335.4kb microduplication in chromosome band Xp11.2p11.3 associated with developmental delay, growth retardation, autistic disorder and dysmorphic features

Alesi, Viola; Bértoli, Marta; Barrano, Giuseppe; Torres, Bárbara; Pusceddu, Silvia; Pastorino, Myriam; Perria, C; Nardone, Anna Maria; Novelli, Antonio; Serra, G

doi:10.1016/j.gene.2012.05.031

Cited by 14 publications

(12 citation statements)

References 20 publications

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“…Zinc finger proteins are the largest class of DNA binding proteins and play a critical role in regulating many biological processes. Both genes have been previously linked with intellectual disability, developmental delay, and ASD (Kleefstra et al 2004; Alesi et al 2012), but they are relatively understudied with unknown functional impact, and in the case of ZNF81, one unaffected male was documented with a truncating variant (Piton et al 2013). ZNF182 is widely expressed in the brain, whereas ZNF81 shows lower expression, but data from the Genotype-Tissue Expression (GTEx) project reveals that both genes are preferentially expressed in the cerebellum (Carithers et al 2015).…”

Section: Resultsmentioning

confidence: 99%

Whole-genome sequencing in a family with twin boys with autism and intellectual disability suggests multimodal polygenic risk

McKenna

Koomar

Vervier

et al. 2018

Cold Spring Harb Mol Case Stud

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Over the past decade, a focus on de novo mutations has rapidly accelerated gene discovery in autism spectrum disorder (ASD), intellectual disability (ID), and other neurodevelopmental disorders (NDDs). However, recent studies suggest that only a minority of cases are attributable to de novo mutations, and instead these disorders often result from an accumulation of various forms of genetic risk. Consequently, we adopted an inclusive approach to investigate the genetic risk contributing to a case of male monozygotic twins with ASD and ID. At the time of the study, the probands were 7 yr old and largely nonverbal. Medical records indicated a history of motor delays, sleep difficulties, and significant cognitive deficits. Through whole-genome sequencing of the probands and their parents, we uncovered elevated common polygenic risk, a coding de novo point mutation in CENPE, an ultra-rare homozygous regulatory variant in ANK3, inherited rare variants in NRXN3, and a maternally inherited X-linked deletion situated in a noncoding regulatory region between ZNF81 and ZNF182. Although each of these genes has been directly or indirectly associated with NDDs, evidence suggests that no single variant adequately explains the probands’ phenotype. Instead, we propose that the probands’ condition is due to the confluence of multiple rare variants in the context of a high-risk genetic background. This case emphasizes the multifactorial nature of genetic risk underlying most instances of NDDs and aligns with the “female protective model” of ASD.

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Section: Resultsmentioning

confidence: 99%

Whole-genome sequencing in a family with twin boys with autism and intellectual disability suggests multimodal polygenic risk

McKenna

Koomar

Vervier

et al. 2018

Cold Spring Harb Mol Case Stud

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“…Recently, a duplication of the same chromosomal region was shown to cause similar phenotype [24]. Case #15 was another chromosome imbalance identified in a distant patient that has been defined as an unbalanced translocation between long arms of chromosomes 10 and 13 after cytogenetic re-evaluation.…”

Section: Resultsmentioning

confidence: 99%

Molecular karyotyping by array CGH in a Russian cohort of children with intellectual disability, autism, epilepsy and congenital anomalies

