American Journal of Medical Genetics (Neuropsychiatric Genetics) 114:689– 692 (2002)
Letter to the Editor
Williams Syndrome Cognitive Profile Also
Characterizes Velocardiofacial/DiGeorge Syndrome
To the Editor:
Williams-Beuren Syndrome (WBS) is a contiguous
gene deletion disorder characterized by a distinctive
facies, supravalvar aortic stenosis and other vascular
abnormalities, hypercalcemia, mild to moderate mental
retardation, a unique personality, and a specific cognitive profile [Jones and Smith, 1975; Bellugi et al., 1997;
Mervis et al., 1999a]. This syndrome has been the
subject of extensive neuropsychological investigation,
due to its notable pattern of neurocognitive ‘‘peaks and
valleys,’’ involving relative strengths in language and
facial processing, and profound impairment in spatial
cognition [Bellugi et al., 1994; Mervis et al., 1999b]. WBS
is caused by a hemizygous deletion of !1.5 megabases
at chromosome 7q11.23 (Fig. 1), which includes LIMkinase1, a gene which is strongly expressed in the brain,
particularly in the cerebral cortex [Frangiskakis et al.,
1996]. Mervis et al. [1999b] propose that 1) WBS is
associated with an identifiable and very distinctive
cognitive profile, and 2) there is a specific genetic basis
for the extreme difficulties with visuospatial construction evidenced by most individuals with this syndrome.
They cite evidence from neuropsychological comparisons of patients with small deletions in the WBS critical
region to those with more standard deletions, in order to
support the claim that ‘‘LIM-kinase1hemizygosity contributes to the difficulties individuals with Williams
Syndrome evidence in visuospatial construction’’. Specifically, they find that those individuals with smaller
deletions that include Elastin, but not LIMK1, do not
evidence any cognitive or personality aspects of the WBS
phenotype. Mervis et al. [1999b] conclude from these
findings that ‘‘hemizygous deletion of LIMK1 on chromosome 7 forms a foundation for the deficit in visuo-
Grant sponsor: NIH; Grant numbers: K08-HD01174, PO1DC02027.
*Correspondence to: Carrie E. Bearden, Ph.D., Children’s
Hospital of Philadelphia and University of Pennsylvania, Center
for Cognitive Neuroscience, 3815 Walnut St., Philadelphia, PA
19104. E-mail: bearden@psych.upenn.edu
Received 7 March 2002; Accepted 19 March 2002
DOI 10.1002/ajmg.10539
! 2002 Wiley-Liss, Inc.
spatial constructive cognition evidenced in WBS.’’ The
generality of this observation has been questioned by
other investigators [Tassabehji et al., 1999], who found
that three subjects with small deletions did not fit the
criteria for the characteristic Williams Syndrome
Cognitive Profile (WSCP, see Appendix) despite their
LIMK1 deletions, leading them to conclude that LIMK1
deletion may be a ‘‘necessary but not sufficient’’ condition for the WSCP.
We have noted a strikingly similar cognitive and
neuroanatomic profile in a large proportion of patients
with another, more common microdeletion syndrome,
Velocardiofacial/DiGeorge Syndrome (22q11.2 Deletion
Syndrome). This multiple-malformation syndrome is
characterized by structural and functional palate anomalies, conotruncal cardiac malformations, immunodeficiency, hypocalcemia, and typical facial anomalies
[Shprintzen et al., 1981; McDonald-McGinn et al., 1997].
Similar to WBS, the disorder is also characterized by low
IQ (with average full-scale IQ in the borderline range),
learning disabilities, and a characteristic cognitive and
behavioral phenotype [Moss et al., 1999; Bearden et al.,
2001]. In the majority of cases (!90%), the syndrome
results from a common three-Mb deletion at chromosome 22q11.2 (Fig. 2) [Carlson et al., 1997]. Applying the
Wechsler [1991] equivalents of the psychometric criteria
for the WSCP outlined by Mervis et al. [2000] to a group
of 97 patients with the 22q Deletion Syndrome (22q DS),
we found that 61 of these patients meet all criteria for
the WSCP, yielding a sensitivity of .63 (Bearden and
Wang, manuscript in preparation). While this is somewhat lower than the sensitivity of .88 for individuals
with molecularly defined WBS, as reported by Mervis
et al. [2000], it is notable that the profile characterizes
almost 2/3 of subjects with 22q11.2 deletions, despite the
fact that these criteria were specifically tailored to best
fit the putatively unique cognitive profile of WBS.
