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Neurocognitive and familial moderators of psychiatric risk in velocardiofacial (22q11.2 deletion) syndrome: a longitudinal study

  • W. R. Kates (a1), N. Russo (a2), W. M. Wood (a2), K. M. Antshel (a1) (a2), S. V. Faraone (a1) and W. P. Fremont (a1)...



Although risk for psychosis in velocardiofacial (22q11.2 deletion) syndrome (VCFS) is well established, the cognitive and familial factors that moderate that risk are poorly understood.


A total of 75 youth with VCFS were assessed at three time points, at 3-year intervals. Time 1 (T1) psychiatric risk was assessed with the Behavior Assessment System for Children (BASC). Data reduction of BASC scores yielded avoidance–anxiety and dysregulation factors. Time 2 (T2) neuropsychological and family function and time 3 (T3) prodromal/overt psychosis were assessed. Poisson regression models tested associations between T3 positive prodromal symptoms/overt psychosis and T1 psychiatric risk, T2 cognitive and familial factors, and their interactions.


T1 avoidance–anxiety ratings predicted T3 prodromal/overt psychosis. T2 verbal learning scores moderated this association, such that individuals with low avoidance–anxiety scores and stronger verbal learning skills were the least likely to demonstrate prodromal/overt psychosis at T3. Low scores on a T2 visual vigilance task also predicted T3 prodromal/overt psychosis, independently of the effect of T1 avoidance–anxiety scores. T1 dysregulation scores did not predict T3 prodromal/overt psychosis in a linear manner. Instead, the association between dysregulation and prodromal/overt psychosis was amplified by T2 levels of family organization, such that individuals with low dysregulation scores and low family organization scores were the most likely to exhibit T3 prodromal/overt psychosis.


Significant moderators of psychiatric risk in VCFS include verbal learning skills as well as levels of family organization, carrying implications for early identification and preventative treatment of youth with VCFS at highest risk for psychosis.


Corresponding author

* Address for correspondence: W. R. Kates Ph.D., Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. (Email:


