2.0 CE Credits - Special Issue: The Neuropsychology of Neurodevelopmental Disorders (JINS 24:9, 2018): CE Bundle 1

apa-logo_white_screenThe International Neuropsychological Society is approved by the American Psychological Association to sponsor continuing education for psychologists. The International Neuropsychological Society maintains responsibility for this program and its content.
Educational Objectives
  1. Describe the clinical features of Pitt-Hopkins Syndrome (PTHS).
  2. Discuss the unique phenotype of the present PTHS case study.
  3. Describe why a young child with sickle cell anaemia should be considered for early baseline neuropsychological assessment.
  4. List the subdomains of executive function where a child with sickle cell anaemia might show delay or deficits at preschool age.
  5. List the genes that have a critical influence on the cognitive, behavioural and adaptive profile of people with Williams syndrome.
  6. Discuss how genes influence cognitive, behavioural and adaptive characteristics in people with Williams syndrome.
  7. Describe verbal fluency abilities in youth with sex chromosome aneuploidies.
  8. Compare performance across groups as they differ as a function of extra X number and X vs. Y status.

Course Information
Target Audience:Intermediate
Availability:Date Available: 2019-04-01
You may obtain CE for this JINS package at any time.
Offered for CEYes
CostMembers $20
Non-Members $30
Refund PolicyThis JINS package is not eligible for refunds
CE Credits2.0


Neurodevelopmental disorders are conditions that involve early insult or abnormality in the developing central nervous system and are associated with a wide spectrum of abilities. These conditions begin during the early developmental period (usually conceptualized as prenatally though the first 3 years of life), affect day-to-day functioning, and are often lifelong. Because the “typical” development of the nervous system has been altered in individuals with neurodevelopmental disorders, reorganization and competition for function occur, usually resulting in skill patterns that are less efficient than among individuals without such conditions. The timing of these alterations or developmental disruptions is also relevant, as different neural systems are selectively vulnerable to injury at different phases of prenatal and post-natal development. As a result, the behavioral and cognitive dysfunction associated with early neural damage can range from subtle (or absent) to diffuse and profound. Moreover, the functional impairments can be observed immediately in some individuals, while in others, the full range of deficits may not manifest until later in life, even though the neurobiological basis of the condition is present earlier (Rudel, 1981).

Among children with neurodevelopmental disorders, the trajectory is often “off developmental track” relative to the trajectory of typically developing children. Developmental delays (i.e., patterns of skill development that should have occurred earlier in life) are often observed early in life. While functional catch-up is possible, it is often incomplete, and the resulting maturational timelines based on typical development become less applicable (Mahone, Slomine, & Zabel, 2018).

Neurodevelopmental disorders are highly prevalent. Recent estimates from the Centers for Disease Control and Prevention (CDC) in the United States show that around one in six, or approximately 17%, of children ages 3 through 17 years have one or more neurodevelopmental disabilities (Boyle et al., 2011). The rates also are increasing, and the CDC reports may underestimate the actual prevalence worldwide. In the past 25 years, medical advances have improved the life course of several genetic, medical, and neurodevelopmental conditions, making them more survivable and compatible with life (e.g., very low birth weight preterm infants, congenital hydrocephalus) and extending the expected lifespan of others (e.g., cystic fibrosis, sickle cell disease). Due to higher survival rates and lifespans extending into adulthood, increased attention has been given to the development of self-management and independence skills and the transition into older adolescence and young adulthood (Tarazi, Mahone, & Zabel, 2007; Warschausky, Kaufman, Evitts, Schutt, & Hurvitz, 2017; Zabel, Jacobson, & Mahone, 2013). Given these considerations, the assessment and study of individuals with neurodevelopmental disorders is of significant interest to neuropsychologists.

Classification of neurodevelopmental disorders can be conceptualized using two primary approaches, one emphasizing behavior (without explicit reference to etiology), and the other emphasizing etiological medical, genetic, and neurological factors (Mahone et al., 2018). In the field of neuropsychology, those neurodevelopmental disorders defined on the basis of behavior (including attention-deficit/hyperactivity Disorder, ADHD; learning disabilities, LDs; autism spectrum disorders, ASDs; and intellectual disability, ID) have received considerable emphasis, in part because of their prevalence and overall public health relevance (Leigh & Du, 2015; Mahone & Denckla, 2017; Mahone & Mapou, 2014). Neurodevelopmental disorders diagnosed on the basis of known or presumed medical etiologic factors have received somewhat less emphasis among neuropsychologists. Such conditions include those with genetic, environmental (injury, infection, teratogens), or multi-factorial medical etiologies.

This special issue of the Journal of the International Neuropsychological Society focuses upon such conditions with known medical or genetic etiologies, and includes 11 papers presenting innovative and novel data related to the neuropsychology (including identification of biomarkers) of specific neurodevelopmental disorders. Included in the issue are seven studies reporting new empirical findings, two critical reviews, and two case reports. The timing of this special issue follows on the heels of the 50th anniversary of the implementation of US PL-88-164 (“Mental Retardation Facilities Construction Act”), which, in 1967, provided financial support for the development 18 University Affiliated Programs (emphasizing treatment for neurodevelopmental disorders), and 12 Research Centers dedicated to research of neurodevelopmental disorders, all of which have contributed to the scientific innovations that have improved the lives of individuals with neurodevelopmental disorders and their families.

The issue begins with seven empirical studies, emphasizing disorders (both rare and more common) with genetic and associated medical etiologies, with samples ranging in age from early childhood through young adult. Williams syndrome is a rare genetic condition, often associated with intellectual disability and significant visuospatial dysfunction. In the first paper, Prieto-Corona and colleagues report on neuropsychological and functional outcomes in children with Williams syndrome, with and without the additional (even rarer) deletion of the GTF2IRD2 gene. They showed that those individuals with the additional genetic deletion had even greater dysfunction in visuospatial and social cognition, compared to those with without the deletion.

Antschel et al. report findings from a rich, 9-year longitudinal dataset of individuals with 22q11.2 deletion syndrome, a disorder associated with high risk for functional impairment and psychosis. They found that early executive function, especially working memory deficits, were associated with later functional impairment, but that the association was seen in both those with and without the disorder, highlighting the importance of early assessment of executive and cognitive control skills as predictors of later outcome.

There is considerable sexual dimorphism observed among individuals with neurodevelopmental disorders. The study of individuals with sex chromosome aneuploidies—conditions characterized by abnormal numbers of X or Y chromosomes, for example, Klinefelter syndrome (XXY) or Turner syndrome (XO)—provides a highly relevant framework to investigate the etiology of some sex differences in development and function. In this issue, Udhnani and colleagues and Maiman and colleagues report on a less studied variant of sex chromosome aneuploidies—those with trisomies, tetrasomies, and pentasomies—showing an association between these variants and reductions in verbal fluency, with severity of deficits related linearly to the number of supernumerary X chromosomes.

The dystrophinopathies (including Duchenne and Becker muscular dystrophies) are X-linked muscle diseases associated with abnormal expression of the protein dystrophin. These conditions affect primarily males and result in a wide range of functional cognitive deficits. Fee and colleagues report on neuropsychological performance in a sample of 50 boys with muscular dystrophy, grouped by gene mutation position relative to exon 43. They found that boys with mutation downstream from exon 43 showed greater academic deficits, relative to those with mutation upstream of exon 43.

Medical and surgical advances contribute to an increasing number of individuals surviving congenital heart disease (CHD) and its treatment. King et al. report on neuroimaging findings in a sample of adolescents and young adults with CHD, showing reduced cerebellar volumes, with reductions predictive of executive and cognitive control functions.

The manifestation of neurobehavioral dysfunction among children with neurodevelopmental disorders often occurs early in life. Downes and colleagues present a case control study of executive functions in preschoolers with sickle cell disease (SCD). In their sample, performance-based reductions in inhibitory control and cognitive flexibility were more pronounced than parent reports of similar functions, highlighting the importance of direct assessment of executive control skills in preschoolers with SCD.

Down syndrome (DS) represents the most common genetic etiology of intellectual disability, and is associated with a wide range of medical complications and skill difficulties, especially those implicating hippocampally mediated functions. Edgin and colleagues reported minimal effects of a fast-mapping strategy, hypothesized to incrementally improve word retention, but instead showed that individuals with DS do retain novel words effectively, but only when presented during learning trials in small groups. In a related review, Hammer and colleagues provide a succinct overview of structural anatomic neuroimaging studies of individuals with DS, highlighting widespread reductions in cerebral volume early in life, with smaller effects (relative reductions) observed by adolescence.