Mervis and colleagues [2000] found that only four of 56
subjects in an IQ-matched contrast group of mixed
etiology met the WSCP criteria (specificity ¼ .93), leading them to conclude that these combined criteria depict
a profile that is ‘‘rare for individuals who do not have
WBS.’’ In comparison to a contrast group of individuals
with 22q DS, however, the specificity of the WSCP
criteria is quite poor (.37). Thus, while this cognitive
profile may be unusual, our findings demonstrate that it
is not unique to WBS.
690
Bearden et al.
Fig. 1.
Map of typical !1.5 Mb Williams syndrome deletion region (figure courtesy of M. Tassabehji).
Other neurogenetic disorders (e.g., Turner syndrome,
Fragile X) have a similar pattern of cognitive abilities,
involving deficits in arithmetic and visuospatial abilities, with a relative strength in rote verbal memory
[Reiss et al., 2000a; Kwon et al., 2001]. This pattern is
commonly referred to as a ‘‘Nonverbal Learning Disorder’’ [Rourke, 1995]. In the case of Fragile X syndrome,
the characteristic cognitive impairments have been
attributed to the absence of the FMR1 gene product
(FMRP) in neurons, resulting in abnormal morphology
of dendritic spines and a reduction in the length of
synapses in the cortex [Rudelli et al., 1985; Hinton et al.,
1991]. Turner syndrome, a genetic disorder characterized by partial or complete absence of one of the two
X chromosomes in a phenotypic female, is also characterized neuropsychologically by deficits in visualspatial/perceptual skills and attention [Pennington
et al., 1985; Olney and Schaefer, 1998]. While the
molecular etiology of these cognitive deficits is incompletely understood in Turner syndrome, an MRI study of
females with this disorder found decreased proportional
volumes primarily in the region of the parietal lobe, an
area known to be linked to visuospatial function [Reiss
et al., 1995].
Several studies have described a characteristic neuroanatomy of WBS, suggesting a possible underlying
pathophysiology for the cognitive deficits. Gross anatomical findings in WBS consist mainly of overall volume
reduction, with curtailment in the posterior-parietal
and occipital regions [Galaburda and Bellugi, 2000;
Reiss et al., 2000b]. Notably, similar volumetric reductions in parietal and occipital brain regions have been
noted in the 22q DS population [Eliez et al., 2000; Kates
et al., 2001]. Thus, it is important to examine candidate
neurodevelopmental genes in the 22q11.2 region that
might have similar effects. Goosecoid-like (GSCL) is one
Fig. 2. Map of typical !3 Mb Velocardiofacial/DiGeorge syndrome
deletion region (figure courtesy of B.S. Emanuel).
potential candidate; this gene in the 22q11 region is
expressed early during embryogenesis in a limited
number of tissues [Gottlieb et al., 1997], and has been
hypothesized to be responsible for abnormal development of posterior brain regions in 22q DS [Eliez et al.,
2001]. However, one notable difference between the
characteristic neuroanatomy of WBS as compared to
22q DS is that subjects with Williams syndrome have
been reported to have significant increases in the volume
of the posterior vermis and the neocerebellar hemispheres relative to normal controls [Jernigan et al.,
1993; Wang and Bellugi, 1993], while 22q DS subjects
show decreased volumes in cerebellar regions concomitant with parietal—occipital reduction [Eliez et al.,
2000]. While subjects with WBS tend to be unusually
socially outgoing and overly friendly [Jones et al., 2000],
subjects with 22q DS are often described as withdrawn
[Swillen et al., 1999] or as having flat affect [Bassett
et al., 1998], and have an elevated incidence of autisticspectrum diagnoses [Niklasson et al., 2001]. In addition,
subjects with both Fragile X and Joubert syndrome also
typically possess social and communication problems
resembling autistic behavior [Cohen et al., 1991;
Holroyd et al., 1991], and these disorders have both
have been shown to have decreased cerebellar vermal
areas [Holroyd et al., 1991; Guerreiro et al., 1998]. Thus,
comparison of neurogenetic disorders with prominent
affective components suggests that there may be a
possible relationship between posterior vermis size and
level of social drive.