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Allen, TM, Hersch, J, Schoch, K, Curtiss, K, Hooper, SR, Shashi, V (2014). Association of the family environment with behavioral and cognitive outcomes in children with chromosome 22q11.2 deletion syndrome. Journal of Intellectual Disability Research 58, 3147.
Antshel, KM, Aneja, A, Strunge, L, Peebles, J, Fremont, WP, Stallone, K, Abdulsabur, N, Higgins, AM, Shprintzen, RJ, Kates, WR (2007 a). Autistic spectrum disorders in velo-cardio facial syndrome (22q11.2 deletion). Journal of Autism and Developmental Disorders 37, 17761786.
Antshel, KM, Faraone, SV, Fremont, W, Monuteaux, MC, Kates, WR, Doyle, A, Mick, E, Biederman, J (2007 b). Comparing ADHD in velocardiofacial syndrome to idiopathic ADHD: a preliminary study. Journal of Attention Disorders 11, 6473.
Antshel, KM, Fremont, W, Roizen, NJ, Shprintzen, R, Higgins, AM, Dhamoon, A, Kates, WR (2006). ADHD, major depressive disorder, and simple phobias are prevalent psychiatric conditions in youth with velocardiofacial syndrome. Journal of the American Academy of Child and Adolescent Psychiatry 45, 596603.
Antshel, KM, Shprintzen, R, Fremont, W, Higgins, AM, Faraone, SV, Kates, WR (2010). Cognitive and psychiatric predictors to psychosis in velocardiofacial syndrome: a 3-year follow-up study. Journal of the American Academy of Child and Adolescent Psychiatry 49, 333344.
Bassett, AS, Chow, EW, AbdelMalik, P, Gheorghiu, M, Husted, J, Weksberg, R (2003). The schizophrenia phenotype in 22q11 deletion syndrome. American Journal of Psychiatry 160, 15801586.
Baum, KM, Walker, EF (1995). Childhood behavioral precursors of adult symptom dimensions in schizophrenia. Schizophrenia Research 16, 111120.
Bebbington, P, Kuipers, L (1994). The predictive utility of expressed emotion in schizophrenia: an aggregate analysis. Psychological Medicine 24, 707718.
Botto, LD, May, K, Fernhoff, PM, Correa, A, Coleman, K, Rasmussen, SA, Merritt, RK, O'Leary, LA, Wong, LY, Elixson, EM, Mahle, WT, Campbell, RM (2003). A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112, 101107.
Cornblatt, B, Obuchowski, M, Roberts, S, Pollack, S, Erlenmeyer-Kimling, L (1999). Cognitive and behavioral precursors of schizophrenia. Developmental Psychopathology 11, 487508.
DeHerdt, A, Wampers, M, Vancampfort, D, De Hert, M, Vanhees, L, Demunter, H, Van Bouwel, L, Brunner, E, Probst, M (2013). Neurocognition in clinical high risk young adults who did or did not convert to a first schizophrenic psychosis: a meta-analysis. Schizophrenia Research 149, 4855.
Delis, DC, Kramer, JH, Kaplan, E, Ober, BA (1994). California Verbal Learning Test – Children's Version. Psychological Corporation: San Antonio, TX.
Dragt, S, Nieman, DH, Scultze-Lutter, F, van der Meer, F, Becker, H, de Haan, L, Dingemans, PM, Birchwood, M, Patterson, P, Salokangas, RK, Heinimaa, M, Heinz, A, Juckel, G, Graf von Reventlow, H, French, P, Stevens, H, Ruhrmann, S, Klosterkötter, J, Linszen, DH (2012). Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis. Acta Psychiatrica Scandinavica 125, 4553.
Dragt, S, Nieman, DH, Veltman, D, Becker, HE, van de Fliert, R, de Haan, L, Linszen, DH (2011). Environmental factors and social adjustment as predictors of a first psychosis in subjects at ultra high risk. Schizophrenia Research 125, 6976.
Feinstein, C, Eliez, S, Blasey, C, Reiss, AL (2002). Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk. Biological Psychiatry 51, 312318.
Golden, CJ (1978). Stroop Color and Word Test. Stoelting: Chicago, IL.
Golding-Kushner, KJ, Weller, G, Shprintzen, RJ (1985). Velo-cardio-facial syndrome: language and psychological profiles. Journal of Craniofacial Genetics and Developmental Biology 5, 259266.
Gordon, M, McClure, FD, Aylward, GP (1989). Gordon Diagnostic System. Gordon Diagnostic Systems: Dewitt, NY.
Gothelf, D, Feinstein, C, Thomson, T, Gu, E, Penniman, L, Van Stone, E, Kwon, H, Eliez, S, Reiss, AL (2007). Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. American Journal of Psychiatry 164, 663669.
Gothelf, D, Frisch, A, Munitz, H, Rockah, R, Laufer, N, Mozes, T, Hermesh, H, Weizman, A, Frydman, M (1999). Clinical characteristics of schizophrenia associated with velo-cardio-facial syndrome. Schizophrenia Research 35, 105112.
