Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders

Nagamani, Sandesh C.S.; Erez, Ayelet; Ben‐Zeev, Bruria; Frydman, Moshe; Winter, Susan; Zeller, Robert S.; El-Khechen, Dima; Escobar, Luis; Stankiewicz, Paweł; Patel, Ankita; Cheung, Sau Wai

doi:10.1038/ejhg.2012.157

Cited by 60 publications

(66 citation statements)

References 38 publications

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“…We controlled for population stratification, applied filters which are stringent for CNV studies, and utilized 2 different CNV calling algorithms to ensure comprehensive detection of CNVs. Some of the reported CNV regions in this study were indeed characterized as disease conferring across a spectrum of phenotypes and therefore provide confidence in our study findings [Butler et al, 2005;Bailey et al, 2008;Diskin et al, 2009;Glessner et al, 2009Glessner et al, , 2010Ehli et al, 2012;Stadler et al, 2012;Lalani et al, 2013;Nagamani et al, 2013;Ukkola-Vuoti et al, 2013;Chettier et al, 2014;Szatkiewicz et al, 2014;Furuya et al, 2015].…”

supporting

confidence: 77%

“…In addition to the observed associations with BC phenotype, the identified CNV regions also were shown to be associated with other diseases (show pleiotropy) such as autism, schizophrenia, multiple sclerosis, and congenital cardiovascular disease [Vandepoele et al, 2005;Glessner et al, 2009;Kao et al, 2010;Stadler et al, 2012;Lalani et al, 2013;Nagamani et al, 2013;Szatkiewicz et al, 2014;Li et al, 2016].…”

Section: Discussionmentioning

confidence: 88%

“…Subsets of CNV loci identified ( table 2 ) harbored genes that are known to play a role in BC: (1) NBPF9 and an adjacent gene, PDE4DIP, are evolutionarily conserved and exhibit CNVRs; these gene loci are mutated in BC and in neuroblastoma [Diskin et al, 2009;O'Bleness et al, 2012;Horvath et al, 2013]; (2) the AUTS2 gene was shown to be prognostic for BC recurrence and is also an integral member of the PAM50 prognostic gene cluster [Chanrion et al, 2008;Stadler et al, 2012;Nagamani et al, 2013]; (3) ASTN2 gene rearrangements are prognostic in BC Hampton et al, 2009]; and (4) SGCD is known to mediate paclitaxel sensitivity [Conrad et al, 2010b;Eng et al, 2011;Beck et al, 2013;Chettier et al, 2014].…”

Section: Discussionmentioning

confidence: 99%

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A Genome-Wide Association Study to Identify Potential Germline Copy Number Variants for Sporadic Breast Cancer Susceptibility

Sapkota

Narasimhan

Kumaran

et al. 2016

Cytogenet Genome Res

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Breast cancer (BC) predisposition in populations arises from both genetic and nongenetic risk factors. Structural variations such as copy number variations (CNVs) are heritable determinants for disease susceptibility. The primary objectives of this study are (1) to identify CNVs associated with sporadic BC using a genome-wide association study (GWAS) design; (2) to utilize 2 distinct CNV calling algorithms to identify concordant CNVs as a strategy to reduce false positive associations in the hypothesis-generating GWAS discovery phase, and (3) to identify potential candidate CNVs for follow-up replication studies. We used Affymetrix SNP Array 6.0 data profiled on Caucasian subjects (422 cases/348 controls) to call CNVs using algorithms implemented in Nexus Copy Number and Partek Genomics Suite software. Nexus algorithm identified CNVs associated with BC (731 autosomal CNVs with >5% frequency in the total sample and Q < 0.05). Thirteen CNVs were identified when Partek algorithm-called CNVs were overlapped with Nexus-identified CNVs; these CNVs showed concordances for frequency, effect size, and direction. Coding genes present within BC-associated CNVs were known to play a role in disease etiology and prognosis. Long noncoding RNAs identified within CNVs showed tissue-specific expression, indicating potential functional relevance of the findings. The identified candidate CNVs warrant independent replication.