In summary, while the cognitive and neuroanatomic
profiles of WBS do indeed make it a compelling model for
elucidating complex gene-brain-behavior relationships,
cross-syndrome comparisons can isolate candidate genes
which may have similar distal effects on brain development, resulting in similar neurocognitive patterns.
Thus, we argue that 1) the ‘‘Williams syndrome cognitive profile’’ is not unique, and 2) the putative effects of
hemizygous LIM-kinase1 deletion on cognition and neuroanatomy are non-specific. Rather, LIMK1 may have
similar effects on neural development as other candidate neurodevelopmental genes, and hemizygosity for
any of these genes may result in a final common pathway
of anomalous brain development, which is the underlying basis of this characteristic cognitive profile. While
we fully agree with Mervis et al. [2000] in their conclusion that ‘‘this research demonstrates the importance of
systematic phenotypic methods . . . to the efficient search
for associations between behavior and genotype,’’ we
would like to highlight the additional point that comparison not only across domains, but across syndromes, is
Letter to the Editor
critical to determine both the unique and shared effects
of particular genes on brain and cognition.
ACKNOWLEDGMENTS
Dr. Elaine Zackai, Dr. Beverly Emanuel, and Donna
McDonald-McGinn are gratefully acknowledged for
their support.
APPENDIX
Criteria for WSCP [from Mervis et al., 2000]1
1. Pattern-Construction T score < mean T score for core
subtests
2. Pattern-Construction T score < Digit-recall T score
3. Pattern-Construction T score < 20th percentile
4. T-score for either Digit Recall, Naming/Definitions,
or Similarities, > 1st percentile
Additional Criteria
1. Digit Recall T score > mean T score
2. Naming/Definitions T score > Pattern-Construction
T score
3. Similarities T score > Pattern-Construction T score
REFERENCES
Bassett AS, Hodgkinson K, Chow EW, Correia S, Scutt LE, Weksberg R.
1998. 22q11 deletion syndrome in adults with schizophrenia. Am J Med
Genet 81:328–337.
Bearden CE, Woodin M, Wang PP, Moss E, McDonald-McGinn D, Zackai E,
Cannon TD. 2001. Neuropsychological function in the chromosome 22
deletion syndrome: selective deficit in visual-spatial memory. J Clin Exp
Neuropsychol 23:447–464.
Bellugi U, Wang PP, Jernigan TL. 1994. Williams syndrome: an unusual
neuropsychological profile. In: Broman SH, Grafman J, editors.
Atypical cognitive deficits in developmental disorders: implications
for brain function. Hillsdale, NJ: Lawrence Erlbaum Associates. p 23–
56.
Bellugi U, Klima ES, Wang PP. 1997. Cognitive and neural development:
clues from genetically based syndromes. In: Magnusson D, editor. The
lifespan development of individuals: behavioral, neurobiological, and
psychosocial perspectives: a synthesis. New York, NY: Cambridge
University Press. p 223–243.
Carlson C, Sirotkin H, Pandita R, Goldberg R, McKie J, Wadey R, Patanjali
SR, Weissman SM, Anyane-Yeboa K, Warburton D, Scambler P,
Shprintzen R, Kucherlapati R, Morrow BE. 1997. Molecular definition
of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am J
Hum Genet 61:620–629.
Cohen IL, Sudhalter V, Pfadt A, Jenkins EC, Brown WT, Vietze PM. 1991.
Why are autism and the fragile-X syndrome associated? Conceptual and
methodological issues. Am J Hum Genet 48:195–202.
Eliez S, Schmitt JE, White CD, Reiss AL. 2000. Children and adolescents
with velocardiofacial syndrome: a volumetric MRI study. Am J
Psychiatry 157:409–415.