Gothelf, D, Gruber, R, Presburger, G, Dotan, I, Brand-Gothelf, A, Burg, M, Inbar, D, Steinberg, T, Frisch, A, Apter, A, Weizman, A (2003). Methylphenidate treatment for attention-deficit/hyperactivity disorder in children and adolescents with velocardiofacial syndrome: an open-label study. Journal of Clinical Psychiatry 64, 11631169.
Gothelf, D, Lombrosso, PJ (2001). Genetics of childhood disorders: XXV. Velocardiofacial syndrome. Journal of the American Academy of Child and Adolescent Psychiatry 40, 489491.
Heaton, RK, Chelune, GJ, Talley, JL, Kay, GG, Curtiss, G (1993). Wisconsin Card Sort Test Manual: Revised and Expanded. Psychological Assessment Resources, Inc.: Odessa, FL.
Johnstone, EC, Ebmeier, KP, Miller, P, Owens, DG, Lawrie, SM (2005). Predicting schizophrenia: findings from the Edinburgh High-Risk Study. British Journal of Psychiatry 186, 1825.
Kaufman, J, Birmaher, B, Brent, D, Rao, U, Flynn, C, Moreci, P, Williamson, D, Ryan, N (1997). Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. Journal of the American Academy of Child and Adolescent Psychiatry 36, 980988.
Khandaker, GM, Barnett, JH, White, IR, Jones, PB (2011). A quantitative meta-analysis of population-based studies of premorbid intelligence and schizophrenia. Schizophrenia Research 132, 220227.
Kim, HS, Shin, NY, Kim, E, Park, HY, Hong, KS, Kwon, JS (2011). Social cognition and neurocognition as predictors of conversion to psychosis in individuals at ultra-high risk. Schizophrenia Research 130, 170175.
Kohler, CG, Turner, TH, Gur, RE, Gur, RC (2004). Recognition of facial emotions in neuropsychiatric disorders. CNS Spectrums 9, 267274.
Lajiness-O'Neill, RR, Beaulieu, I, Titus, JB, Asamoah, A, Bigler, ED, Bawle, EV, Pollack, R (2005). Memory and learning in children with 22q11.2 deletion syndrome: evidence for ventral and dorsal stream disruption? Child Neuropsychology 11, 5571.
Lencz, T, Smith, CW, McLaughlin, D, Auther, A, Nakayama, E, Hovey, L, Cornblatt, BA (2006). Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biological Psychiatry 59, 863871.
Levene, JE, Lancee, W, Seeman, MV, Skinner, H, Freeman, SJ (2009). Family and patient predictors of symptomatic status in schizophrenia. Canadian Journal of Psychiatry 54, 446451.
McNeil, BJ, Hanley, JA (1984). Statistical approaches to the analysis of receiver operating characteristic (ROC) curves. Medical Decision Making 4, 137150.
Michie, PT, Kent, A, Stienstra, R, Castine, R, Johnston, J, Dedman, K, Wichmann, H, Box, J, Rock, D, Rutherford, E, Jablensky, A (2000). Phenotypic markers as risk factors in schizophrenia: neurocognitive functions. Australian and New Zealand Journal of Psychiatry 34 (Suppl.), S74S85.
Miettunen, J, Tormanen, S, Murray, GK, Jones, PB, Maki, P, Ebeling, H, Moilanen, I, Taanila, A, Heinimaa, M, Joukamaa, M, Veijola, J (2008). Association of cannabis use with prodromal symptoms of psychosis in adolescence. British Journal of Psychiatry 192, 470471.
Miller, TJ, McGlashan, TH, Rosen, JL, Cadenhead, K, Cannon, T, Ventura, J, McFarlane, W, Perkins, DO, Pearlson, GD, Woods, SW (2003). Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability. Schizophrenia Bulletin 29, 703715.
Miller, TJ, McGlashan, TH, Woods, SW, Stein, K, Driesen, N, Cocoran, CM, Hoffman, R, Davidson, L (1999). Symptom assessment in schizophrenic prodromal states. Psychiatric Quarterly 70, 273287.
Moos, RH, Moos, BM (2009). Family Environment Scale Manual and Sampler Test: Development, Applications, and Research, 4th edn. Mind Garden, Inc.: Palo Alto, CA.
Murphy, KC (2002). Schizophrenia and velo-cardio-facial syndrome. Lancet 359, 426430.
Murphy, KC, Owen, MJ (2001). Velo-cardio-facial syndrome: a model for understanding the genetics and pathogenesis of schizophrenia. British Journal of Psychiatry 179, 397402.
O'Brien, MP, Gordon, JL, Bearden, CE, Lopez, S, Kopelowicz, A, Cannon, TD (2006). Positive family environment predicts improvement in symptoms and social functioning among adolescents at imminent risk for onset of psychosis. Schizophrenia Research 81, 269275.
Oskarsdottir, S, Belfrage, M, Sandstedt, E, Viggedal, G, Uvebrant, P (2005). Disabilities and cognition in children and adolescents with 22q11 deletion syndrome. Developmental Medicine and Child Neurology 47, 177184.
