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

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8 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 languageEnglish
Pages (from-to)2172-2181
Number of pages10
JournalAmerican Journal of Medical Genetics, Part A
Volume176
Issue number10
DOIs
StatePublished - 1 Oct 2018
Externally publishedYes

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

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