Eliez S, Schmitt JE, White CD, Wellis VG, Reiss AL. 2001. A quantitative
MRI study of posterior fossa development in velocardiofacial syndrome.
Biol Psychiatry 49:540–546.
691
Frangiskakis JM, Ewart AK, Morris CA, Mervis CB, Bertrand J, Robinson
BF, Klein BP, Ensing GJ, Everett LA, Green ED, Proschel C, Gutowski
NJ, Noble M, Atkinson DL, Odelberg SJ, Keating MT. 1996. LIMkinase1 hemizygosity implicated in impaired visuospatial constructive
cognition. Cell 86:59–69.
Galaburda AM, Bellugi U. 2000. V. Multi-level analysis of cortical
neuroanatomy in Williams syndrome. J Cogn Neurosci 12:74–88.
Gottlieb S, Emanuel BS, Driscoll DA, Sellinger B, Wang Z, Roe B, Budarf
ML. 1997. The DiGeorge syndrome minimal critical region contains a
goosecoid-like (GSCL) homeobox gene that is expressed early in human
development. Am J Hum Genet 60:1194–1201.
Guerreiro MM, Camargo EE, Kato M, Marques-de-Faria AP, Ciasca SM,
Guerreiro CA, Netto JR, Moura-Ribeiro MV. 1998. Fragile X syndrome.
Clinical, electroencephalographic and neuroimaging characteristics.
Arq Neuropsiquiatr 56:18–23.
Hinton VJ, Brown WT, Wisniewski K, Rudelli RD. 1991. Analysis of neocortex
in three males with the fragile X syndrome. Am J Med Genet 41:289–294.
Holroyd S, Reiss AL, Bryan RN. 1991. Autistic features in Joubert
syndrome: a genetic disorder with agenesis of the cerebellar vermis.
Biol Psychiatry 29:287–294.
Jernigan TL, Bellugi U, Sowell E, Doherty S, Hesselink JR. 1993. Cerebral
morphologic distinctions between Williams and Down syndromes. Arch
Neurol 50:186–191.
Jones KL, Smith DW. 1975. The Williams elfin facies syndrome. A new
perspective. J Pediatr 86:718–723.
Jones W, Bellugi U, Lai Z, Chiles M, Reilly J, Lincoln A, Adolphs R. 2000. II.
Hypersociability in Williams syndrome. J Cogn Neurosci 12:30–46.
Kates WR, Burnette CP, Jabs EW, Rutberg J, Murphy AM, Grados M,
Geraghty M, Kaufmann WE, Pearlson GD. 2001. Regional cortical white
matter reductions in velocardiofacial syndrome: a volumetric MRI
analysis. Biol Psychiatry 49:677–684.
Kwon H, Menon V, Eliez S, Warsofsky IS, White CD, Dyer-Friedman J,
Taylor AK, Glover GH, Reiss AL. 2001. Functional neuroanatomy of
visuospatial working memory in fragile X syndrome: relation to
behavioral and molecular measures. Am J Psychiatry 158:1040–1051.
McDonald-McGinn DM, LaRossa D, Goldmuntz E, Sullivan K, Eicher P,
Gerdes M, Moss E, Wang P, Solot C, Schultz P, Lynch D, Bingham P,
Keenan G, Weinzimer S, Ming JE, Driscoll D, Clark BJ 3rd, Markowitz
R, Cohen A, Moshang T, Pasquariello P, Randall P, Emanuel BS, Zackai
EH. 1997. The 22q11.2 deletion: screening, diagnostic workup, and
outcome of results; report on 181 patients. Genet Test 1:99–108.
Mervis CB, Morris CA, Bertrand J, Robinson BF. 1999a. Williams syndrome:
findings from an integrated program of research. In: Tager-Flusberg H,
editor. Vol. Neurodevelopmental disorders. Developmental cognitive
neuroscience. Cambridge, MA: MIT Press. p 65–110.
Mervis CB, Robinson BF, Pani JR. 1999b. Visuospatial construction. Am J
Hum Genet 65:1222–1229.
Mervis CB, Robinson BF, Bertrand J, Morris CA, Klein-Tasman BP,
Armstrong SC. 2000. The Williams syndrome cognitive profile. Brain
Cogn 44:604–628.