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supporting

confidence: 77%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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A Genome-Wide Association Study to Identify Potential Germline Copy Number Variants for Sporadic Breast Cancer Susceptibility

Sapkota

Narasimhan

Kumaran

et al. 2016

Cytogenet Genome Res

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“…(These items were selected because they occurred in at least two unrelated individuals with AUTS2 syndrome.) 1, [3][4][5][6][7][8][9][10][11] frameshift in the full-length AUTS2 transcript, likely to cause haploinsufficiency. Both men have intellectual disability, an autism spectrum disorder, feeding difficulties after birth, mild distal joint contractures and mild dysmorphic features.…”

Section: Discussionmentioning

confidence: 99%

Two male adults with pathogenic AUTS2 variants, including a two-base pair deletion, further delineate the AUTS2 syndrome

Beunders

Munnik

et al. 2014

Eur J Hum Genet

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AUTS2 syndrome is characterized by low birth weight, feeding difficulties, intellectual disability, microcephaly and mild dysmorphic features. All affected individuals thus far were caused by chromosomal rearrangements, variants at the base pair level disrupting AUTS2 have not yet been described. Here we present the full clinical description of two affected men with intragenic AUTS2 variants (one two-base pair deletion in exon 7 and one deletion of exon 6). Both variants are de novo and are predicted to cause a frameshift of the full-length transcript but are unlikely to affect the shorter 3 0 transcript starting in exon 9. The similarities between the phenotypes of both men are striking and further support that AUTS2 syndrome is a single gene disorder. ( European Journal of Human Genetics INTRODUCTIONDisruption of AUTS2 by translocations, inversions or deletions causes a syndromic form of intellectual disability. 1 Forty-four pathogenic disruptions of AUTS2 have been described: 6 translocations and 2 inversions with one breakpoint in AUTS2 and 36 deletions (with a size of 50 kb to 4.5 Mb) containing at least one exon and a maximum of two downstream genes. In most cases parental DNA was available.De novo occurrence could be confirmed in the majority of the patients, but in five families the deletions were inherited from an affected parent (twice), an unaffected father (once) or a parent of whom no clinical data were available (twice). 1-11 A detailed study of 17 affected individuals with a disruption of AUTS2 revealed a distinct AUTS2 syndrome characterized by intellectual disability, microcephaly, mild short stature, feeding problems, hypertonia or hypotonia and facial features, including ptosis, highly arched eyebrows, narrow mouth and micro/retrognathia. 1 The AUTS2 syndrome severity score, expressed as the sum of all features seen more than once in unrelated affected individuals, is a measure of the severity and specificity of the phenotype. The median AUTS2 syndrome severity score of individuals with a genomic rearrangement/ deletion involving the 3 0 region of AUTS2 was significantly higher than that of individuals with 5 0 deletions. The 3 0 end of the gene harbors an alternative transcript that is (like the full-length transcript) expressed in human brain and starts in exon 9. The short transcript is able to rescue the phenotype of AUTS2 zebrafish morphants. These two observations indicate that the 3 0 region of AUTS2 contains important functional domains. 1 Here we report a deletion of two nucleotides, the first pathogenic variant at the base pair level, in a young adult with a syndromic form

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“…However, mechanisms underlying this process has not yet been well understood. The Autism susceptibility candidate 2 (AUTS2) is crucial in neurodevelopment and is a candidate gene for numerous neurological disorders such as autism spectrum disorders [1], intellectual disability [2,3] and developmental delay [4,5]. Literatures also show that this gene is also associated with acute lymphoblastic leukemia [6], alcoholism [7,8] and schizophrenia [9].…”

Section: Introductionmentioning

confidence: 99%

AUTS2 is a potential therapeutic target for pancreatic cancer patients with liver metastases

Han

Mou

et al. 2015

Medical Hypotheses

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Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders

Cited by 60 publications

References 38 publications

A Genome-Wide Association Study to Identify Potential Germline Copy Number Variants for Sporadic Breast Cancer Susceptibility

A Genome-Wide Association Study to Identify Potential Germline Copy Number Variants for Sporadic Breast Cancer Susceptibility

Two male adults with pathogenic AUTS2 variants, including a two-base pair deletion, further delineate the AUTS2 syndrome

AUTS2 is a potential therapeutic target for pancreatic cancer patients with liver metastases

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