Neurofibromatosis type 1 (NF1) is a genetic neurocutaneous disorder associated with learning disabilities, ADHD, and an increased risk for brain tumors. Beaussart and colleagues provide a meta-analysis of 19 studies of individuals with NF1, emphasizing executive control skills. They concluded that, in general, working memory and planning skills were relatively more affected than inhibitory control in this population, and that relative difficulties (compared to those without NF1) tend to increase with age through adolescence.

The two final papers in this issue highlight the utility of case studies, especially in rare conditions. Tan et al. report on an individual with Pitt-Hopkins syndrome (PHS), a rare genetic disorder caused by insufficient expression of the TCF4 gene. Nearly all of the few prior published reports on PHS highlight severe intellectual and functional deficits and minimal language use. This case report instead presents findings from an individual who, despite many cognitive limitations, showed some relatively spared language function. In the final paper for this special issue, Kim et al. report on an intervention using different spacing methods to improve word list learning in a young adult with congenital amnesia secondary to premature birth and associated hypoxic-ischemic injury. They found that word recognition improved with repetitions spaced, rather than massed.

As illustrated in this set of papers, neuropsychological studies of neurodevelopmental disorders typically are conducted from a developmental perspective with an increasingly interdisciplinary approach that frequently draws upon (and informs) a refined understanding of endophenotypes and biomarkers. The ultimate hope, of course, is that these research approaches will inform more effective treatment and optimal developmental outcomes for the target populations.

It was a pleasure organizing these papers into this special issue, and we thank the authors for their contribution to this unique collection of studies demonstrating the importance of rigorous neuropsychological inquiry into neurodevelopmental conditions. It is our hope that the readers of the Journal of the International Neuropsychological Society find this collection valuable and are able to build off of the innovative and novel neuropsychological findings in the specific neurodevelopmental disorders presented within.

Individual Titles, Authors, and Articles:

Pitt-Hopkins Syndrome: A Unique Case Study
  • Alexander Tan | Children’s Health Children’s Medical Center, Dallas, Texas, University of Texas Southwestern Medical Center, Dallas, Texas
  • Kimberly Goodspeed | Children’s Health Children’s Medical Center, Dallas, Texas, University of Texas Southwestern Medical Center, Dallas, Texas
  • Veronica Bordes Edgar | Children’s Health Children’s Medical Center, Dallas, Texas, University of Texas Southwestern Medical Center, Dallas, Texas

E-mail address | alexandertanphd@gmail.com

The authors have no conflicts of interest or sources of financial support to disclose.


Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder caused by insufficient expression of the TCF4 gene. Most cases are characterized by severe intellectual disability, absent speech, motor delays, and autism spectrum disorder. Many have abnormal brain imaging,dysmorphic facial features, and medical comorbidities: myopia, constipation, epilepsy, and apneic spells. The present case study expands existing understanding ofthis disorder by presenting a unique phenotype with higher cognitive abilities and fewer medical comorbidities.


The present casestudy reports on a 13-year-old, Caucasian male with a recent diagnosis of PTHS following genetic testing (i.e., whole exome sequencing). He was referred for a neuropsychologicalevaluation to document his neurocognitive functioning to assist with intervention planning.


Evaluation of intellectual, attention/executive,memory, visual-motor/fine-motor, academic, adaptive, and emotional/behavioral functioning revealed global impairment across all areas of functioning. However, he demonstratedabilities beyond what has been detailed in the literature, including use of full sentences, capacity to learn and solve novel problems, basic academic functioning,and independent ambulation.


Children with PTHS may demonstrate a spectrum of abilities beyond what has been documented in theliterature thus far. Failure to recognize this spectrum can result in late identification of an accurate diagnosis. (JINS, 2018,24, 995–1002)

