1950; Sladen, 1972; Zerbin-Rudin, 19671 . Ingenious reading tests and multivariate psychoeducational analyses have been employed in recent studies [Finucci et al, 1976; Foch and DeFries, 1975; Lewitter and DeFries, 19751. Although generation-to-generationtransmission of dyslexia is commonly observed, no single pattern of transmission can account for the many pedigrees and no underlying neurophysiologic or biochemical mechanisms have been identified. It is likely that this common phenotype is heterogeneous. Our present studies are based upon two observations: first, that the types of spelling errors that dyslexic persons make may be strikingly dysphonetic in some and clearly phonetic in others [Boder, 1970, 1971; Johnson and Mykleburst, 19671 (teachers note that some dyslexic children learn better orally, while others do much better with visually presented material); second, that in dyslexic individuals cortical evoked-potential recordings after visual stimuli may show attenuated amplitude over the left parietal area, where incoming sensory information is processed [Conners, 1970; Preston et al, 1974, 19771. We have combined educational and spelling test results with individual histories and evoked-potential studies to characterize probands who are dyslexic as visual-predominance or auditory-predominance subtypes. We then examined the histories and spelling difficulties of relatives of these probands to determine whether the phenotypic heterogeneity may be genetic. METHODS
Twenty-one families having multiple members with specific dyslexia were selected through the cooperation of the Puget Sound Chapter of the Orton Society and the Shoreline School District. The protocols for study were first presented for approval to the Research and Development Committee of the School District, including parent representatives; then informed written consent was obtained from a parent at the time of testing at the University of Washington. In all cases an effort was made to help the children as well to understand the purposes of the studies. Diagnosis of dyslexia was based upon one or more of the following: school academic records, Slingerland Screening Test results from the schools, parent interviews, and type of spelling errors with a list of 25 words selected from Boder [1970] .* All IQ scores (WISC) were average or above (range 100-1 38). Probands designated as dyslexic gave test results at least two years lower than expected for chronologic age and nonverbal IQ. All had been placed in classes for reading-disabled children in a school district well-recognized for its interest and early support of these programs. Adults gave a history of similar difficulties, as well as significant impact on career choices. Historical information was particularly important in assessing older children and parents, some of whom had overcome their earlier reading disability. Criteria for Subtyping
Individual probands were classified in the auditory-predominance subtype of dyslexia if their history and test results showed dysphonetic spelling errors, striking mis*List of words: fast, farm, like, white, ready, laugh, awake, almost, guess, earth, marry, important, business, promise, wonderful, rough, position, genius, scholar, immense, tourist, doubt, across, red (color), said.
Genetic Heterogeneity of Dyslexia
335
pronunciations, greater difficulty in learning from oral presentations, and/or poorer performance on the auditory components of the Slingerland battery. Individual probands were classified in the visual-predominance subtype of dyslexia if their history and test results showed phonetic spelling errors, no tendency to mispronunciation or confusion of sounds, greater difficulty in learning from printed or visually presented materials, relative facility in learning from oral presentations, poorer performance on the visual components of the Slingerland battery, and/or persistence of reversals. A few probands were considered to have mixed subtype of dyslexia in that distinctive features of each subtype above were noted. Some of the data for subtyping were obtained from school records and from uniform spelling tests; other, often critical, information came from the anecdotal histories (some examples are given below) volunteered by the affected individual or a relative. The latter data seem to support the subtyping at a clinical and intuitive level without multivariate discriminant analyses of psychologic test batteries. Neurophysiological Testing
Averaged evoked responses to visual and auditory stimuli were recorded from at least one member of each family. As previously described [Weber and Omenn, 19771, subjects were seated in a reclining chair with recording electrodes positioned over each parietal area referenced to linked mastoid electrodes. This electrode placement provides two hemispheric readings, each referenced to the same neutral position, which conforms with Kooi’s objection [1972] to the placement in Comers’s original investigation of hemispheric asymmetry [1970]. To minimize contamination of the EEG signals by movement artifacts, the two hemispheric recordings were telemetered to an adjacent control room. There the EEG signals were recorded on magnetic tape for offline analysis. The visual stimulus was a light flash produced by a photostimulator positioned 100 cm from the subject’s nose. The auditory stimulus was a 200 millisecond burst of white noise presented through binaural earphones at a level of 7 0 dB SPL. Each subject received a randomized presentation of 64 light flashes and 64 noise bursts. To maintain a relatively stable arousal level during testing, each subject was randomly assigned to push a button for either the light flash or the noise burst. The mean duration of the variable interstimulus interval was 3.7 seconds. Four averaged evoked responses (2 stimuli X 2 hemispheres) were obtained from each subject. Amplitude measurements for the visual evoked responses (VERs) and auditory evoked responses (AERs) were obtained by measuring the difference between a negative wave with a latency of approximately 150 milliseconds and the next positive wave occurring at about 200 milliseconds (see Fig. 1). Other components, including a late positive wave, were examined as well. All response amplitudes were converted to microvolt values for statistical analyses.
