A Co-segregating Microduplication of Chromosome 15q11.2 Pinpoints Two Risk Genes for Autism Spectrum Disorder

Overview

Journal Am J Med Genet B Neuropsychiatr Genet

Specialties Genetics
Neurology
Psychiatry

Date 2009 Dec 24

PMID 20029941

Citations 55

Authors

Bert Van der Zwaag

Wouter G Staal

Ron Hochstenbach

Martin Poot

Henk A Spierenburg

Maretha V de Jonge

Nienke E Verbeek

Ruben van t Slot

Michael A van Es

Frank J Staal

Christine M Freitag

Jacobine E Buizer-Voskamp

Marcel R Nelen

Leonard H van den Berg

Hans K Ploos van Amstel

Herman van Engeland

J Peter H Burbach

Affiliations

Soon will be listed here.

Abstract

High resolution genomic copy-number analysis has shown that inherited and de novo copy-number variations contribute significantly to autism pathology, and that identification of small chromosomal aberrations related to autism will expedite the discovery of risk genes involved. Here, we report a microduplication of chromosome 15q11.2, spanning only four genes, co-segregating with autism in a Dutch pedigree, identified by SNP microarray analysis, and independently confirmed by FISH and MLPA analysis. Quantitative RT-PCR analysis revealed over 70% increase in peripheral blood mRNA levels for the four genes present in the duplicated region in patients, and RNA in situ hybridization on mouse embryonic and adult brain sections revealed that two of the four genes, CYFIP1 and NIPA1, were highly expressed in the developing mouse brain. These findings point towards a contribution of microduplications at chromosome 15q11.2 to autism, and highlight CYFIP1 and NIPA1 as autism risk genes functioning in axonogenesis and synaptogenesis. Thereby, these findings further implicate defects in dosage-sensitive molecular control of neuronal connectivity in autism. However, the prevalence of this microduplication in patient samples was statistically not significantly different from control samples (0.94% in patients vs. 0.42% controls, P = 0.247), which suggests that our findings should be interpreted with caution and indicates the need for studies that include large numbers of control subjects to ascertain the impact of these changes on a population scale.

Citing Articles

Chromosome 15q11-q13 Duplication Syndrome: A Review of the Literature and 14 New Cases.

Bisba M, Malamaki C, Constantoulakis P, Vittas S Genes (Basel). 2024; 15(10).

PMID: 39457428 PMC: 11507414. DOI: 10.3390/genes15101304.

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

Boen R, Kaufmann T, van der Meer D, Frei O, Agartz I, Ames D Biol Psychiatry. 2023; 95(2):147-160.

PMID: 37661008 PMC: 7615370. DOI: 10.1016/j.biopsych.2023.08.018.

Overexpression of the autism candidate gene pathologically enhances olivo-cerebellar signaling in mice.

Busch S, Simmons D, Gama E, Du X, Longo F, Gomez C Front Cell Neurosci. 2023; 17:1219270.

PMID: 37545882 PMC: 10399232. DOI: 10.3389/fncel.2023.1219270.

SREBP modulates the NADP/NADPH cycle to control night sleep in Drosophila.

Mariano V, Kanellopoulos A, Aiello G, Lo A, Legius E, Achsel T Nat Commun. 2023; 14(1):763.

PMID: 36808152 PMC: 9941135. DOI: 10.1038/s41467-022-35577-8.

No signs of neurodegenerative effects in 15q11.2 BP1-BP2 copy number variant carriers in the UK Biobank.

Boen R, Kaufmann T, Frei O, van der Meer D, Djurovic S, Andreassen O Transl Psychiatry. 2023; 13(1):61.

PMID: 36807331 PMC: 9938862. DOI: 10.1038/s41398-023-02358-w.