  1. Amiel, J., Rio, M., de Pontual, L., Redon, R., Malan, V., Boddaert, N., & Colleaux, L. (2007). Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. American Journal of Human Genetics, 80(5), 988–993. CrossRef  Google Scholar 
  2. Andrieux, J., Lepretre, F., Cuisset, J.M., Goldenberg, A., Delobel, B., Manouvrier-Hanu, S., & Holder-Espinasse, M. (2008). Deletion 18q21.2q21.32 involving TCF4 in a boy diagnosed by CGH-array. European Journal of Medical Genetics, 51(2), 172–177. CrossRef  Google Scholar 
  3. Armani, R., Archer, H., Clarke, A., Vasudevan, P., Zweier, C., Ho, G., & Christodoulou, J. (2012). Transcription factor 4 and myocyte enhancer factor 2C mutations are not common causes of Rett syndrome. American Journal of Medical Genetics Part A, 158A(4), 713–719. CrossRef  Google Scholar 
  4. Blake, D.J., Forrest, M., Chapman, R.M., Tinsley, C.L., O’Donovan, M.C., & Owen, M.J. (2010). TCF4, schizophrenia, and Pitt-Hopkins syndrome. Schizophrenia Bulletin, 36(3), 443–447. CrossRef  Google Scholar  PubMed 
  5. Brockschmidt, A., Filippi, A., Charbel Issa, P., Nelles, M., Urbach, H., Eter, N., & Weber, R.G. (2011). Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model. Human Genetics, 130(5), 645–655. CrossRef  Google Scholar 
  6. Brockschmidt, A., Todt, U., Ryu, S., Hoischen, A., Landwehr, C., Birnbaum, S., & Weber, R.G. (2007). Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. Human Molecular Genetics, 16(12), 1488–1494. CrossRef  Google Scholar  PubMed 
  7. Cody, J.D., Sebold, C., Heard, P., Carter, E., Soileau, B., Hasi-Zogaj, M., & Hale, D.E. (2015). Consequences of chromosome 1iq deletions. American Journal of Medical Genetics, 169(3), 265–280. CrossRef  Google Scholar 
  8. de Pontual, L., Mathieu, Y., Golzio, C., Rio, M., Malan, V., Boddaert, N., & Amiel, J. (2009). Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. Human Mutation, 30(4), 669–676. CrossRef  Google Scholar  PubMed 
  9. de Winter, C.F., Baas, M., Bijlsma, E.K., van Heukelingen, J., Routledge, S., & Hennekam, R.C. (2016). Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an internet questionnaire system. Orphanet Journal of Rare Diseases, 12(11), 37. CrossRef  Google Scholar 
  10. Engelen, J.J., Moog, U., Weber, J., Haagen, A.A., van Uum, C.M., & Hamers, A.J. (2003). Deletion of chromosome region 18q21.1 → 18q21.3 in a patient without clinical features of the 18q- phenotype. American Journal of Medical Genetics Part A, 119A(3), 356–359. CrossRef  Google Scholar 
  11. Forrest, M.P., Hill, M.J., Quantock, A.J., Martin-Rendon, E., & Blake, D.J. (2014). The emerging roles of TCF4 in disease and development. Trends in Molecular Medicine, 20(6), 322–331. CrossRef  Google Scholar  PubMed 
  12. Giurgea, I., Missirian, C., Cacciagli, P., Whalen, S., Fredriksen, T., Gaillon, T., & Moncla, A. (2008). TCF4 deletions in Pitt-Hopkins Syndrome. Human Mutation, 29(11), E242–E251. CrossRef  Google Scholar  PubMed 
  13. Goodspeed, K., Newom, C., Morris, M.A., Powell, C., Evans, P., & Golla, S. (2018). Pitt-Hopkins syndrome: A review of current literature, clinical approach, and 23-patient case series. Journal of Child Neurology, 33(3), 233–244. CrossRef  Google Scholar  PubMed 
  14. Green, E.D., Rubin, E.M., & Olson, M.V. (2017). The future of DNA sequencing. Nature, 550(7675), 179–181. CrossRef  Google Scholar  PubMed 
  15. Hasi, M., Soileau, B., Sebold, C., Hill, A., Hale, D.E., O’Donnell, L., & Cody, J.D. (2011). The role of the TCF4 gene in the phenotype of individuals with 18q segmental deletions. Human Genetics, 130(6), 777–787. CrossRef  Google Scholar  PubMed 
  16. Kalscheuer, V.M., Feenstra, I., Van Ravenswaaij-Arts, C.M., Smeets, D.F., Menzel, C., Ullmann, R., & Ropers, H.H. (2008). Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome. American Journal of Medical Genetics Part A, 146A(16), 2053–2059. CrossRef  Google Scholar 
  17. Marangi, G., Ricciardi, S., Orteschi, D., Lattante, S., Murdolo, M., Dallapiccola, B., & Zollino, M. (2011). The Pitt-Hopkins syndrome: Report of 16 new patients and clinical diagnostic criteria. American Journal of Medical Genetics, 155A(7), 1536–1545. CrossRef  Google Scholar  PubMed 
  18. Marangi, G., & Zollino, M. (2015). Pitt-Hopkins syndrome and differential diagnosis: A molecular and clinical challenge. Journal of Pediatric Genetics, 4(3), 168–176. CrossRef  Google Scholar  PubMed 
  19. Michelson, D.J., Shevell, M.I., Sherr, E.H., Moeschler, J.B., Gropman, A.L., & Ashwal, S. (2011). Evidence report: Genetic and metabolic testing on children with global developmental delay: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology, 77(17), 1629–1635. CrossRef  Google Scholar  PubMed 
  20. Nolan, D., & Carlson, M. (2016). Whole exome sequencing in pediatric neurology patients; clinical implications and estimated cost analysis. Journal of Child Neurology, 31(7), 887–894. CrossRef  Google Scholar  PubMed 
  21. Ouvrier, R. (2008). Hyperventilation and the Pitt-Hopkins syndrome. Developmental Medicine and Child Neurology, 50(7), 481. CrossRef  Google Scholar  PubMed 
  22. Peippo, M., Simola, K.O., Valanne, L.K., Larsen, A.T., Kahkonen, M., Auranen, M.P., & Ignatius, J. (2006). Pitt-Hopkins syndrome in two patients and further definition of the phenotype. Clinical Dysmorphology, 15(2), 47–54. CrossRef  Google Scholar  PubMed 
  23. Pitt, D., & Hopkins, I. (1978). A syndrome of mental retardation, wide mouth and intermittent overbreathing. Australian Paediatric Journal, 14(3), 182–184. Google Scholar  PubMed 
  24. Rosenfeld, J.A., Leppig, K., Ballif, B.C., Thiese, H., Erdie-Lalena, C., Bawle, E., & Shaffer, L.G. (2009). Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Genetics in Medicine, 11(11), 797–805. CrossRef  Google Scholar  PubMed 
  25. Sepp, M., Pruunsild, P., & Timmusk, T. (2012). Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects. Human Molecular Genetics, 21(13), 2873–2888. CrossRef  Google Scholar  PubMed 
  26. Stavropoulous, D.J., MacGregor, D.L., & Yoon, G. (2010). Mosaic microdeletion 18q21 as a cause of mental retardation. European Journal of Medical Genetics, 53(6), 396–399. CrossRef  Google Scholar 
  27. Sweatt, J.D. (2013). Pitt-Hopkins Syndrome: Intellectual disability due to loss of TCF4-regulated gene transcription. Experimental and Molecular Medicine, 3(45), e21. CrossRef  Google Scholar 
  28. Takano, K., Lyons, M., Moyes, C., Jones, J., & Schwartz, C.E. (2010). Two percent of patients suspected of having Angelman syndrome have TCF4 mutations. Clinical Genetics, 78(3), 282–288. CrossRef  Google Scholar  PubMed 
  29. Van Balkom, I.D., Vuijk, P.J., Franssens, M., Hoek, H.W., & Hennekam, R.C. (2012). Development, cognition, and behaviour in Pitt-Hopkins syndrome. Developmental Medicine & Child Neurology, 54(10), 925–931. CrossRef  Google Scholar  PubMed 
  30. Whalen, S., Heron, D., Gaillon, T., Moldovan, O., Rossi, M., Devillard, F., & Giurgea, I. (2012). Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: Clinical score and further delineation of the TCF4 mutational spectrum. Human Mutation, 33(1), 64–72. CrossRef  Google Scholar  PubMed 
  31. Zweier, C., Peippo, M.M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., & Rauch, A. (2007). Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). American Journal of Human Genetics, 80(5), 994–1001. CrossRef  Google Scholar 
  32. Zweier, C., Sticht, H., Bijlsma, E.K., Clayton-Smith, J., Boonen, S.E., Fryer, A., & Rauch, A. (2008). Further delineation of Pitt-Hopkins syndrome: Phenotypic and genotypic description of 16 novel patients. Journal of Medical Genetics, 45(11), 738–744. CrossRef  Google Scholar  PubMed 
Assessment of Executive Functions in Preschool Children With Sickle Cell Anemia
  • Michelle Downes | School of Psychology, University College Dublin, Dublin, Ireland, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
  • Fenella J. Kirkham | Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
  • Paul T. Telfer | Department of Haematology, Barts Health NHS Trust, Royal London Hospital, London, United Kingdom
  • Michelle de Haan | Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, United Kingdom

E-mail address | Michelle.Downes@ucd.ie

None of the authors have potential conflicts of interest to be disclosed.


Children with sickle cell anemia (SCA) are commonly reported to experience executive dysfunction. However, the development of executivefunction (EF) in preschool-age children without stroke in this patient population has not been investigated so it is unclear when and how these deficits emerge.


This case-control study examines the feasibility of assessing the early development of executive functioning in 22 preschool children years with SCAin the domains of processing speed, working memory, attention, inhibitory control, and cognitive flexibility, as well as everyday function, in comparison to matchedcontrol children.


A pattern of potential deficits in early emerging executive skills was observed in the domains of inhibitorycontrol and cognitive flexibility. Parents reported no differences for everyday EF and no significant differences were observed for working memory and processingspeed.


Results suggest that deficits in everyday executive difficulties, working memory, and processing speed, as commonlyreported for older children with SCA, may not yet have emerged at this early developmental stage, despite specific deficits in cognitive flexibility and inhibitorycontrol on behavioral measures. The feasibility of using available executive measures with preschool age children to characterize the development of early EF skillsis discussed. (JINS, 2018, 24, 949–954)