RESULTS Subtyping of Dyslexia in the 21 Probands
Using the historical, spelling, and school test criteria outlined under Methods, 11 probands were classified as visual-predominant, 7 as auditory-predominant, and 3 as mixed subtypes of dyslexia. These individuals are identified by arrows in the pedigrees for these families, grouped according to subtypes of the probands in Figures 2-4. Since handedness is sometimes thought to be an important element in dyslexia, handedness was recorded
336
Omenn and Weber
P Visual
,Auditory Auditory
-1
1opv
I I
Fig. 1. Example of auditory and visual averaged evoked responses from a single individual
for all of the probands. Among the 21 children only two were left-handed and one ambidextrous. Some of the distinctive historical features in these children will be given below in the accounts of their families. Evoked-Potential Recordings
Visual inspection of the AERs and VERs from each subject revealed no consistent evidence of flattening of the responses over the left hemisphere. There were children who demonstrated smaller evoked responses over the left than the right, but other children showed the opposite asymmetry. A comparison of the left/right amplitude differences revealed no significant differences for either the AER or the VER. Dividing the children according to subtypes of sensory processing predominantly affected, by handedness, or by types of spelling errors produced no evidence of hemispheric asymmetry within any subgroup. In three large families, 11 affected and 9 unaffected members were tested, also showing no consistent differences [Weber and Omenn, 19771. Thus, the deviations from symmetry observed in some of our subjects and in previous reports may well be attributable to random variability in measurement, at least when nonlinguistic stimuli are employed. Subtyping of Dyslexia in the Relatives of Dyslexic Probands
As much information as possible was obtained about sibs of the children tested and about parents and other relatives. Evoked-potential studies on relatives were abandoned after the analyses summarized above were completed on the many members of three families and all of the other probands. Spelling tests on all first-degree relatives were obtained later in nine of the families. In many cases, highly distinctive information about school difficulties and persistent problems of visual or auditory functioning was obtained.
Genetic Heterogeneity of Dyslexia
337
However, in other cases the available information was simply insufficient to warrant classification by subtype; these individuals are marked “uncharacterized” in the pedigrees. Relatives beyond first-degree relatives are indicated only when sufficient information was obtained to assess whether they were dyslexic. Families With Auditory-Predominant Dyslexia (Fig. 2)
The 15-year-old proband in family A-1 made frequent mispronunciations, substituted similar-sounding words for the intended word often with embarrassing results, kept her vocabulary limited to avoid errors, and had predominantly auditory-component errors on the Slingerland battery; she copied well, however, Her youngest sister, father, and paternal grandfather were all predisposed to misprounciations and all had difficulty reading. On spelling, the three sisters and the father all made numerous errors, including strikingly dysphonetic errors. The mother’s spelling and handwriting were perfect. The 11-year-old proband in family A-2 had both visual and auditory difficulties on the Slingerland tests, but was poorer on the auditory components; in addition, he commonly confused sounds and made what were considered by classmates and family to be comical word substitutions. His older brother, though a good student at the university, still mispells easy words and mispronounces, reversing syllables. The middle brother had reading difficulties in school but was unavailable for testing and no distinctive historical information was volunteered; he was uncharacterized as to subtype. The mother and
21
20911
cb6cIO36
7 13
12
10
5
3
r n i 3 7 I 12
10
7
3
Fig 2. Pedigrees of 7 families in which the proband had the auditory-predominant type of dyslexia. Auditory-type dyslexia; Visual-type dyslexia; Mixed-type dyslexia; @ Dyslexia uncharac ter ized.
