Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects

the International 22q11.2 Brain and Behavior Consortium; Rosemarie Fritsch

doi:10.1002/ajmg.a.40359

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects

the International 22q11.2 Brain and Behavior Consortium, Rosemarie Fritsch

Facultad de Medicina

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p =.002), verbal IQ was decreased by 8.17 points (p =.0002) and performance IQ was decreased by 4.03 points (p =.028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.

Original language	English
Pages (from-to)	2172-2181
Number of pages	10
Journal	American Journal of Medical Genetics, Part A
Volume	176
Issue number	10
DOIs	https://doi.org/10.1002/ajmg.a.40359
State	Published - 1 Oct 2018

Bibliographical note

Funding Information:
National Institutes of Health, Grant/Award Numbers: R01 HL084410, P01 HD070454, U01 MH101720, R21HL118637, 5T32GM007491-41, R01 MH085903, R01 MH064824; American Heart Association, Grant/Award Number: 14PRE199800006; FONDECYT-Chile, Grant/Award Numbers: 1130392 and 1171014; Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research, Grant/Award Numbers: MOP-97800 and MOP-89066; University of Toronto McLaughlin Centre; Swiss National Science Foundation, Grant/Award Numbers: FNS 324730_121996 and FNS 324730_144260; National Center of Competence in Research (NCCR) “Synapsy- The Synaptic bases of Mental Diseases”, Grant/Award Number: 51NF40-158776; Flemish Science Foundation, Grant/Award Number: FWO G.0E1117N; Charles E.H. Upham chair in Pediatrics

Funding Information:
We would like to thank all patients with 22q11.2DS who enrolled in research and provided DNA as well as clinical records. We thank colleagues in the Molecular Cytogenetics core lab at Einstein for technical support. We thank Mark Zeffren, Nousin Haque, Antoneta Preldakaj, John Bruppacher, Daniel Arroyo, Michael Gleeson and Dominique Calan-drillo for technical support at Einstein. We also greatly appreciate the laboratory effort of Dr. Frédérique Bena who works with SE and SEA (Institute of Genetics and Genomics of Geneva, Switzerland) and Oanh Tran and Andrea Jin who work with BSE (Division of Human Genetics, the Children’s Hospital of Philadelphia). This work was supported by grants National Institutes of Health R01 HL084410 (BSE, BEM, DMM, TG, AB), P01 HD070454 (EG, LEM, AJA, BSE, DMM, EEM, TG, TW, HN, CLC), U01 MH101720 (BSE, BEM, DMM, GR, AB, EC, AS, DG, SE, FT, NP, CEB, TJS, EVD, TVA, WRK, TG, TW), R21HL118637 (TW, BEM, TG, EG), National Institutes of Health 5T32GM007491-41 (JHC), American Heart Association 14PRE199800006 (JHC). GR was supported by the FONDECYT-Chile (grants 1130392 and 1171014). ASB was supported by the Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research funding (MOP-97800 and MOP-89066), and the University of Toronto McLaughlin Centre. CEB was supported by the National Institutes of Health (R01 MH085903). WRK was supported by the National Institutes of Health (R01 MH064824). SE was supported by the Swiss National Science Foundation (FNS 324730_121996; FNS 324730_144260) and the National Center of Competence in Research (NCCR) “Synapsy-The Synaptic bases of Mental Diseases” (51NF40-158776). JV was supported by the Flemish Science Foundation (FWO G.0E1117N). BSE was supported by funds from the Charles E.H. Upham chair in Pediatrics.