  1. Anderson, P. (2002). Assessment and development of executive functioning (EF) during childhood. Child Neuropsychology, 8(2), 71–82. CrossRef  Google Scholar  PubMed 
  2. Baldeweg, T., Hogan, A.M., Saunders, D.E., Telfer, P., Gadian, D.G., Vargha‐Khadem, F., &&Kirkham, F.J. (2006). Detecting white matter injury in sickle cell disease using voxel‐based morphometry. Annals of Neurology, 59(4), 662–672. CrossRef  Google Scholar  PubMed 
  3. Berg, C., Edwards, D.F., & King, A. (2012). Executive function performance on the children’s kitchen task assessment with children with sickle cell disease and matched controls. Child Neuropsychology, 18(5), 432–448. CrossRef  Google Scholar  PubMed 
  4. Berkelhammer, L.D., Williamson, A.L., Sanford, S.D., Dirksen, C.L., Sharp, W.G., Margulies, A.S., && Prengler, R.A. (2007). Neurocognitive sequelae of pediatric sickle cell disease: A review of the literature. Child Neuropsychology, 13(2), 120–131. CrossRef  Google Scholar  PubMed 
  5. Burkhardt, L., Lobitz, S., Koustenis, E., Rueckriegel, S.M., & Hernaiz, D.P. (2017). Cogntive and fine motor deficits in pediatric sickle cell disease cohort of mixed ethnic origin. Annals of Hematology, 96(2), 199–213. CrossRef  Google Scholar 
  6. Daly, D.B., Kral, M.C., & Tarazi, R.A. (2011). The role of neuropsychological evaluation in pediatric sickle cell disease. The Clinical Neuropsychologist, 25(6), 903–925. CrossRef  Google Scholar  PubMed 
  7. Drazen, C.H., Abel, R., Gabir, M., Farmer, G., & King, A.A. (2016). Prevalence of developmental delay and contributing factors among children with sickle cell disease. Pediatric Blood & Cancer, 63(3), 504–510. CrossRef  Google Scholar  PubMed 
  8. Fuglestad, A.J., Whitley, M.L., Carlson, S.M., Boys, C.J., Eckerle, J.K., Fink, B.A., && Wozniak, J.R. (2014). Executive functioning deficits in preschool children with fetal alcohol spectrum disorders. Child Neuropsychology, 21(6), 716–731. CrossRef  Google Scholar  PubMed 
  9. Glass, P., Brennan, T., Wang, J., Luchtman-Jones, L., Hsu, L., Bass, C.M.,& Cheng, Y.I. (2012). Neurodevelopmental deficits among infants and toddlers with sickle cell disease. Journal of Developmental and Behavioral Pediatrics, 34(6), 399–405. CrossRef  Google Scholar 
  10. Hensler, M., Wolfe, K., Lebensburger, J., Nieman, J., Barnes, M., Nolan, W.,& Madan-Swain, A. (2014). Social skills and executive function among youth with sickle cell disease: A preliminary investigation. Journal of Pediatric Psychology, 39(5), 493–500. CrossRef  Google Scholar  PubMed 
  11. Hijmans, C.T., Fijnvandraat, K., Grootenhuis, M.A., van Geloven, N., Heijboer, H., Peters, M., && Oosterlaan, J. (2011). Neurocognitive deficits in children with sickle cell disease: A comprehensive profile. Pediatric Blood & Cancer, 56(5), 783–788. CrossRef  Google Scholar  PubMed 
  12. Hogan, A.M., Telfer, P.T., Kirkham, F.J., & de Haan, M. (2013). Precursors of executive function in infants with sickle cell anemia. Journal of Child Neurology, 28(10), 1197–1202. CrossRef  Google Scholar  PubMed 
  13. Hollocks, M.J., Kok, T.B., Kirkham, F.J., Gavlak, J., Inusa, B.P., DeBaun, M.R., &&de Haan, M. (2012). Nocturnal oxygen desaturation and disordered sleep as a potential factor in executive dysfunction in sickle cell anemia. Journal of the International Neuropsychological Society, 18(1), 168. CrossRef  Google Scholar  PubMed 
  14. Kral, M.C., & Brown, R.T. (2004). Transcranial Doppler ultrasonography and executive dysfunction in children with sickle cell disease. Journal of Pediatric Psychology, 29(3), 185–195. CrossRef  Google Scholar  PubMed 
  15. Nabors, N.A., & Freymuth, A.K. (2002). Attention deficits in children with sickle cell disease. Perceptual and Motor Skills, 95(1), 57–67. CrossRef  Google Scholar  PubMed 
  16. Ruffieux, N., Njamnshi, A.K., Wonkam, A., Hauert, C.A., Chanal, J., Verdon, V., & Ngamaleu, R.N. (2013). Association between biological markers of sickle cell disease and cognitive functioning amongst Cameroonian children. Child Neuropsychology, 19(2), 143–160. CrossRef  Google Scholar  PubMed 
  17. Schatz, J., & Roberts, C.W. (2007). Neurobehavioral impact of sickle cell disease in early childhood. Journal of the International Neuropsychological Society, 13(6), 933–943. CrossRef  Google Scholar  PubMed 
  18. Smith, K.E., & Scahtz, J. (2016). Working memory in children with neurocognitive effects from sickle cell disease: Contributions of the central executive and processing speed. Developmental Neuropsychology, 41(4), 231–244. CrossRef  Google Scholar  PubMed 
  19. Tarazi, R.A., Grant, M.L., Ely, E., & Barakat, L.P. (2007). Neuropsychological functioning in preschool-age children with sickle cell disease: The role of illness-related and psychosocial factors. Child Neuropsychology, 13(2), 155–172. CrossRef  Google Scholar  PubMed 
  20. Vichinsky, E.P., Neumayr, L.D., Gold, J.I., Weiner, M.W., Rule, R.R., Truran, D., &McMahon, L. (2010). Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA, 303(18), 1823–1831. CrossRef  Google Scholar  PubMed 
  21. Yarboi, J., Compas, B.E., Brody, G.H., White, D., Patterson, J.R., Ziara, K., && King, A. (2017). Association of social-environmental factors with cognitive function in children with sickle cell disease. Child Neuropsychology, 23(3), 343–360. CrossRef  Google Scholar  PubMed 
Cognitive, Behavioral, and Adaptive Profiles in Williams Syndrome With and Without Loss of GTF2IRD2
  • Carlos Alberto Serrano-Juárez | Laboratorio de Neurometría, Facultad de Estudios Superiores Iztacala, UNAM, Los Reyes Iztacala, Tlalnepantla, Estado de México, CP
  • Carlos Alberto Venegas-Vega | Servicio de Genética, Hospital General de México “Dr. Eduardo Liceaga”, Cuauhtémoc, CDMX, CP
  • Ma. Guillermina Yáñez-Téllez | Laboratorio de Neurometría, Facultad de Estudios Superiores Iztacala, UNAM, Los Reyes Iztacala, Tlalnepantla, Estado de México, CP
  • Mario Rodríguez-Camacho | Laboratorio de Neurometría, Facultad de Estudios Superiores Iztacala, UNAM, Los Reyes Iztacala, Tlalnepantla, Estado de México, CP
  • Juan Silva-Pereyra | Laboratorio de Neurometría, Facultad de Estudios Superiores Iztacala, UNAM, Los Reyes Iztacala, Tlalnepantla, Estado de México, CP
  • Hermelinda Salgado-Ceballos | Unidad de Investigación Médica en Enfermedades Neurológicas, Hospital de Especialidades, CMN “Siglo XXI”, IMSS
  • Belén Prieto-Corona | Laboratorio de Neurometría, Facultad de Estudios Superiores Iztacala, UNAM, Los Reyes Iztacala, Tlalnepantla, Estado de México, CP

E-mail address | bemapado@gmail.com

All authors involved in this investigation declare no conflicts of interest.


Williams syndrome (WS) is a neurodevelopmental disorder that results from a heterozygous microdeletion on chromosome 7q11.23. Most of the time, the affected region contains~1.5 Mb of sequence encoding approximately 24 genes. Some 5–8% of patients with WS have a deletion exceeding 1.8 Mb, thereby affecting two additional genes, includingGTF2IRD2. Currently, there is no consensus regarding the implications of GTF2IRD2 loss for the neuropsychologicalphenotype of WS patients.


The present study aimed to identify the role of GTF2IRD2 in the cognitive,behavioral, and adaptive profile of WS patients.


Twelve patients diagnosed with WS participated, four with GTF2IRD2 deletion (atypical WS group), and eight without this deletion (typical WS group). The age range of both groups was 7–18 years old. Each patient’s 7q11.23 deletionscope was determined by chromosomal microarray analysis. Cognitive, behavioral, and adaptive abilities were assessed with a battery of neuropsychological tests.


Compared with the typical WS group, the atypical WS patients with GTF2IRD2 deletion had more impaired visuospatial abilities and more significant behavioralproblems, mainly related to the construct of social cognition.


These findings provide new evidence regarding the influenceof the GTF2IRD2 gene on the severity of behavioral symptoms of WS related to social cognition and certain visuospatial abilities. (JINS, 2018, 24, 896–904)