Pukrop, R, Ruhrmann, S, Schultze-Lutter, F, Bechdolf, A, Brockhaus-Dumke, A, Klosterkötter, J (2007). Neurocognitive indicators for a conversion to psychosis: comparison of patients in a potentially initial prodromal state who did or did not convert to a psychosis. Schizophrenia Research 92, 116125.
Reininghaus, U, Morgan, C, Simpson, J, Dazzan, P, Morgan, K, Doody, G, Bhugra, D, Leff, J, Jones, P, Murray, R, Fearon, P, Craig, T (2008). Unemployment, social isolation, achievement-expectation mismatch and psychosis: findings from the AESOP study. Social Psychiatry and Psychiatric Epidemiology 43, 743751.
Reynolds, CR, Kamphaus, RW (1992). Behavior Assessment System for Children. American Guidance Service: Circle Pines, MN.
Rubin, DB, Schenker, N (1991). Multiple imputation in health-care databases: an overview and some applications. Statistics in Medicine 10, 585598.
Schlosser, DA, Zinberg, JL, Lowey, RL, Casey-Gannon, S, O'Brien, MP, Bearden, CE, Vinogradov, S, Cannon, TD (2010). Predicting the longitudinal effects of the family environment on prodromal symptoms and functioning in patients at-risk for psychosis. Schizophrenia Research 118, 6975.
Seidman, LJ, Giuliano, AJ, Meyer, EC, Addington, J, Cadenhead, KS, Cannon, TD, McGlashan, TH, Perkins, DO, Tsuang, MT, Walker, EF, Woods, SW, Bearden, CE, Christensen, BK, Hawkins, K, Heaton, R, Keefe, RS, Heinssen, R, Cornblatt, BA (2010). North American Prodrome Longitudinal Study (NAPLS) group. Neuropsychology of the prodrome to psychosis in the NAPLS consortium: relationship to family history and conversion to psychosis. Archives of General Psychiatry 67, 578588.
Shprintzen, R (2008). Velo-cardio-facial syndrome: 30 years of study. Developmental Disabilities Research Reviews 14, 310.
Swets, JA (1982). Sensitivities and specificities of diagnostic tests. JAMA 248, 548549.
Swets, JA (1986 a). Form of empirical ROCs in discrimination and diagnostic tasks: implications for theory and measurement of performance. Psychological Bulletin 99, 181198.
Swets, JA (1986 b). Indices of discrimination or diagnostic accuracy: their ROCs and implied models. Psychological Bulletin 99, 110117.
Swets, JA, Pickett, RM (1982). Evaluation of Diagnostic Systems: Methods from Signal Detection Theory. Academic Press: New York.
Swillen, A, Vandeputte, L, Cracco, J, Maes, B, Ghesquiere, P, Devriendt, K, Fryns, JP (1999). Neuropsychological, learning and psychosocial profile of primary school aged children with the velo-cardio-facial syndrome (22q11 deletion): evidence for a nonverbal learning disability? Child Neuropsychology 5, 230241.
Thomson, GH (1951). The Factorial Analysis of Human Ability. University of London Press: London.
Vorstman, JA, Morcus, ME, Duijff, SN, Klaassen, PW, Heineman-de Boer, JA, Beemer, FA, Swaab, H, Kahn, RS, van Engeland, H (2006). The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. Journal of the American Academy of Child and Adolescent Psychiatry 45, 11041113.
Vorstman, JAS, Breetvelt, EJ, Duijff, SN, Eliez, S, Schneider, M, Jalbrzikowski, M et al. and the International 22q11.2 Brain Behavior Consortium (in press). A cognitive decline precedes the onset of psychosis in patients with the 22q11.2 deletion syndrome. JAMA Psychiatry.
Wechsler, D (1991). Wechsler Intelligence Scale for Children, 3rd edn. Psychological Corporation: San Antonio, TX.
Wechsler, D (1994). Wechsler Adult Intelligence Scale, 3rd edn. Psychological Corporation: San Antonio, TX.
Wechsler, D (1997). WMS-III: Wechsler Memory Scale Administration and Scoring Manual, 3rd edn. Psychological Corporation: San Antonio, TX.
Whyte, MC, Brett, C, Harrison, LK, Byrne, M, Miller, P, Lawrie, SM, Johnstone, EC (2006). Neuropsychological performance over time in people at high risk of developing schizophrenia and controls. Biological Psychiatry 59, 730739.
Woodin, M, Wang, PP, Aleman, D, McDonald-McGinn, D, Zackai, E, Moss, E (2001). Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion. Genetics in Medicine 3, 3439.
Yung, AR, Phillips, LJ, Yuen, HP, Francey, SM, McFarlane, CA, Hallgren, M, McGorry, PD (2003). Psychosis prediction: 12-month follow up of a high-risk (“prodromal”) group. Schizophrenia Research 60, 2132.



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