Funding Information:
information National Institutes of Health, Grant/Award Numbers: R01 HL084410, P01 HD070454, U01 MH101720, R21HL118637, 5T32GM007491-41, R01 MH085903, R01 MH064824; American Heart Association, Grant/Award Number: 14PRE199800006; FONDECYT-Chile, Grant/Award Numbers: 1130392 and 1171014; Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research, Grant/Award Numbers: MOP-97800 and MOP-89066; University of Toronto McLaughlin Centre; Swiss National Science Foundation, Grant/Award Numbers: FNS 324730_121996 and FNS 324730_144260; National Center of Competence in Research (NCCR) ?Synapsy- The Synaptic bases of Mental Diseases?, Grant/Award Number: 51NF40-158776; Flemish Science Foundation, Grant/Award Number: FWO G.0E1117N; Charles E.H. Upham chair in PediatricsWe would like to thank all patients with 22q11.2DS who enrolled in research and provided DNA as well as clinical records. We thank colleagues in the Molecular Cytogenetics core lab at Einstein for technical support. We thank Mark Zeffren, Nousin Haque, Antoneta Preldakaj, John Bruppacher, Daniel Arroyo, Michael Gleeson and Dominique Calandrillo for technical support at Einstein. We also greatly appreciate the laboratory effort of Dr. Fr?d?rique Bena who works with SE and SEA (Institute of Genetics and Genomics of Geneva, Switzerland) and Oanh Tran and Andrea Jin who work with BSE (Division of Human Genetics, the Children's Hospital of Philadelphia). This work was supported by grants National Institutes of Health R01 HL084410 (BSE, BEM, DMM, TG, AB), P01 HD070454 (EG, LEM, AJA, BSE, DMM, EEM, TG, TW, HN, CLC), U01 MH101720 (BSE, BEM, DMM, GR, AB, EC, AS, DG, SE, FT, NP, CEB, TJS, EVD, TVA, WRK, TG, TW), R21HL118637 (TW, BEM, TG, EG), National Institutes of Health 5T32GM007491-41 (JHC), American Heart Association 14PRE199800006 (JHC). GR was supported by the FONDECYT-Chile (grants 1130392 and 1171014). ASB was supported by the Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research funding (MOP-97800 and MOP-89066), and the University of Toronto McLaughlin Centre. CEB was supported by the National Institutes of Health (R01 MH085903). WRK was supported by the National Institutes of Health (R01 MH064824). SE was supported by the Swiss National Science Foundation (FNS 324730_121996; FNS 324730_144260) and the National Center of Competence in Research (NCCR) ?Synapsy-The Synaptic bases of Mental Diseases? (51NF40-158776). JV was supported by the Flemish Science Foundation (FWO G.0E1117N). BSE was supported by funds from the Charles E.H. Upham chair in Pediatrics. This work is in compliance with the ethical standards of the Committee of Clinical Investigation of Albert Einstein College of Medicine (Internal Review Board #1999-201).

Publisher Copyright:
© 2018 Wiley Periodicals, Inc.

Keywords

22q11.2 deletion syndrome
IQ
deletion size
intellectual disability
low copy repeat
segmental duplication

Access to Document

10.1002/ajmg.a.40359

Cite this

@article{2d8a57ca1b524bbbbd8bf109af372278,

title = "Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects",

abstract = "The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p =.002), verbal IQ was decreased by 8.17 points (p =.0002) and performance IQ was decreased by 4.03 points (p =.028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.",

keywords = "22q11.2 deletion syndrome, IQ, deletion size, intellectual disability, low copy repeat, segmental duplication, 22q11.2 deletion syndrome, Deletion size, Intellectual disability, IQ, Low copy repeat, Segmental duplications",