  1. Adolphs, R. (2009). The social brain: Neural basis of social knowledge. Annual Review of Psychology, 60, 693–716. doi: 10.1146/annurev.psych.60.110707.163514 CrossRef  Google Scholar  PubMed 
  2. Allen Brain Atlas. (2010). Allen Institute for Brain Science. Retrieved from human.brain-map.org Google Scholar 
  3. Atkinson, J. (2017). Visual brain development: A review of “Dorsal stream vulnerability”- motion, mathematics, amblyopia, actions, and attention. Journal of Vision, 17(3), 1–24. doi: 10.1167/17.3.26 Google Scholar  PubMed 
  4. Atkinson, J., Anker, S., Braddick, O., Nokes, L., Mason, A., & Braddick, F. (2001). Visual and visuospatial development in young children with williams syndrome. Developmental Medicine & Child Neurology, 43, 330–337. CrossRef  Google Scholar  PubMed 
  5. Atkinson, J., & Braddick, O. (2011). From genes to brain development to phenotypic behavior: “Dorsal-stream vulnerability” in relation to spatial cognitiion, attention, and planning of actions in Williams syndrome (WS) and other development disorders. Progress in Brain Research, 189, 261–283. doi: 10.1016/B978-0-444-53884-0.00029-4 CrossRef  Google Scholar 
  6. Atkinson, J., & Braddick, O. (2012). Visual attention in the first years: Typical development and develompental disorders. Development Medicine & Child Neurology, 54, 589–595. doi: 10.1111/j.469-8749.2012.04294.x CrossRef  Google Scholar 
  7. Atkinson, J., & Nardini, M. (2008). The neuropsychology of visuospatial and visuomotor development. In J. Reed & J. Warner-Rogers (Eds.), Child neuropsychology: Concepts, theory and practice (pp. 183–217). Chichester, UK: Wiley-Blackwell. Google Scholar 
  8. Bellugi, U., Järvinen-Pasley, A., Doyle, T., Reilly, J., Reiss, A., & Korenberg, J. (2007). Affect, Social Behavior, and the Brain in Williams Syndrome. Current Directions in Psychological Science, 16(2), 99–104. CrossRef  Google Scholar 
  9. Bellugi, U., Lichtenberger, L., Mills, D., Galaburda, A., & Korenberg, J. (1999). Briding cognition, the brain and molecular genetics: Evidence from Williams syndrome. Trends in Neuroscience, 22, 197–207. CrossRef  Google Scholar 
  10. Botta, A., Novelli, G., Mari, A., Sabani, M., Korenberg, J., Osborne, L., Dallapiccola, B. (1999). Detection of an atypical 7q11.23 deletion in Williams syndrome patients which does not include the STX1A and FZD3 genes. Journal of Medical Genetics, 36, 478–480. doi: 10.1136/jmg.36.6.478 Google Scholar 
  11. Broadbent, H., Farran, E., Chin, E., Metcalfe, K., Tassabehji, M., Turnpenny, P., Karmiloff-Smith, A. (2014). Genetic contributions to visuospatial cognition in Williams syndrome: Insights from two contrasting partial deletion patients. Journal of Neurodevelopmental Disorders, 6, 18. CrossRef  Google Scholar  PubMed 
  12. Capirci, O., Sabbadini, L., & Volterra, V. (1996). Language development in Williams syndrome: A case study. Cognitive Neuropsychology, 1017–1039. CrossRef  Google Scholar 
  13. Chailangkarn, T., Noree, C., & Muotri, A. R. (2018). The contribution of GTF2I haploinsufficiency to Williams syndrome. Molecular and Cellular Probes, 40, 45–51. doi: https://doi.org/10.1016/j.mcp.2017.12.005 CrossRef  Google Scholar  PubMed 
  14. Colantuoni, C., Lipska, B. K., Hyde, T. M., Tao, R., Leek, J. T., Colantuoni, E. A., Kleinman, J. E. (2011). Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature, 478, 519–523. doi: 10.1038/nature10524 CrossRef  Google Scholar  PubMed 
  15. Crespi, B. J., & Hurd, P. L. (2014). Cognitive-behavioral phenotypes of Williams syndrome are associated with genetic variation in the GTF2I gene, in a healthy popoulation. BMC Neuroscience, 15, 127. CrossRef  Google Scholar 
  16. D’Souza, D., Booth, R., Connolly, M., Happe, F., & Karmiloff-Smith, A. (2016). Rethinking the concepts of ‘local or global processors’: Evidence from Williams syndrome, Down syndrome, and Autism Spectrum Disorders. Developmental Science, 19(3), 452–468. doi: 10.1111/desc.12312 CrossRef  Google Scholar  PubMed 
  17. Edelmann, L., Prosnitz, A., Pardo, S., Bhatt, J., Cohen, N., Lauriat, T., McInnes, A. (2007). An atypical deltion of the Williams-Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism. Journal of Medical Genetics, 44, 136–143. doi: 10.1136/jmg.2006.044537 CrossRef  Google Scholar 
  18. Enkhmandakh, B., Makeyev, A., Erdenechimeg, L., Ruddle, F., Chimge, N.-O., Tussie-Luna, M. I., Bayarsaihan, D. (2009). Essential functions of the Williams-Beuren syndrome-associated TFII-I genes in embryonic development. Proceedings of the National Academy of Sciences of the United States of America, 106(1), 181–186. doi: 10.1073pnas.0811531106 CrossRef  Google Scholar  PubMed 
  19. Fernández-Pinto, I., Santamaría, P., Sánchez-Sánchez, F., Carrasco, M. A., & Del Barrio, V. (2015). Sistema de Evaluación de Niños y Adolescentes. SENA. Madrid: TEA Ediciones. Google Scholar 
  20. Ferrero, G., Howald, C., Micale, L., Biamino, E., Augello, B., Fusco, C., Merla, G. (2010). An atypical 7q11.23 deletion normal IQ Williams-Beuren syndrome patient. European Journal of Human Genetics, 18, 33–38. CrossRef  Google Scholar  PubMed 
  21. Frangiskakis, M., Ewart, A., Morris, C. A., Mervis, C., Bertrand, J., Robinson, B., Keating, M. T. (1996). LIM-kinase1 hemizygosity implicated in impaired visuospatial cosntructive cognition. Cell, 86, 59–69. CrossRef  Google Scholar  PubMed 
  22. Frostig, M. (1999). Figuras y Formas: Guía del Maestro. México: Panamericana. Google Scholar 
  23. Gao, M., Bellugi, U., Dai, L., Mills, D., Sobel, E., Lange, K., & Korenberg, J. (2010). Intelligence in Williams Syndrome is related to STX1A, which encodes a component of the presynaptic SNARE complex. PLoS One, 5(4), e10292. doi: 10.1371/journal.pone.0010292 CrossRef  Google Scholar  PubMed 
  24. Garayzábal, E. (2005). Síndrome de Williams: Materiales y análisis pragmático. Valencia: Universitat de Valencia. Google Scholar 
  25. Garayzábal, E., & Cuetos, F. (2008). Aprendizaje de la lectura en los niños con síndrome de Williams. Psicothema, 20(4), 672–677. Google Scholar 
  26. García-Nonell, C., Rigau-Ratera, E., Artigas-Pallarés, J., García-Sánchez, C., & Estévez-González, A. (2003). Síndrome de Williams: Memoria, funciones visuoespaciales y funciones visuoconstructivas. Revista de Neurología, 37, 826–830. Google Scholar 
  27. Gray, V., Karmiloff-Smith, A., Funnell, E., & Tassabehji, M. (2006). In-depht analysis of spatil cognition in Williams syndrome: A critical assessment of the role of the LIMK1 gene. Neuropsychologia, 44, 679–685. doi: 10.1016/j.neuropsychologia.2005.08.008 CrossRef  Google Scholar 
  28. Hammill, D., Pearson, N., & Voress, J. (2016). DTVP-3: Método de evaluación de la percepción visual de Frostig. México: Manual Moderno. Google Scholar 
  29. Harrison, P., & Oakland, T. (2008). Sistema para la Evaluación de la Conducta Adaptativa (ABAS II). Madrid: TEA Ediciones. Google Scholar 
  30. Hirota, H., Matsuoka, R., Chen, X.-N., Salandanan, L., Lincoln, A., Rose, F., Korenberg, J. (2003). Williams syndrome deficits in visual spatial processing linked to GTF2IRD1 and GTF2I on chromosome 7q11.23. Genetics in Medicine, 5(4), 311–321. doi: 10.1097/01.GIM.0000076975.10224.67 CrossRef  Google Scholar  PubMed 
  31. Hoeft, F., Dai, L., Haas, B. W., Sheau, K., Mimura, M., Mills, D., Reiss, A. (2014). Mapping genetically controlled neural circuits of social behavior and visuo-motor integration by a preliminary examination of atypical deletions with Williams syndrome. PLoS One, 9(8). doi: e104088. doi:10.1371/journal.pone.0104088 CrossRef  Google Scholar  PubMed 
  32. Karmiloff-Smith, A., Broadbent, H., Farran, E., Longhi, E., D’Souza, D., Metcalfe, K., Sansbury, F. (2012). Social cognition in Williams Syndrome: Genotype/phenotype insights from partial deletion patients. Frontiers in Psychology, 3(168). doi: 10.3389/fpsyg.2012.00168 CrossRef  Google Scholar  PubMed 
  33. Karmiloff-Smith, A., Grant, J., Ewing, S., Carette, M., Metcalfe, K., Donnai, D. Tassabehji, M. (2003). Using case study comparisons to explore genotype-phenotype correlations in Williams-Beuren syndrome. Journal of Medical Genetics, 40, 136–140. doi: 10.1136/jmg.40.2.136 CrossRef  Google Scholar  PubMed 