Iourov

Куринная

et al. 2012

Mol Cytogenet

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BackgroundArray comparative genomic hybridization (CGH) has been repeatedly shown to be a successful tool for the identification of genomic variations in a clinical population. During the last decade, the implementation of array CGH has resulted in the identification of new causative submicroscopic chromosome imbalances and copy number variations (CNVs) in neuropsychiatric (neurobehavioral) diseases. Currently, array-CGH-based technologies have become an integral part of molecular diagnosis and research in individuals with neuropsychiatric disorders and children with intellectual disability (mental retardation) and congenital anomalies. Here, we introduce the Russian cohort of children with intellectual disability, autism, epilepsy and congenital anomalies analyzed by BAC array CGH and a novel bioinformatic strategy.ResultsAmong 54 individuals highly selected according to clinical criteria and molecular and cytogenetic data (from 2426 patients evaluated cytogenetically and molecularly between November 2007 and May 2012), chromosomal imbalances were detected in 26 individuals (48%). In two patients (4%), a previously undescribed condition was observed. The latter has been designated as meiotic (constitutional) genomic instability resulted in multiple submicroscopic rearrangements (including CNVs). Using bioinformatic strategy, we were able to identify clinically relevant CNVs in 15 individuals (28%). Selected cases were confirmed by molecular cytogenetic and molecular genetic methods. Eight out of 26 chromosomal imbalances (31%) have not been previously reported. Among them, three cases were co-occurrence of subtle chromosome 9 and 21 deletions.ConclusionsWe conducted an array CGH study of Russian patients suffering from intellectual disability, autism, epilepsy and congenital anomalies. In total, phenotypic manifestations of clinically relevant genomic variations were found to result from genomic rearrangements affecting 1247 disease-causing and pathway-involved genes. Obviously, a significantly lesser part of them are true candidates for intellectual disability, autism or epilepsy. The success of our preliminary array CGH and bioinformatic study allows us to expand the cohort. According to the available literature, this is the first comprehensive array CGH evaluation of a Russian cohort of children with neuropsychiatric disorders and congenital anomalies.

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“…We could identify 4 genes within these chromosomal segments; SPACA5 (Sperm Acrosome-Associated Protein 5), ZNF630 (zinc finger protein 630), SSX6 (synovial sarcoma, X breakpoint 6), and PCDH11X (protocadherin 11 X-linked). In a comparative genomic hybridization (CGH) array analysis a duplication of SPACA5 (and ZNF81/ZNF182 ) has been described in a boy with developmental delay, autistic features, and growth and speech delay [ 44 ]. SSX6 belongs to the SSX gene family, whereas SSX1 , 2 and 4 have found to be involved in synovial sarcomas, SSX6 is expressed in melanoma cell lines [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Novel Loci for Non-Syndromic Coarctation of the Aorta in Sporadic and Familial Cases

et al. 2015

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BackroundCoarctation of the aorta (CoA) accounts for 5-8% of all congenital heart defects. CoA can be detected in up to 20% of patients with Ullrich-Turner syndrome (UTS), in which a part or all of one of the X chromosomes is absent. The etiology of non-syndromic CoA is poorly understood. In the present work, we test the hypothesis that rare copy number variation (CNV) especially on the gonosomes, contribute to the etiology of non-syndromic CoA.MethodsWe performed high-resolution genome-wide CNV analysis using the Affymetrix SNP 6.0 microarray platform for 70 individuals with sporadic CoA, 3 families with inherited CoA (n=13) and 605 controls. Our analysis comprised genome wide association, CNV burden and linkage. CNV was validated by multiplex ligation-dependent probe amplification.ResultsWe identified a significant abundance of large (>100 kb) CNVs on the X chromosome in males with CoA (p=0.005). 11 out of 51 (~ 22%) male cases had these large CNVs. Association analysis in the sporadic cohort revealed 14 novel loci for CoA. The locus on 21q22.3 in the sporadic CoA cohort overlapped with a gene locus identified in all familial cases of CoA (candidate gene TRPM2). We identified one CNV locus within a locus with high multipoint LOD score from a linkage analysis of the familial cases (SEPT9); another locus overlapped with a region implicated in Kabuki syndrome. In the familial cases, we identified a total of 7 CNV loci that were exclusively present in cases but not in unaffected family members.ConclusionOf all candidate loci identified, the TRPM2 locus was the most frequently implicated autosomal locus in sporadic and familial cases. However, the abundance of large CNVs on the X chromosome of affected males suggests that gonosomal aberrations are not only responsible for syndromic CoA but also involved in the development of sporadic and non-syndromic CoA and their male dominance.

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335.4kb microduplication in chromosome band Xp11.2p11.3 associated with developmental delay, growth retardation, autistic disorder and dysmorphic features

Cited by 14 publications

References 20 publications

Whole-genome sequencing in a family with twin boys with autism and intellectual disability suggests multimodal polygenic risk

Whole-genome sequencing in a family with twin boys with autism and intellectual disability suggests multimodal polygenic risk

Molecular karyotyping by array CGH in a Russian cohort of children with intellectual disability, autism, epilepsy and congenital anomalies

Novel Loci for Non-Syndromic Coarctation of the Aorta in Sporadic and Familial Cases

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