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maternal grandfather have both overcome early difficulties to be good readers, but the grandfather mispronounces commonly (“a family joke”) while the mother relied almost entirely upon visual recall. Similar histories were obtained on the probands in families A-3 through A-6. It is likely that the 19-year-oldbrother in A-6 and possibly the father also have predominantly auditory difficulties, but they were not personally examined and spelling tests were not obtained on them, so they are considered uncharacterized. In family A-7, the proband frequently spells without vowels (dysphonetic) and her 1l-yearold brother described to the authors a “hopgrasser” he had encountered on his walk to the clinic, without recognizing the mispronunciation. The 13-year-old brother has predominant difficulty with oral instructions, while the father was said to be better with verbal instructions. A summary of the subtyping of the first-degree relatives in this group of families is given in Table I. Families With Visual-Predominant Dyslexia (Fig. 3)
The proband in family V-1 is a 16-year-old girl who still has frequent reversals, as did her brothers. All of them and their father had multiple spelling errors, all phonetic. Proband V-2 had persistent reversals, made all phonetic errors and memorized well from listening; both of her parents and all three sibs had completely phonetic multiple spelling errors and a history of reading difficulties. Similar histories and test results were obtained for the other probands and various relatives marked as visual-predominant dyslexia. In some cases comments were volunteered that the child would fail on open-book test or had great difficulty recognizing printed words used in his speech or did much better when the teacher dictated. The degree of reading difficulty varied among family members; relatives who had not been forced to repeat a year in school or who simply didn’t like to read were not counted as dyslexic. Family V-5 contains numerous cousins who had been extensively tested in Seattle-area schools and who were in Specific Learning Disability (SLD) classes. Families of Probands With Mixed Type of Dyslexia (Fig. 4)
Proband M-1 had marked reading difficulties, mispronounced, had copy reversals, inserted wrong letters in spelling, yet also made many phonetic errors. Proband M-2 was frustrated by both visually presented and orally presented materials and had marked deficiencies on all components of the Slingerland battery. Proband M-3 had a good vocabulary, but was the worst speller in his family; he was far below grade level in reading despite special efforts, still reversed numbers and also mispronounced. Designation of these three families as mixed type of dyslexia was based only on the assessment of the proband; among the family members all combinations of difficulties were noted. The father of M-3 gave a particularly revealing history for auditory-predominant dyslexia; he had been incapable of distinguishing the long and short signals necessary to master the Morse code during marine training. TABLE I. Type of Dyslexia in First-Degree Relatives Type of dyslexia in proband Verbal Auditory Mixed
N
Verbal
Auditory
Mixed
Uncharacterized
Total
11
17
1 2
1 10 3
1 0 5
5
I
24 18 12
3
I 2
Genetic Heterogeneity of Dyslexia
3 39
N&7ha 16
8
II
8
h 6 y9
3
43
44
48
49
19 17 15 14 16
d i a
9.12
10
8
mh-9
v 10
v11
F - i d m - a h3 18
16 915
I3
8
18 18 17 912
9
Fig. 3. Pedigrees of 11 families in which the proband had the visual-predominant type of dyslexia Symbols same as in Fig. 2.
Segregation Ratios for Dyslexia According to Subtype
The distribution of subtypes of dyslexia among the dyslexic first-degree relatives who could be characterized provides very suggestive support for the hypothesis that the phenotypic subtypes reflect independent familial predispositions (Table I). Visual-predominant dyslexia clustered in families of probands with that subtype, and auditorypredominant dyslexia clustered in families of probands with the auditory-predominant subtype. For all three subtypes, the ratio of affected to unaffected among sibs and parents was close to 50%; the ascertainment of families with more than one member affected certainly provided a bias that may account for the prevalence somewhat in excess of 50% (Table 11). These results and the pedigrees themselvos are consistent with transmission of autosomal dominant alleles strongly predisposing to dyslexia subtypes; however, the apparent complexity of the pedigrees, with cases of dyslexia among second- and third-degree relatives on either side in a number of families, allows other interpretations. For example, on a polygenic model, one would expect a higher prevalence of dyslexia among the relatives of probands of the less frequently affected sex, namely females. Table I1 includes analysis by sex, omitting because of small numbers the subtyping for phenotypic and genetic heterogeneity. The higher proportion affected among relatives of female than among relatives of male probands is not a significant difference (x’ = 1.5, p > 0.3).
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M1
16
14 912
II
9
8
16
13
8
M2
n
I
I
1
M3
Fig 4. Pedigrees of 3 Pdmilies in which the proband had the mixed-type of dyslexia. Symbols same as in Fig. 2.
DISCUSSION
Genetic analyses of dyslexia as a single phenotypic entity have been unsuccessful in identifying any uniform pattern of transmission. In part, the high prevalence of dyslexia in the population may be responsible, in that many unlikely pedigrees may occur by chance. However, the present results, together with many earlier observations, strongly point to phenotypic and genetic heterogeneity of dyslexia. Delineation of visualpredominant and auditory-predominant subtypes of dyslexia, if confirmed in systematic investigations, may prove valuable for application of reading stress tests to asymptomatic relatives (Finucci et al, 1976), for discriminant analysis of multiple psychoeducational batteries (Foch and DeFries, 1975), and for neurophysiologic (Comers, 1970; Preston et al, 1974,1977; Weber and Omenn, 1977) and eventually biochemical elucidation of the mechanisms of the genetic predispositions. As in many other phenotypes in medical genetics, recognition of heterogeneity may be essential both for investigation of underlying mechanisms and for design of more effective preventive and therapeutic educational regimens.
