Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes

Gregorio, Eleonora Di; Riberi, Evelise; Belligni, Elga Fabia; Biamino, Elisa; Spielmann, Malte; Ala, Ugo; Calcia, Alessandro; Bagnasco, Irene; Carli, Diana; Gai, Giorgia; Giordano, Mara; Guala, Andrea; Keller, Roberto; Mandrile, Giorgia; Arduino, Carlo; Maffè, Antonella; Naretto, Valeria Giorgia; Sirchia, Fabio; Sorasio, Lorena; Ungari, Silvana; Zonta, Andrea; Zacchetti, Giovanna; Talarico, Flavia; Pappi, Patrizia; Cavalieri, Simona; Giorgio, Elisa; Mancini, Cecilia; Ferrero, Marta; Brussino, Alessandro; Savin, Elisa; Gandione, Marina; Pelle, Alessandra; Giachino, Daniela; Marchi, Mario; Restagno, Gabriella; Provero, Paolo; Silengo, Margherita; Grosso, Enrico; Buxbaum, Joseph D.; Pasini, Barbara; Rubeis, Silvia De; Brusco, Alfredo; Ferrero, Giovanni Battista

doi:10.1111/cge.13009

Cited by 49 publications

(41 citation statements)

References 45 publications

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“…In this study, the CMA in 63 individuals with DD/ID revealed pathogenic CNVs in 20 (32%) cases. This diagnostic yield is higher than the yields obtained in earlier studies (Miller et al 2010;Wincent et al 2011;Palmer et al 2014;Vianna et al 2016;Di Gregorio et al 2017). However, the reason for this higher detection rate was the inclusion of 12 individuals with abnormal karyotype results prior to the CMA.…”

Section: Discussionmentioning

confidence: 57%

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Phenotype comparison among individuals with developmental delay/intellectual disability with or without genomic imbalances

Souza

Santos

Sgardioli

et al. 2019

J intellect Disabil Res

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Background The chromosomal microarray analysis (CMA) is recommended as a first‐tier test for individuals with developmental delay (DD)/intellectual disability (ID) and/or multiple congenital anomalies. However, owing to high costs, this technique is not widely performed for diagnostic purposes in several countries. The aim of this study was to identify clinical features that could favour the hypothesis of genomic imbalances (GIs) in individuals with DD/ID. Methods The sample consisted of 63 individuals, and all of them underwent a detailed evaluation by a clinical geneticist and were investigated by the CMA. They were divided into two groups. Group A composed of 20 individuals with pathogenic copy number variants (CNVs); and group B composed of 43 individuals with normal CMA results or variants of uncertain clinical significance (VUS). Results Pathogenic GIs were found in 20 cases (32%), including 11 individuals with an abnormal karyotype, VUS was found in five individuals (8%) and the results were normal in 38 individuals (60%). Major anomalies were found in 15/20 (75%) individuals in group A against 35/43 (81%) in group B. Dysmorphisms (≥5) were found in 17/20 (85%) in group A and 41/43 (95%) in group B. The most frequent major anomalies detected in group A were congenital heart disease, epilepsy and renal malformation; and in group B, they were malformations of central nervous system, congenital heart disease, microcephaly, epilepsy and hearing impairment. There was no significant statistical difference among the frequencies in groups A and B. Conclusions Evidences point that every individual with DD/ID, with no specific clinical suspicion, should have screening for GIs as a first‐tier test, regardless of the presence or absence of additional major anomalies or dysmorphisms. Future studies with a similar design would be helpful, especially in countries where the access to new technologies is still limited.

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Section: Discussionmentioning

confidence: 57%

“…; Di Gregorio et al . ). However, the reason for this higher detection rate was the inclusion of 12 individuals with abnormal karyotype results prior to the CMA.…”

Section: Discussionmentioning

confidence: 97%

Phenotype comparison among individuals with developmental delay/intellectual disability with or without genomic imbalances