author = "{the International 22q11.2 Brain and Behavior Consortium} and Yingjie Zhao and Tingwei Guo and Ania Fiksinski and Elemi Breetvelt and McDonald-McGinn, {Donna M.} and Crowley, {Terrence B.} and Alexander Diacou and Maude Schneider and Stephan Eliez and Ann Swillen and Jeroen Breckpot and Joris Vermeesch and Chow, {Eva W.C.} and Doron Gothelf and Sasja Duijff and Rens Evers and {van Amelsvoort}, {Th{\'e}r{\`e}se A.} and {van den Bree}, Marianne and Michael Owen and Maria Niarchou and Bearden, {Carrie E.} and Claudia Ornstein and Maria Pontillo and Antonino Buzzanca and Stefano Vicari and Marco Armando and Murphy, {Kieran C.} and Clodagh Murphy and Sixto Garcia-Minaur and Nicole Philip and Linda Campbell and Jaume Morey-Ca{\~n}ellas and Jasna Raventos and Jordi Rosell and Damian Heine-Suner and Shprintzen, {Robert J.} and Gur, {Raquel E.} and Elaine Zackai and Emanuel, {Beverly S.} and Tao Wang and Kates, {Wendy R.} and Bassett, {Anne S.} and Vorstman, {Jacob A.S.} and Morrow, {Bernice E.} and Antonarakis, {Stylianos E.} and Kevin Antshel and Celso Arango and Massimo Biondi and Anna Blonska and Erik Boot and Rosemarie Fritsch",

note = "Funding Information: National Institutes of Health, Grant/Award Numbers: R01 HL084410, P01 HD070454, U01 MH101720, R21HL118637, 5T32GM007491-41, R01 MH085903, R01 MH064824; American Heart Association, Grant/Award Number: 14PRE199800006; FONDECYT-Chile, Grant/Award Numbers: 1130392 and 1171014; Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research, Grant/Award Numbers: MOP-97800 and MOP-89066; University of Toronto McLaughlin Centre; Swiss National Science Foundation, Grant/Award Numbers: FNS 324730_121996 and FNS 324730_144260; National Center of Competence in Research (NCCR) “Synapsy- The Synaptic bases of Mental Diseases”, Grant/Award Number: 51NF40-158776; Flemish Science Foundation, Grant/Award Number: FWO G.0E1117N; Charles E.H. Upham chair in Pediatrics Funding Information: We would like to thank all patients with 22q11.2DS who enrolled in research and provided DNA as well as clinical records. We thank colleagues in the Molecular Cytogenetics core lab at Einstein for technical support. We thank Mark Zeffren, Nousin Haque, Antoneta Preldakaj, John Bruppacher, Daniel Arroyo, Michael Gleeson and Dominique Calan-drillo for technical support at Einstein. We also greatly appreciate the laboratory effort of Dr. Fr{\'e}d{\'e}rique Bena who works with SE and SEA (Institute of Genetics and Genomics of Geneva, Switzerland) and Oanh Tran and Andrea Jin who work with BSE (Division of Human Genetics, the Children{\textquoteright}s Hospital of Philadelphia). This work was supported by grants National Institutes of Health R01 HL084410 (BSE, BEM, DMM, TG, AB), P01 HD070454 (EG, LEM, AJA, BSE, DMM, EEM, TG, TW, HN, CLC), U01 MH101720 (BSE, BEM, DMM, GR, AB, EC, AS, DG, SE, FT, NP, CEB, TJS, EVD, TVA, WRK, TG, TW), R21HL118637 (TW, BEM, TG, EG), National Institutes of Health 5T32GM007491-41 (JHC), American Heart Association 14PRE199800006 (JHC). GR was supported by the FONDECYT-Chile (grants 1130392 and 1171014). ASB was supported by the Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research funding (MOP-97800 and MOP-89066), and the University of Toronto McLaughlin Centre. CEB was supported by the