  34. Kravitz, D., Saleem, K., Baker, C., & Mishkin, M. (2011). A new neural framework for visuospatial processing. Nature Reviews, 12, 217–230. doi: 10.1038/nrn3008 CrossRef  Google Scholar  PubMed 
  35. Li, L., Huang, L., Luo, Y., Huang, X., Lin, S., & Fang, Q. (2015). Differing microdeletion sizes and breakpoints in chromosome 7q11.23 in Williams-Beuren syndrome detected by chromosomal microarray analysis. Molecular Syndromology, 6, 268–275. doi: 10.1159/000443942 CrossRef  Google Scholar 
  36. Makeyev, A., Erdenechimeg, L., Mungunsukh, O., Roth, J., Enkhmandakh, B., Ruddle, F., &Bayarsaihan, D. (2004). GTF2IRD2 is located in the Williams-Beuren syndrome critical region 7q11.23 and encodes a protein with two TFII-I-like kelix-loop-helix repeats. Proceedings of the National Academy of Sciences of the United States of America, 101(30), 11052–11057. CrossRef  Google Scholar  PubMed 
  37. Martens, M., Wilson, S., & Reutens, D. (2008). Research review: Williams syndrome, a critical review of the cognitive, behavioral, and neuroanatomical phenotype. The Journal of Child Psychology and Psychiatry, 49, 576–608. CrossRef  Google Scholar  PubMed 
  38. Matute, E., Rosselli, M., & Ardila, A. (2014). Evaluación Neuropsicológica Infantil-II. México: Manual Moderno. Google Scholar 
  39. Mervis, C., & Morris, C. A. (2007). Williams syndrome. In M. Mazzocco & J. Ross (Eds.), Neurogenetic developmental disorders. London: The MIT Press. Google Scholar 
  40. Meyer-Linderberg, A., Kohn, P., Mervis, C., Kippenhan, J. S., Olsen, R., Morris, C. A., & Berman, K. F. (2004). Neural basis of genetically determined visuospatial construction deficit in Williams syndrome. Neuron, 43, 623–631. CrossRef  Google Scholar 
  41. Meyer-Linderberg, A., Mervis, C., & Berman, K. F. (2006). Neural mechanisms in Williams syndrome: A unique window to genetic influences on cognition and behaviour. Nature Reviews, 7, 380–393. doi: 10.1038/nrn1906 CrossRef  Google Scholar 
  42. Mimura, M., Hoeft, F., Kato, M., Kobayashi, N., Sheau, K., Piggot, J., Reiss, A. (2010). A preliminary study of orbitofrontal activation and hypersociability in Williams Syndrome. Journal of Neurodevolopmental Disorders, 2, 93–98. doi:10.1007/s11689-009-9041-8 CrossRef  Google Scholar  PubMed 
  43. Mobbs, D., Eckert, M., Menon, V., Mills, D., Korenberg, J., Galaburda, A., Reiss, A. (2007). Reduced parietal and visual cortical activation during global processing in Williams syndrome. Developmental Medicine & Child Neurology, 49, 433–438. CrossRef  Google Scholar  PubMed 
  44. Morris, C. A., Mervis, C., Hobart, H., Gregg, R., Bertrand, J., Ensing, G., Stock, D. (2003). GTF2I Hemizygosity implicated in mental retardation in Williams Syndrome: Genotype-phenotype analysis of five families with deletions in the Williams Syndrome region. American Journal of Medical Genetics. Part A, 123A(1), 45–59. doi: 10.1002/ajmg.a.20496 CrossRef  Google Scholar  PubMed 
  45. Osborne, L. (2010). Animal models of Williams syndrome. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 154C(2), 209–219. doi: 10.1002/ajmg.c.30257 CrossRef  Google Scholar 
  46. Ostrosky-Solís, F., Guevara-López, U., & Matute, E. (2012). Neuropsi Atención y Memoria. México: Manual Moderno. Google Scholar 
  47. Palmer, S., Taylor, K. M., Santucci, N., Widago, J., Chan, Y.-K. A., Yeo, J.-L., Hardeman, E. (2012). GTF2IRD2 from the Williams-Beuren critical region encodes a mobile-element-derived fusion protein that antagonizes the action of its related family members. Journal of Cell Science, 125, 5040–5050. doi: 10.1242/jcs.102798 CrossRef  Google Scholar  PubMed 
  48. Porter, M., & Coltheart, M. (2006). Global and local processing in Williams syndrome, autism, and down syndrome: Perception, attention, and construction. Developmental Neuropsychology, 30(3), 771–789. doi: 10.1207/s15326942dn3003_1 CrossRef  Google Scholar  PubMed 
  49. Porter, M., Dobson-Stone, C., Kwok, J., Schofield, P., Beckett, W., & Tassabehji, M. (2012). A role of transcription factor GTF2IRD2 in Executive Function in Williams-Beuren Syndrome. PLoS One, 7(10). doi: 10.1371/journal.pone.0047457 CrossRef  Google Scholar  PubMed 
  50. Shamay-Tsoory, S. G., Tomer, R., Goldsher, D., Berger, B. D., & Aharon-Peretz, J. (2004). Impairment in cognitive and affective empathy in patients with brain lesions: Anatomical and cognitive correlates. Journal of Clinical and Experimental Neuropsychology, 26(8), 1113–1127. CrossRef  Google Scholar  PubMed 
  51. Tassabehji, M., Metcalfe, K., Karmiloff-Smith, A., Carette, M., Grant, J., Dennis, N., Donnai, D. (1999). Williams syndrome: Use of chromosomal microdeletions as a toll to dissect cognitive and physical phenotypes. American Journal of Human Genetics, 64, 118–125. CrossRef  Google Scholar 
  52. Tipney, H., Hinsley, T., Brass, A., Metcalfe, K., Donnai, D., & Tassabehji, M. (2004). Isolation and characterisation of GTF2IRD2, a novel fusion gene and member of the TFII-I family of transcription factors, deleted in Williams-Beuren syndrome. European Jorunal of Human Genetics, 12, 551–560. CrossRef  Google Scholar  PubMed 
  53. Uhlén, M., Fagerberg, L., Hallström, B., Lindskog, C., Oksvold, P., Mardinoglu, A., Fredrik, P. (2015). Tissue-based map of the human proteome. Science, 347(6620), 1260419. doi: 10.1126/science.1260419 CrossRef  Google Scholar  PubMed 
  54. Vandeweyer, G., Van der Aa, N., Reyniers, E., & Kooy, F. , F. (2012). The contribution of CLIP2 haploinsuffieciency to the clinical manifestations of the Williams-Beurens syndrome. The American Journal of Human Genetics, 90, 1071–1078. doi: 10.1016/j.ajhg.2012.04.02. CrossRef  Google Scholar 
  55. Venegas Vega, C. A. (2012). Pruebas citogenéticas basadas en microarreglos. In V. Del Castillo Ruiz, R. D. Uranga Hernández, & G. Zafra de la Rosa (Eds.), Genética Clínica. México: Manual Moderno. Google Scholar 
  56. Wang, Y.-K., Spörle, R., Paperna, T., Schughart, K., & Francke, U. (1999). Characterization and expression pattern of the frizzled Gene Fzd9, the mouse homolog of FZD9 whics is deleted in Williams-Beuren Syndrome. Genomics, 57, 235–248. CrossRef  Google Scholar  PubMed 
  57. Wechsler, D. (2007). Escala Wechsler de Inteligencia para Niños y Adolescentes-IV. México: Manual Moderno. Google Scholar 
  58. Wechsler, D. (2014). Escala Wechsler de Inteligencia para Adultos-IV. México: Manual Moderno. Google Scholar 
  59. Young, E. J., Lipina, T., Tam, E., Mandel, A., Clapcote, S. J., Bechard, A. R., Osborne, L. (2008). Reduced fear and aggression and altered serotonin metabolism in GTF2IRD1-targeted mice. Genes, Brain and Behavior, 7, 224–234. doi: 10.1111/j.1601-183X.2007.00343.x CrossRef  Google Scholar  PubMed 
  60. Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Schoize, A. R., O’KeefeS., . . . S., . . . Wu, J. Q. (2014). An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. Journal of Neuroscience, 34(36), 11929–11947. doi: https://doi.org/10.1523/JNEUROSCI.1860-14.2014 CrossRef  Google Scholar  PubMed 
Phonemic and Semantic Verbal Fluency in Sex Chromosome Aneuploidy: Contrasting the Effects of Supernumerary X versus Y Chromosomes on Performance
  • Manisha Udhnani | Department of Psychology, Drexel University, Philadelphia, Pennsylvania
  • Moshe Maiman | Department of Psychology, Drexel University, Philadelphia, Pennsylvania
  • Jonathan D. Blumenthal | Developmental Neurogenomics Unit, National Institute of Mental Health, Bethesda, Maryland
  • Liv S. Clasen | Developmental Neurogenomics Unit, National Institute of Mental Health, Bethesda, Maryland
  • Gregory L. Wallace | Department of Speech, Language, & Hearing Sciences, The George Washington University, Washington, DC
  • Jay N. Giedd | Department of Psychiatry, University of California San Diego, San Diego, California
  • Armin Raznahan | Developmental Neurogenomics Unit, National Institute of Mental Health, Bethesda, Maryland
  • Nancy Raitano Lee | Department of Psychology, Drexel University, Philadelphia, Pennsylvania