References

Rainier S, Chai J, Tokarz D, Nicholls R, Fink J . NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet. 2003; 73(4):967-71. PMC: 1180617. DOI: 10.1086/378817. View

Peiffer D, Le J, Steemers F, Chang W, Jenniges T, Garcia F . High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping. Genome Res. 2006; 16(9):1136-48. PMC: 1557768. DOI: 10.1101/gr.5402306. View

Van der Zwaag B, Franke L, Poot M, Hochstenbach R, Spierenburg H, Vorstman J . Gene-network analysis identifies susceptibility genes related to glycobiology in autism. PLoS One. 2009; 4(5):e5324. PMC: 2683930. DOI: 10.1371/journal.pone.0005324. View

Burbach J, Van der Zwaag B . Contact in the genetics of autism and schizophrenia. Trends Neurosci. 2009; 32(2):69-72. DOI: 10.1016/j.tins.2008.11.002. View

Veltman M, Craig E, Bolton P . Autism spectrum disorders in Prader-Willi and Angelman syndromes: a systematic review. Psychiatr Genet. 2005; 15(4):243-54. DOI: 10.1097/00041444-200512000-00006. View

Hellemans J, Mortier G, De Paepe A, Speleman F, Vandesompele J . qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome Biol. 2007; 8(2):R19. PMC: 1852402. DOI: 10.1186/gb-2007-8-2-r19. View

Schenck A, Bardoni B, Langmann C, Harden N, Mandel J, Giangrande A . CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein. Neuron. 2003; 38(6):887-98. DOI: 10.1016/s0896-6273(03)00354-4. View

Vorstman J, Staal W, van Daalen E, van Engeland H, Hochstenbach P, Franke L . Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry. 2005; 11(1):1, 18-28. DOI: 10.1038/sj.mp.4001781. View

Abrahams B, Geschwind D . Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008; 9(5):341-55. PMC: 2756414. DOI: 10.1038/nrg2346. View

10.

Van der Zwaag B, Burbach J, Scharfe C, Oefner P, Brunner H, Padberg G . Identifying new candidate genes for hereditary facial paresis on chromosome 3q21-q22 by RNA in situ hybridization in mouse. Genomics. 2005; 86(1):55-67. DOI: 10.1016/j.ygeno.2005.03.007. View

11.

Morrow E, Yoo S, Flavell S, Kim T, Lin Y, Hill R . Identifying autism loci and genes by tracing recent shared ancestry. Science. 2008; 321(5886):218-23. PMC: 2586171. DOI: 10.1126/science.1157657. View

12.

Stefansson H, Rujescu D, Cichon S, Pietilainen O, Ingason A, Steinberg S . Large recurrent microdeletions associated with schizophrenia. Nature. 2008; 455(7210):232-6. PMC: 2687075. DOI: 10.1038/nature07229. View

13.

Murthy S, Nygren A, El Shakankiry H, Schouten J, Al Khayat A, Ridha A . Detection of a novel familial deletion of four genes between BP1 and BP2 of the Prader-Willi/Angelman syndrome critical region by oligo-array CGH in a child with neurological disorder and speech impairment. Cytogenet Genome Res. 2007; 116(1-2):135-40. DOI: 10.1159/000097433. View

14.

Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T . Strong association of de novo copy number mutations with autism. Science. 2007; 316(5823):445-9. PMC: 2993504. DOI: 10.1126/science.1138659. View

15.

Doornbos M, Sikkema-Raddatz B, Ruijvenkamp C, Dijkhuizen T, Bijlsma E, Gijsbers A . Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet. 2009; 52(2-3):108-15. DOI: 10.1016/j.ejmg.2009.03.010. View

16.

Bolton P, Dennis N, Browne C, Thomas N, Veltman M, Thompson R . The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. Am J Med Genet. 2002; 105(8):675-85. DOI: 10.1002/ajmg.1551. View

17.

Nowicki S, Tassone F, Ono M, Ferranti J, Croquette M, Goodlin-Jones B . The Prader-Willi phenotype of fragile X syndrome. J Dev Behav Pediatr. 2007; 28(2):133-8. DOI: 10.1097/01.DBP.0000267563.18952.c9. View

18.

Miller D, Shen Y, Weiss L, Korn J, Anselm I, Bridgemohan C . Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet. 2008; 46(4):242-8. PMC: 4090085. DOI: 10.1136/jmg.2008.059907. View

19.

Pujana M, Nadal M, Guitart M, Armengol L, Gratacos M, Estivill X . Human chromosome 15q11-q14 regions of rearrangements contain clusters of LCR15 duplicons. Eur J Hum Genet. 2002; 10(1):26-35. DOI: 10.1038/sj.ejhg.5200760. View

20.

Marshall C, Noor A, Vincent J, Lionel A, Feuk L, Skaug J . Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008; 82(2):477-88. PMC: 2426913. DOI: 10.1016/j.ajhg.2007.12.009. View