National Institutes of Health (R01 MH085903). WRK was supported by the National Institutes of Health (R01 MH064824). SE was supported by the Swiss National Science Foundation (FNS 324730_121996; FNS 324730_144260) and the National Center of Competence in Research (NCCR) “Synapsy-The Synaptic bases of Mental Diseases” (51NF40-158776). JV was supported by the Flemish Science Foundation (FWO G.0E1117N). BSE was supported by funds from the Charles E.H. Upham chair in Pediatrics. Funding Information: information National Institutes of Health, Grant/Award Numbers: R01 HL084410, P01 HD070454, U01 MH101720, R21HL118637, 5T32GM007491-41, R01 MH085903, R01 MH064824; American Heart Association, Grant/Award Number: 14PRE199800006; FONDECYT-Chile, Grant/Award Numbers: 1130392 and 1171014; Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research, Grant/Award Numbers: MOP-97800 and MOP-89066; University of Toronto McLaughlin Centre; Swiss National Science Foundation, Grant/Award Numbers: FNS 324730_121996 and FNS 324730_144260; National Center of Competence in Research (NCCR) ?Synapsy- The Synaptic bases of Mental Diseases?, Grant/Award Number: 51NF40-158776; Flemish Science Foundation, Grant/Award Number: FWO G.0E1117N; Charles E.H. Upham chair in PediatricsWe would like to thank all patients with 22q11.2DS who enrolled in research and provided DNA as well as clinical records. We thank colleagues in the Molecular Cytogenetics core lab at Einstein for technical support. We thank Mark Zeffren, Nousin Haque, Antoneta Preldakaj, John Bruppacher, Daniel Arroyo, Michael Gleeson and Dominique Calandrillo for technical support at Einstein. We also greatly appreciate the laboratory effort of Dr. Fr?d?rique Bena who works with SE and SEA (Institute of Genetics and Genomics of Geneva, Switzerland) and Oanh Tran and Andrea Jin who work with BSE (Division of Human Genetics, the Children's Hospital of Philadelphia). This work was supported by grants National Institutes of Health R01 HL084410 (BSE, BEM, DMM, TG, AB), P01 HD070454 (EG, LEM, AJA, BSE, DMM, EEM, TG, TW, HN, CLC), U01 MH101720 (BSE, BEM, DMM, GR, AB, EC, AS, DG, SE, FT, NP, CEB, TJS, EVD, TVA, WRK, TG, TW), R21HL118637 (TW, BEM, TG, EG), National Institutes of Health 5T32GM007491-41 (JHC), American Heart Association 14PRE199800006 (JHC). GR was supported by the FONDECYT-Chile (grants 1130392 and 1171014). ASB was supported by the Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research funding (MOP-97800 and MOP-89066), and the University of Toronto McLaughlin Centre. CEB was supported by the National Institutes of Health (R01 MH085903). WRK was supported by the National Institutes of Health (R01 MH064824). SE was supported by the Swiss National Science Foundation (FNS 324730_121996; FNS 324730_144260) and the National Center of Competence in Research (NCCR) ?Synapsy-The Synaptic bases of Mental Diseases? (51NF40-158776). JV was supported by the Flemish Science Foundation (FWO G.0E1117N). BSE was supported by funds from the Charles E.H. Upham chair in Pediatrics. This work is in compliance with the ethical standards of the Committee of Clinical Investigation of Albert Einstein College of Medicine (Internal Review Board #1999-201). Publisher Copyright: {\textcopyright} 2018 Wiley Periodicals, Inc.",