E-mail address | nrl39@drexel.edu

The authors report no conflict of interest.


Past research suggests that youth with sex chromosome aneuploidies (SCAs) present with verbal fluency deficits. However, most studieshave focused on sex chromosome trisomies. Far less is known about sex chromosome tetrasomies and pentasomies. Thus, the current research sought to characterize verbalfluency performance among youth with sex chromosome trisomies, tetrasomies, and pentasomies by contrasting how performance varies as a function of extra X number andX versus Y status.


Participants included 79 youth with SCAs and 42 typically developing controls matchedon age, maternal education, and racial/ethnic background. Participants completed the phonemic and semantic conditions of a verbal fluency task and an abbreviated intelligencetest.


Both supernumerary X and Y chromosomes were associated with verbal fluency deficits relative to controls. These impairmentsincreased as a function of the number of extra X chromosomes, and the pattern of impairments on phonemic and semantic fluency differed for those with a supernumeraryX versus Y chromosome. Whereas one supernumerary Y chromosome was associated with similar performance across fluency conditions, one supernumeraryX chromosome was associated with relatively stronger semantic than phonemic fluency skills.


Verbal fluency skills in youth withsupernumerary X and Y chromosomes are impaired relative to controls. However, the degree of impairment varies across groups and task condition. Further research intothe cognitive underpinnings of verbal fluency in youth with SCAs may provide insights into their verbal fluency deficits and help guide future treatments. (JINS,2018, 24, 917–927)