Souza

Santos

Sgardioli

et al. 2019

J intellect Disabil Res

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“…Furthermore, psychotic manifestations and ASD are frequently observed in the clinical practice, and it is particularly worth noting that some patients, diagnosed with ASD in their childhood, show a schizophrenic development in adolescence or adulthood, accompanied by psychotic and neurodegenerative aspects (Keller, Piedimonte, Bianco, Bari, & Cauda, ). These clinical data might be accounted for by finding out common genetic roots at the basis of neurodevelopment disorders, which bring about phenotypic expressions with different timings and modalities, due to epigenetic factors affecting the production of proteins with regulatory function over the brain organization and development (Di Gregorio, et al, ). This hypothesis is supported by the clinical examination of families of patients with ASD, in which phenotypic expressions bear psychiatric disorders different from ASD, OCSD, and SCZD (Biamino, et al, ).…”

Section: Discussionmentioning

confidence: 99%

The morphometric co‐atrophy networking of schizophrenia, autistic and obsessive spectrum disorders

Cauda

Nani

Costa

et al. 2018

Human Brain Mapping

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By means of a novel methodology that can statistically derive patterns of co-alterations distribution from voxel-based morphological data, this study analyzes the patterns of brain alterations of three important psychiatric spectra-that is, schizophrenia spectrum disorder (SCZD), autistic spectrum disorder (ASD), and obsessive-compulsive spectrum disorder (OCSD). Our analysis provides five important results. First, in SCZD, ASD, and OCSD brain alterations do not distribute randomly but, rather, follow network-like patterns of co-alteration. Second, the clusters of co-altered areas form a net of alterations that can be defined as morphometric co-alteration network or co-atrophy network (in the case of gray matter decreases). Third, within this network certain cerebral areas can be identified as pathoconnectivity hubs, the alteration of which is supposed to enhance the development of neuronal abnormalities. Fourth, within the morphometric co-atrophy network of SCZD, ASD, and OCSD, a subnetwork composed of eleven highly connected nodes can be distinguished. This subnetwork encompasses the anterior insulae, inferior frontal areas, left superior temporal areas, left parahippocampal regions, left thalamus and right precentral gyri. Fifth, the co-altered areas also exhibit a normal structural covariance pattern which overlaps, for some of these areas (like the insulae), the co-alteration pattern. These findings reveal that, similarly to neurodegenerative diseases, psychiatric disorders are characterized by anatomical alterations that distribute according to connectivity constraints so as to form identifiable morphometric co-atrophy patterns.

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“…Even if TAD-boundary disruption was considered as a well-established model of deleterious mechanism underlying genetic diseases, this mechanism has been shown in only a relatively low number of diseases (Spielmann et al 2018). In addition, large cohort studies identified TAD-boundary disruption as the disease-causing mechanism only in a low proportion of patients, ranging from 0.3% to 11.8% (Di Gregorio et al 2017;Ibn-Salem et al 2014). In light of these data, we wondered whether TAD boundary disruptions could occur without resulting in an observable phenotype.…”

Section: Discussionmentioning

confidence: 99%

Lessons from the analysis of TAD boundary deletions in normal population

Smol

Sigé

Thuillier

et al. 2020

Preprint

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Topologically Associating Domains (TAD)-boundaries induce spatial constraints, allowing interaction between regulatory elements and promoters only within their TAD. Their disruption could lead to disease, through gene-expression deregulation. This mechanism has been shown in only a relatively low number of diseases and a relatively low proportion of patients, raising the possibility of TAD boundary disruption without phenotypical consequence. We investigated, therefore, the occurrence of TAD boundaries disruption in the general population. Coordinates of 307,430 benign deletions from public databases were crossed with 36 Hi-C datasets. Differences in gene content and gene localization were compared in the TADs, according to the possible disruption of their boundaries by a deletion found in the general population. TADs with no deletion encompassing their boundaries (R-TAD) represented 38% of TADs. Enrichment in OMIM genes as well as in morbid genes was observed in R-TADs and genes in R-TADs were found to localize closer to the boundaries.Our results support recent publications tempering the impact of breaking TADs on gene expression with a majority of broken TADs in the general population. A subgroup of R-TAD emerges from this analysis with enrichment in disease genes and their coordinates could be used to annotate CNV from pangenomic approaches to enhance data interpretation.

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Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes

Abstract: We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.

Cited by 49 publications

References 45 publications

Phenotype comparison among individuals with developmental delay/intellectual disability with or without genomic imbalances

Phenotype comparison among individuals with developmental delay/intellectual disability with or without genomic imbalances

The morphometric co‐atrophy networking of schizophrenia, autistic and obsessive spectrum disorders

Lessons from the analysis of TAD boundary deletions in normal population

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