Genetic Heterogeneity of Dyslexia
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TABLE 11. Prevalence of Dyslexia in First-Degree Relatives Type of dyslexia in proband
Sibs (> 7 years old)
N
Male
Verbal Auditory Mixed
11
3
619 7/10 518
Total
21
All females All males
8 13
7
Female
Parents Father
Mother
8/13 217 314
6/11 617 313
4/11 317 113
24/44 18/31 12/18
18/27
13/24
15/21
8/21
54/93
9113 9/14
8/10 511 4
618
418 4/13
27/39 27/54
9/13
Total
Our phenotypic categories of visual-predominant, auditory-predominant , and mixed subtypes of dyslexia probably are related to the subtypes classified by Boder from spelling patterns as dyseidetic (phonetic), dysphonetic, and mixed (1970, 1971). In an effort to determine whether the Boder phenotypes run true to form within families, we gave the partial list of 25 words (above) to many of the families reported here, in which phonetic and dysphonetic errors segregated according to type of errors in the proband, and to another I 4 cooperative families, among whom those with dysphonetic errors clustered in 6 of the families. The observations upon which the present classification is based include admittedly subjective data gained from the clinical history. However, distinctive features were often volunteered, and the auditory/visual dichotomization was supported in most affected persons by test results in school and/or by spelling performances with standardized word lists. The lack of usefulness of evoked responses in identifying individuals as dyslexic and in localizing brain regions as dysfunctional was disappointing, since such tests might have been applicable to younger sibs before they enter school. Those identified as affected by neurophysiological criteria could be started on compensatory educational programs before encountering grave difficulties in school. It is possible that more meaningful stimuli than light flash and auditory click would be more revealing. Preston et a1 (1977) have compared elements of the visual evoked responses after three-letter words to those after light flashes and found a group difference between dyslexics and normals over the left parietal area; however, individual variation in these measures produced considerable overlap between the two groups. ACKNOWLEDGMENTS
We gratefully acknowledge the assistance of Dorothy Revelle and the teachers and families of the Shoreline School District and the Puget Sound Orton Society. REFERENCES Boder E (1970). Developmental dyslexia: a new diagnostic approach based o n the identification of three subtypes. J School Health 40:289-290. Boder E (197 1). Developmental dyslexia-prevailing diagnostic concepts and a new diagnostic approach. In Myklebust, RH (ed): “Progress in Learning Disabilities.” New York: Grune and Stratton, vol 2, 293-321.
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Conners CK (1970). Cortical visual evoked response in children with learning disorders. Psychophysiol 7:418-428. Critchley M (1970). The Dyslexic Child.” London: Heineman. Finucci JM, Guthrie JT, Childs AL, Abbey H, Childs B (1976). The genetics of specific reading disability. Ann Hum Genet (London)40: 1-23. Foch TT, DeFries JC (1976): Specific reading disability: Discrimination among affected and1 control index cases and their relatives. Behavior Genetics 6: 106. Hallgren B (1950). Specific dislexia (“congenital word-blindness”): A clinical and genetic study. Acta Psychiat Scand Suppl65. Johnson D, Myklebust H (1967). “Learning Disabilities: Educational Principles and Practices.” New York: Grune and Stratton. Klasen EL (1972). “The Syndrome of Specific Dyslexia.” Baltimore: University Park Press. Kooi KA (1972): Letter to Ed. Psychophysiol9:154. Lewitter F , DeFries JC, (1976). Parent-offspring resemblance in reading ability. Behavior Genetics 6: 111. Preston MS, Guthrie JT, Childs B (1974). Visual evoked responses (VERs) in normal and disabled readers. Psychophysiol 11:452-458. Preston MS, Guthrie JT, Kirsch I, Gertman D, Childs B (1977). VERs in normal and disabled adult readers. Psychophysiol 14:8- 14. Staz P, Ross JJ (eds) (1973). “The Disabled Learner. Modern Approaches to the Diagnosis and Instruction of Multi-Handicapped Children.” Rotterdam: Rotterdam University Press. Sladen BK (1972). Some genetic aspects of dyslexia. Bull Orton SOC22:41-53. Weber BA, Omenn GS (1977). Auditory and visual evoked responses in children with familial reading disabilities. J Learn Disab 10:153-158. Zerbin-Rudin E (1967). Congenital word blindness. Bull Orton SOC17:47-54, 1967 E d i t e d by Judith G . Hall