  1. Abreu, N., Argollo, N., Oliveira, F., Cardoso, A. L., Bueno, J. L., & Xavier, G. F. (2013). Semantic and phonologic verbal fluency tests for adolescents with ADHD. Clinical Neuropsychiatry, 10(2), 63–71. Google Scholar 
  2. Ardila, A., Ostrosky‐Solís, F., & Bernal, B. (2006). Cognitive testing toward the future: The example of Semantic Verbal Fluency (ANIMALS). International Journal of Psychology, 41(5), 324–332. CrossRef  Google Scholar 
  3. Bender, B. G., Linden, M. G., & Harmon, R. J. (2001). Neuropsychological and functional cognitive skills of 35 unselected adults with sex chromosome abnormalities. American Journal of Medical Genetics, 102(4), 309–313. CrossRef  Google Scholar  PubMed 
  4. Bender, B. G., Linden, M. G., & Robinson, A. (1987). Environment and developmental risk in children with sex chromosome abnormalities. Journal of the American Academy of Child Adolescent Psychiatry, 26(4), 499–503. doi:10.1097/00004583-198707000-00006 CrossRef  Google Scholar  PubMed 
  5. Bender, B. G., Linden, M. G., & Robinson, A. (1989). Verbal and spatial processing efficiency in 32 children with sex chromosome abnormalities. Pediatric Research, 25(6), 577–579. CrossRef  Google Scholar  PubMed 
  6. Benjamini, Y., & Hochberg, Y. 1995. Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society: Series B (Methodological), 57, 289–300. Google Scholar 
  7. Bishop, D. V., & Snowling, M. J. (2004). Developmental dyslexia and specific language impairment: Same or different?. Psychological Bulletin, 130(6), 858. CrossRef  Google Scholar  PubMed 
  8. Bojesen, A., Juul, S., & Gravholt, C. H. (2003). Prenatal and postnatal prevalence of Klinefelter syndrome: A national registry study. Journal of Clinical Endocrinology & Metabolism, 88(2), 622–626. doi:10.1210/jc.2002-021491 CrossRef  Google Scholar  PubMed 
  9. Bowie, C. R., Leung, W. W., Reichenberg, A., McClure, M. M., Patterson, T. L., Heaton, R. K., &Harvey, P. D. (2008). Predicting schizophrenia patients’ real-world behavior with specific neuropsychological and functional capacity measures. Biological Psychiatry, 63(5), 505–511. CrossRef  Google Scholar  PubMed 
  10. Bruining, H., Swaab, H., Kas, M., & van Engeland, H. (2009). Psychiatric characteristics in a self-selected sample of boys with Klinefelter syndrome. Pediatrics, 123(5), e865–e870. CrossRef  Google Scholar 
  11. Cahn-Weiner, D. A., Boyle, P. A., & Malloy, P. F. (2002). Tests of executive function predict instrumental activities of daily living in community-dwelling older individuals. Applied Neuropsychology, 9(3), 187–191. CrossRef  Google Scholar  PubMed 
  12. Cavalli, E., Duncan, L. G., Elbro, C., El Ahmadi, A., & Colé, P. (2017). Phonemic--Morphemic dissociation in university students with dyslexia: An index of reading compensation? Annals of dyslexia, 67(1), 63–84. Google Scholar 
  13. Claessen, M., Leitão, S., Kane, R., & Williams, C. (2013). Phonological processing skills in specific language impairment. International Journal of Speech-Language Pathology, 15(5), 471–483. CrossRef  Google Scholar  PubMed 
  14. Daneman, M. (1991). Working memory as a predictor of verbal fluency. Journal of Psycholinguistic Research, 20(6), 445–464. CrossRef  Google Scholar 
  15. Gaddes, W. H., & Crockett, D. J. (1975). The Spreen-Benton aphasia tests, normative data as a measure of normal language development. Brain and Language, 2(3), 257–280. CrossRef  Google Scholar  PubMed 
  16. Ghosh, D., & Vogt, A. (2012). Outliers: An evaluation of methodologies. In Joint statistical meetings (pp. 3455–3460). San Diego, CA: American Statistical Association. Google Scholar 
  17. Halperin, J. M., Healey, J. M., Zeitchik, E., Ludman, W. L., & Weinstein, L. (1989). Developmental aspects of linguistic and mnestic abilities in normal children. Journal of Clinical Experimental Neuropsychology, 11(4), 518–528. CrossRef  Google Scholar  PubMed 
  18. Henry, L. A., Messer, D. J., & Nash, G. (2015). Executive functioning and verbal fluency in children with language difficulties. Learning and Instruction, 39, 137–147. CrossRef  Google Scholar 
  19. Henry, J., & Crawford, J. (2005). A meta-analytic review of verbal fluency deficits in schizophrenia relative to other neurocognitive deficits. Cognitive Neuropsychiatry, 10(1), 1–33. CrossRef  Google Scholar  PubMed 
  20. Henry, J. D., & Crawford, J. R. (2004). A meta-analytic review of verbal fluency performance following focal cortical lesions. Neuropsychology, 18(2), 284. CrossRef  Google Scholar  PubMed 
  21. Lee, N. R., Anand, P., Will, E., Adeyemi, E. I., Clasen, L. S., Blumenthal, J. D, Edgin, J. O. (2015). Everyday executive functions in Down syndrome from early childhood to young adulthood: Evidence for both unique and shared characteristics compared to youth with sex chromosome trisomy (XXX and XXY). Frontiers in Behavioral Neuroscience, 9, 264. doi:10.3389/fnbeh.2015.00264 CrossRef  Google Scholar 
  22. Lee, N. R., Wallace, G. L., Adeyemi, E. I., Lopez, K. C., Blumenthal, J. D., Clasen, L. S., & Giedd, J. N. (2012). Dosage effects of X and Y chromosomes on language and social functioning in children with supernumerary sex chromosome aneuploidies: Implications for idiopathic language impairment and autism spectrum disorders. Journal of Child Psychology and Psychiatry, 53(10), 1072–1081. CrossRef  Google Scholar  PubMed 
  23. Lee, N. R., Wallace, G. L., Clasen, L. S., Lenroot, R. K., Blumenthal, J. D., White, S. L., Giedd, J. N. (2011). Executive function in young males with Klinefelter (XXY) syndrome with and without comorbid attention-deficit/hyperactivity disorder. Journal of the International Neuropsychological Society, 17(3), 522–530. CrossRef  Google Scholar  PubMed 
  24. Leggett, V., Jacobs, P., Nation, K., Scerif, G., & Bishop, D. V. (2010). Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: A systematic review. Developmental Medicine & Child Neurology, 52(2), 119–129. CrossRef  Google Scholar  PubMed 
  25. Luo, L., Luk, G., & Bialystok, E. (2010). Effect of language proficiency and executive control on verbal fluency performance in bilinguals. Cognition, 114(1), 29–41. CrossRef  Google Scholar  PubMed 
  26. Moura, O., Simões, M. R., & Pereira, M. (2015). Executive functioning in children with developmental dyslexia. The Clinical Neuropsychologist, 28(1), 20–41. CrossRef  Google Scholar  PubMed 
  27. Nathan, A. M., & Abernathy, T. V. (2012). The impact of verbal skills on writing: A comparison of fifth-grade students with learning disabilities and students with typical development. The Researcher, 24(2), 96–112. Google Scholar 
  28. Nielsen, J., & Wohlert, M. (1991). Sex chromosome abnormalities found among 34,910 newborn children: Results from a 13-year incidence study in Arhus, Denmark. Birth Defects Original Article Series, 26(4), 209–223. Google Scholar 
  29. Polani, P. E. (1977). Abnormal sex chromosomes, behavior and mental disorder. In J. Tanner (Ed.), Developments in psychiatric research (pp. 89–128). London: Hodder and Stoughton. Google Scholar 
  30. Raitano, N. A., Pennington, B. F., Tunick, R. A., Boada, R., & Shriberg, L. D. (2004). Pre‐literacy skills of subgroups of children with speech sound disorders. Journal of Child Psychology and Psychiatry, 45(4), 821–835. CrossRef  Google Scholar  PubMed 
  31. Raznahan, A., Lee, N. R., Greenstein, D., Wallace, G. L., Blumenthal, J. D., Clasen, L. S., & Giedd, J. N. (2014). Globally divergent but locally Convergent X- and Y-Chromosome Influences on cortical development. Cerebral Cortex, 26(1), 70–79. doi:10.1093/cercor/bhu174 CrossRef  Google Scholar  PubMed 
  32. Raznahan, A., Lue, Y., Probst, F., Greenstein, D., Giedd, J., Wang, C., Swerdloff, R. (2015). Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies. Brain Structure and Function, 220(6), 3581–3593. doi:10.1007/s00429-014-0875-9 CrossRef  Google Scholar  PubMed 
  33. Ross, J. L., Zeger, M. P., Kushner, H., Zinn, A. R., & Roeltgen, D. P. (2009). An extra X or Y chromosome: Contrasting the cognitive and motor phenotypes in childhood in boys with 47, XYY syndrome or 47, XXY Klinefelter syndrome. Developmental Disabilities Research Reviews, 15(4), 309–317. CrossRef  Google Scholar  PubMed 
  34. Rovet, J., Netley, C., Bailey, J., Keenan, M., & Stewart, D. (1995). Intelligence and achievement in children with extra X aneuploidy: A longitudinal perspective. American Journal of Medical Genetics, 60(5), 356–363. CrossRef  Google Scholar  PubMed 
  35. Ruff, R. M., Light, R. H., Parker, S. B., & Levin, H. S. (1997). The psychological construct of word fluency. Brain and Language, 57(3), 394–405. CrossRef  Google Scholar  PubMed 
  36. Shao, Z., Janse, E., Visser, K., & Meyer, A. S. (2014). What do verbal fluency tasks measure? Predictors of verbal fluency performance in older adults. Frontiers in Psychology, 5, 772. doi:10.3389/fpsyg.2014.00772 CrossRef  Google Scholar  PubMed 
  37. Simpson, N. H., Addis, L., Brandler, W. M., Slonims, V., Clark, A., Watson, J. Fairfax, B. P. (2014). Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia. Developmental Medicine & Child Neurology, 56(4), 346–353. CrossRef  Google Scholar  PubMed 
  38. Smith‐Spark, J. H., Henry, L. A., Messer, D. J., & Zięcik, A. P. (2017). Verbal and non‐verbal fluency in adults with developmental dyslexia: Phonological processing or executive control problems?. Dyslexia, 23(3), 234–250. CrossRef  Google Scholar  PubMed 
  39. Snowling, M. J., & Hulme, C. (2012). Annual research review: The nature and classification of reading disorders–a commentary on proposals for DSM‐5. Journal of Child Psychology and Psychiatry, 53(5), 593–607. CrossRef  Google Scholar  PubMed 
  40. Strauss, E., Sherman, E. M., & Spreen, O. (2006). A compendium of neuropsychological tests: Administration, norms, and commentary. New York: American Chemical Society. Google Scholar 
  41. Tabachnick, B. G., & Fidell, L. S. (2007). Using multivariate statistics (5th ed.). New York: Allyn and Bacon. Google Scholar 
  42. Tartaglia, N. R., Wilson, R., Miller, J. S., Rafalko, J., Cordeiro, L., Davis, S., Ross, J. (2017). Autism spectrum disorder in males with sex chromosome aneuploidy: XXY/Klinefelter Syndrome, XYY, and XXYY. Journal of Developmental and Behavioral Pediatrics, 38(3), 197–207. doi:10.1097/DBP.0000000000000429 CrossRef  Google Scholar  PubMed 
  43. Tartaglia, N. R., Ayari, N., Hutaff-Lee, C., & Boada, R. (2012). Attention-deficit hyperactivity disorder symptoms in children and adolescents with sex chromosome aneuploidy: XXY, XXX, XYY, and XXYY. Journal of Developmental and Behavioral Pediatrics, 33(4), 309–318. CrossRef  Google Scholar  PubMed 
  44. Tombaugh, T. N., Kozak, J., & Rees, L. (1999). Normative data stratified by age and education for two measures of verbal fluency: FAS and animal naming. Archives of Clinical Neuropsychology, 14(2), 167–177. Google Scholar  PubMed 
  45. Unsworth, N., Spillers, G. J., & Brewer, G. A. (2010). Variation in verbal fluency: A latent variable analysis of clustering, switching, and overall performance. The Quarterly Journal of Experimental Psychology, 64(3), 447–466. CrossRef  Google Scholar 
  46. van Rijn, S., Barneveld, P., Descheemaeker, M. J., Giltay, J., & Swaab, H. (2018). The effect of early life stress on the cognitive phenotype of children with an extra X chromosome (47,XXY/47,XXX). Child Neuropsychology, 24(2), 277–286. doi:10.1080/09297049.2016.1252320 CrossRef  Google Scholar 
  47. van Rijn, S., & Swaab, H. (2015). Executive dysfunction and the relation with behavioral problems in children with 47, XXY and 47, XXX. Genes, Brain, and Behavior, 14(2), 200–208. CrossRef  Google Scholar  PubMed 
  48. Wechsler, D. (1999). Manual for the Wechsler abbreviated intelligence scale. San Antonio, TX: The Psychological Corporation. Google Scholar 
  49. Wechsler, D. (2002). The Wechsler Preschool and Primary Scale of Intelligence – Third Edition. San Antonio, TX: The Psychological Corporation. Google Scholar 
  50. Whiteside, D. M., Kealey, T., Semla, M., Luu, H., Rice, L., Basso, M. R., &Roper, B. (2016). Verbal fluency: Language or executive function measure? Applied Neuropsychology: Adult, 23(1), 29–34. doi:10.1080/23279095.2015.1004574 CrossRef  Google Scholar  PubMed 
  51. Wikström, A. M., & Dunkel, L. (2011). Klinefelter syndrome. Best Practice and Research in Clinical Endocrinology and Metabolism, 25(2), 239–250. doi:10.1016/j.beem.2010.09.006 CrossRef  Google Scholar  PubMed