year = "2018",

month = oct,

day = "1",

doi = "10.1002/ajmg.a.40359",

language = "English",

volume = "176",

pages = "2172--2181",

journal = "American Journal of Medical Genetics, Part A",

issn = "1552-4825",

publisher = "Wiley-Liss Inc.",

number = "10",

}

TY - JOUR

T1 - Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects

AU - the International 22q11.2 Brain and Behavior Consortium

AU - Zhao, Yingjie

AU - Guo, Tingwei

AU - Fiksinski, Ania

AU - Breetvelt, Elemi

AU - McDonald-McGinn, Donna M.

AU - Crowley, Terrence B.

AU - Diacou, Alexander

AU - Schneider, Maude

AU - Eliez, Stephan

AU - Swillen, Ann

AU - Breckpot, Jeroen

AU - Vermeesch, Joris

AU - Chow, Eva W.C.

AU - Gothelf, Doron

AU - Duijff, Sasja

AU - Evers, Rens

AU - van Amelsvoort, Thérèse A.

AU - van den Bree, Marianne

AU - Owen, Michael

AU - Niarchou, Maria

AU - Bearden, Carrie E.

AU - Ornstein, Claudia

AU - Pontillo, Maria

AU - Buzzanca, Antonino

AU - Vicari, Stefano

AU - Armando, Marco

AU - Murphy, Kieran C.

AU - Murphy, Clodagh

AU - Garcia-Minaur, Sixto

AU - Philip, Nicole

AU - Campbell, Linda

AU - Morey-Cañellas, Jaume

AU - Raventos, Jasna

AU - Rosell, Jordi

AU - Heine-Suner, Damian

AU - Shprintzen, Robert J.

AU - Gur, Raquel E.

AU - Zackai, Elaine

AU - Emanuel, Beverly S.

AU - Wang, Tao

AU - Kates, Wendy R.

AU - Bassett, Anne S.

AU - Vorstman, Jacob A.S.

AU - Morrow, Bernice E.

AU - Antonarakis, Stylianos E.