Moss EM, Batshaw ML, Solot CB, Gerdes M, McDonald-McGinn DM,
Driscoll DA, Emanuel BS, Zackai EH, Wang PP. 1999. Psychoeducational profile of the 22q11.2 microdeletion: a complex pattern [see
comments]. J Pediatr 134:193–198.
Niklasson L, Rasmussen P, Oskarsdottir S, Gillberg C. 2001. Neuropsychiatric disorders in the 22q11 deletion syndrome. Genet Med 3:79–84.
Olney AH, Schaefer GB. 1998. Turner syndrome. Ear Nose Throat J 77:812.
Pennington BF, Heaton RK, Karzmark P, Pendleton MG, Lehman R,
Shucard DW. 1985. The neuropsychological phenotype in Turner
syndrome. Cortex 21:391–404.
Reiss AL, Freund LS, Baumgardner TL, Abrams MT, Denckla MB. 1995.
Contribution of the FMR1 gene mutation to human intellectual
dysfunction. Nat Genet 11:331–334.
1
Mervis et al. [2000] employed the Differential Abilities Scale
(DAS) as their primary cognitive assessment measure, whereas
we administered the Wechsler Intelligence Scale for Children
(WISC-III, 3rd edition). The DAS subtests (Pattern-Construction,
Digit Recall, Naming/Definitions, and Similarities) were designed
to be analogous to the Wechsler tests, and are highly correlated
with the respective WISC-III measures (Block Design, Digit Span,
Vocabulary, and Similarities, respectively).
Reiss AL, Eliez S, Schmitt JE, Patwardhan A, Haberecht M. 2000a. Brain
imaging in neurogenetic conditions: realizing the potential of behavioral
neurogenetics research. Ment Retard Dev Disabil Res Rev 6:186–197.
Reiss AL, Eliez S, Schmitt JE, Straus E, Lai Z, Jones W, Bellugi U. 2000b. IV.
Neuroanatomy of Williams syndrome: a high-resolution MRI study.
J Cogn Neurosci 12:65–73.
Rourke BP. 1995. Syndrome of nonverbal learning disabilities: neurodevelopmental manifestations. New York, NY: Guilford Press. p 1–50.
692
Bearden et al.
Rudelli RD, Brown WT, Wisniewski K, Jenkins EC, Laure-Kamionowska
M, Connell F, Wisniewski HM. 1985. Adult fragile X syndrome. Cliniconeuropathologic findings. Acta Neuropathol (Berl) 67:289–295.
Shaikh TM, Kurahashi H, Saitta SC, Hu P, Roe BA, Driscoll DA, McDonaldMcGinn DM, Zackai EH, Budarf ML, Emanuel BS. 2000. Chromosome 22specific low copy repeats and the 22q11.2 deletion syndrome: genomic
organization and deletion endpoint analysis. Hum Mol Genet 9:489–501.
Wang PP, Bellugi U. 1993. Williams syndrome, Down syndrome, and
cognitive neuroscience. Am J Dis Child 147:1246–1251.
Wechsler D. 1991. Wechsler intelligence scale for children. 3rd ed. San
Antonio, TX: The Psychological Corporation.
Shprintzen RJ, Goldberg RB, Young D, Wolford L. 1981. The velo-cardiofacial syndrome: a clinical and genetic analysis. Pediatrics 67:167–172.
Swillen A, Devriendt K, Legius E, Prinzie P, Vogels A, Ghesquiere P, Fryns
JP. 1999. The behavioural phenotype in velo-cardio-facial syndrome
(VCFS): from infancy to adolescence. Genet Couns 10:79–88.
Tassabehji M, Metcalfe K, Karmiloff-Smith A, Carette MJ, Grant J, Dennis
N, Reardon W, Splitt M, Read AP, Donnai D. 1999. Williams syndrome:
use of chromosomal microdeletions as a tool to dissect cognitive and
physical phenotypes. Am J Hum Genet 64:118–125.
Carrie E. Bearden*
Paul P. Wang
Tony J. Simon
Department of Child Development
The Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania