Application of array comparative genomic hybridization in 256 patients with developmental delay or intellectual disability

Bartnik, Magdalena; Nowakowska, Beata; Derwińska, Katarzyna; Wiśniowiecka‐Kowalnik, Barbara; Kędzior, Marta; Bernaciak, Joanna; Ziemkiewicz, Kamila; Gambin, Tomasz; Sykulski, Maciej; Bezniakow, Natalia; Korniszewski, L; Kutkowska-Kaźmierczak, Anna; Klapecki, Jakub; Szczałuba, Krzysztof; Shaw, Chad A.; Mazurczak, Tadeusz; Gambin, Anna; Obersztyn, Ewa; Bocian, Ewa; Stankiewicz, Paweł

doi:10.1007/s13353-013-0181-x

Cited by 47 publications

(56 citation statements)

References 57 publications

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“…In support of this notion, CNV deletions of PSMD12 were reported in two independent investigations on subjects with ID, truncal obesity, and psychiatric symptoms. 56,57 In the first study, three subjects with a complete deletion of PSMD12 had conductive hearing loss and feeding difficulties during infancy in addition to ID. 57 In the second study, the subject with a large deletion including PSMD12 exhibited global DD associated with a cardiac defect, feeding difficulties, and pulmonary infection, 56 clinical findings consistent with those reported in our study.…”

Section: Congenital Malformationsmentioning

confidence: 99%

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Küry¹,

Besnard²,

Ebstein³

et al. 2017

The American Journal of Human Genetics

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Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.Proteolysis by the ubiquitin-proteasome system (UPS) is a tightly regulated biological process in eukaryotic cells and is crucial for their homeostasis, signaling, and fate determination. 1-3 Proteins subjected to degradation are typically marked by polyubiquitin chains to be hydrolyzed in a precise, rapid, timely, and ATP-dependent manner by the 19S regulatory subunit of the 26S proteasome. 3-6 UPS-dependent degradation essentially contributes to proteostasis and plays a key role in neuronal development and function 7,8 by regulating synaptic plasticity, 9,10

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Section: Congenital Malformationsmentioning

confidence: 99%

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Küry¹,

Besnard²,

Ebstein³

et al. 2017

The American Journal of Human Genetics

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“…Because of its high diagnostic yield, effectiveness and health-care possibilities, arraybased screen for CNVs was recommended in 2010 by the American College of Medical Genetics and Genomics as the preferred first clinical genetic diagnostic test for patients with developmental delay, ID or MCA (Newman et al, 2007;Wordsworth et al, 2007;Gijsbers et al, 2009;Manning et al, 2010;Miller et al, 2010;Regier et al, 2010;South and Brothman, 2011;Bartnik et al, 2014) . In addition, microarray analyses provide accurate diagnosis in approximately twice as many cases as classical karyotyping and fluorescent in situ hybridization (Gijsbers et al, 2009;Hochstenbach et al, 2009;Ahn et al, 2010;Miller et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil

et al. 2016

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ABSTRACT. In several patients, intellectual disability and/or congenital malformation may be attributed to chromosomal changes. In this study, we conducted an array-CGH test of 200 patients from the Northeast of Brazil with intellectual disability and/or congenital malformation. Blood samples were collected from the proband and from their parents when possible. DNA was extracted and investigated using the array-CGH test. Findings were evaluated for the pathogenicity in databases of benign and pathogenic changes (ISCA, UCSC, DGV, and DECIPHER). Forty-seven copy number variations (CNVs) were identified in 43/200 (21.5%) patients, including 25/98 (25.5%) in males and 22/102 (21.57%) in females. We considered 33 of these to be clinically significant, reaching a diagnosis rate of 16.5%. The sizes of the CNVs varied from 102 kb to 24 Mb in deletions and from 115 kb to 140 Mb in duplications. In 10/47 (21.3%) patients, the rearrangement involved a sex chromosome. Thirty-nine patients had one chromosomal aberration, while 2 concomitant abnormalities were detected in 4 patients. Ten of 47 CNVs (21.3%) were > 5Mb in size. Fifteen patients had CNVs related to known syndromes. This research highlights the contribution of submicroscopic chromosomal changes to the etiology of intellectual disability and/or congenital malformation, particularly the implication of chromosomal abnormalities detected using an array-CGH test, with a high rate of 16.5%. Thus, our results support the use of array-CGH replacing standard karyotype as the first-tier cytogenetic diagnostic test for patients with multiple congenital anomalies and/or intellectual disability.

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“…Chromosomal microarray is currently indicated as the most cost‐effective genetic test of choice in such instances, as it is superior to G‐banded karyotype with regard to diagnostic yield in individuals with multiple congenital anomalies, neurodevelopmental delays, intellectual disability, and autism, especially in more severely impacted individuals, and is useful in providing diagnostic information for individuals with epilepsy 5, 6, 7.…”

Section: Discussionmentioning

confidence: 99%

Importance of genetic testing in global health during the evaluation of familial microcephaly

Molinero

Broman‐Fulks

Lyons

et al. 2016

Clinical Case Reports

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Application of array comparative genomic hybridization in 256 patients with developmental delay or intellectual disability

Cited by 47 publications

References 57 publications

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil

Importance of genetic testing in global health during the evaluation of familial microcephaly

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