AU - Antshel, Kevin

AU - Arango, Celso

AU - Biondi, Massimo

AU - Blonska, Anna

AU - Boot, Erik

AU - Fritsch, Rosemarie

N1 - Funding Information: National Institutes of Health, Grant/Award Numbers: R01 HL084410, P01 HD070454, U01 MH101720, R21HL118637, 5T32GM007491-41, R01 MH085903, R01 MH064824; American Heart Association, Grant/Award Number: 14PRE199800006; FONDECYT-Chile, Grant/Award Numbers: 1130392 and 1171014; Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research, Grant/Award Numbers: MOP-97800 and MOP-89066; University of Toronto McLaughlin Centre; Swiss National Science Foundation, Grant/Award Numbers: FNS 324730_121996 and FNS 324730_144260; National Center of Competence in Research (NCCR) “Synapsy- The Synaptic bases of Mental Diseases”, Grant/Award Number: 51NF40-158776; Flemish Science Foundation, Grant/Award Number: FWO G.0E1117N; Charles E.H. Upham chair in Pediatrics Funding Information: We would like to thank all patients with 22q11.2DS who enrolled in research and provided DNA as well as clinical records. We thank colleagues in the Molecular Cytogenetics core lab at Einstein for technical support. We thank Mark Zeffren, Nousin Haque, Antoneta Preldakaj, John Bruppacher, Daniel Arroyo, Michael Gleeson and Dominique Calan-drillo for technical support at Einstein. We also greatly appreciate the laboratory effort of Dr. Frédérique Bena who works with SE and SEA (Institute of Genetics and Genomics of Geneva, Switzerland) and Oanh Tran and Andrea Jin who work with BSE (Division of Human Genetics, the Children’s Hospital of Philadelphia). This work was supported by grants National Institutes of Health R01 HL084410 (BSE, BEM, DMM, TG, AB), P01 HD070454 (EG, LEM, AJA, BSE, DMM, EEM, TG, TW, HN, CLC), U01 MH101720 (BSE, BEM, DMM, GR, AB, EC, AS, DG, SE, FT, NP, CEB, TJS, EVD, TVA, WRK, TG, TW), R21HL118637 (TW, BEM, TG, EG), National Institutes of Health 5T32GM007491-41 (JHC), American Heart Association 14PRE199800006 (JHC). GR was supported by the FONDECYT-Chile (grants 1130392 and 1171014). ASB was supported by the Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research funding (MOP-97800 and MOP-89066), and the University of Toronto McLaughlin Centre. CEB was supported by the National Institutes of Health (R01 MH085903). WRK was supported by the National Institutes of Health (R01 MH064824). SE was supported by the Swiss National Science Foundation (FNS 324730_121996; FNS 324730_144260) and the National Center of Competence in Research (NCCR) “Synapsy-The Synaptic bases of Mental Diseases” (51NF40-158776). JV was supported by the Flemish Science Foundation (FWO G.0E1117N). BSE was supported by funds from the Charles E.H. Upham chair in Pediatrics. Funding Information: information National Institutes of Health, Grant/Award Numbers: R01 HL084410, P01 HD070454, U01 MH101720, R21HL118637, 5T32GM007491-41, R01 MH085903, R01 MH064824; American Heart Association, Grant/Award Number: 14PRE199800006; FONDECYT-Chile, Grant/Award Numbers: 1130392 and 1171014; Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research, Grant/Award Numbers: MOP-97800 and MOP-89066; University of Toronto McLaughlin Centre; Swiss National Science Foundation, Grant/Award Numbers: FNS 324730_121996 and FNS 324730_144260; National Center of Competence in Research (NCCR) ?Synapsy- The Synaptic bases of Mental Diseases?, Grant/Award Number: 51NF40-158776; Flemish Science Foundation, Grant/Award Number: FWO G.0E1117N; Charles E.H. Upham chair in PediatricsWe would like to thank all patients with 22q11.2DS who enrolled in research and provided DNA as well as clinical records. We thank colleagues in the Molecular Cytogenetics core lab at Einstein for technical support. We thank Mark Zeffren, Nousin Haque, Antoneta Preldakaj, John Bruppacher, Daniel Arroyo, Michael Gleeson and Dominique Calandrillo for technical support at Einstein. We also greatly appreciate the laboratory effort of Dr. Fr?d?rique Bena who works with SE and SEA (Institute of Genetics and Genomics of Geneva, Switzerland) and Oanh Tran and Andrea Jin who work with BSE (Division of Human Genetics, the Children's Hospital of Philadelphia). This work was supported by grants National Institutes of Health R01 HL084410 (BSE, BEM, DMM, TG, AB), P01 HD070454 (EG, LEM, AJA, BSE, DMM, EEM, TG, TW, HN, CLC), U01 MH101720 (BSE, BEM, DMM, GR, AB, EC, AS, DG, SE, FT, NP, CEB, TJS, EVD, TVA, WRK, TG, TW), R21HL118637 (TW, BEM, TG, EG), National Institutes of Health 5T32GM007491-41 (JHC), American Heart Association 14PRE199800006 (JHC). GR was supported by the FONDECYT-Chile (grants 1130392 and 1171014). ASB was supported by the Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research funding (MOP-97800 and MOP-89066), and the University of Toronto McLaughlin Centre. CEB was supported by the National Institutes of Health (R01 MH085903). WRK was supported by the National Institutes of Health (R01 MH064824). SE was supported by the Swiss National Science Foundation (FNS 324730_121996; FNS 324730_144260) and the National Center of Competence in Research (NCCR) ?Synapsy-The Synaptic bases of Mental Diseases? (51NF40-158776). JV was supported by the Flemish Science Foundation (FWO G.0E1117N). BSE was supported by funds from the Charles E.H. Upham chair in Pediatrics. This work is in compliance with the ethical standards of the Committee of Clinical Investigation of Albert Einstein College of Medicine (Internal Review Board #1999-201). Publisher Copyright: © 2018 Wiley Periodicals, Inc.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p =.002), verbal IQ was decreased by 8.17 points (p =.0002) and performance IQ was decreased by 4.03 points (p =.028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.

AB - The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p =.002), verbal IQ was decreased by 8.17 points (p =.0002) and performance IQ was decreased by 4.03 points (p =.028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.

KW - 22q11.2 deletion syndrome

KW - IQ

KW - deletion size

KW - intellectual disability

KW - low copy repeat

KW - segmental duplication

KW - 22q11.2 deletion syndrome

KW - Deletion size

KW - Intellectual disability

KW - IQ

KW - Low copy repeat

KW - Segmental duplications

UR - http://www.scopus.com/inward/record.url?scp=85054522149&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.40359

DO - 10.1002/ajmg.a.40359

M3 - Article

C2 - 30289625

AN - SCOPUS:85054522149

SN - 1552-4825

VL - 176

SP - 2172

EP - 2181

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

IS - 10

ER -

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects

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