Spectrum of X-linked intellectual disabilities and psychiatric symptoms in a family harbouring a Xp22.12 microduplication encompassing the RPS6KA3 gene

Uliana, Vera; Bonatti, Francesco; Zanatta, Valentina; Mozzoni, Paola; Martorana, Davide

doi:10.1007/s12041-019-1055-8

Cited by 5 publications

(4 citation statements)

References 34 publications

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“…The aberrant region of the X chromosome identified in patient 2 includes many genes linked to neurodevelopmental disorders, such as CDKL5 (the gene responsible for early infantile epileptic encephalopathy [MIM# 300672]) and RPS6KA3 (the gene related to X‐linked intellectual disability [MIM# 300844] and Coffin–Lowry syndrome [MIM# 303600]). As there are similar cases of duplications in this region in association with intellectual disability (Bertini et al, 2015; Lintas et al, 2016; Matsumoto et al, 2013; Sismani et al, 2011; Szafranski et al, 2015; Tejada et al, 2011; Tzschach et al, 2008; Uliana et al, 2019), the copy number gain could be associated with the clinical features observed in patient 2. However, no definite gene related to neurodevelopmental disorders was detected in the aberrant region of chromosome 1 identified in patient 1.…”

Section: Discussionmentioning

confidence: 80%

Breakpoint junction analysis for complex genomic rearrangements with the caldera volcano‐like pattern

et al. 2020

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Chromosomal triplications can be classified into recurrent and nonrecurrent triplications. Most of the nonrecurrent triplications are embedded in duplicated segments, and duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) has been established as one of the mechanisms of triplication. This study aimed to reveal the underlying mechanism of the TRP-DUP-TRP pattern of chromosomal aberrations, in which the appearance of moving averages obtained through array-based comparative genomic hybridization analysis is similar to the shadows of the caldera volcano-like pattern, which were first identified in two patients with neurodevelopmental disabilities. For this purpose, whole-genome sequencing using long-read Nanopore sequencing was carried out to confirm breakpoint junctions. Custom array analysis and Sanger sequencing were also used to detect all breakpoint junctions. As a result, the TRP-DUP-TRP pattern consisted of only two patterns of breakpoint junctions in both patients. In patient 1, microhomologies were identified in breakpoint junctions. In patient 2, more complex architectures with insertional segments were identified. Thus, replication-based mechanisms were considered as a mechanism of the TRP-DUP-TRP pattern.

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Section: Discussionmentioning

confidence: 80%

Breakpoint junction analysis for complex genomic rearrangements with the caldera volcano‐like pattern

et al. 2020

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“…In line with other well-established findings-including that of chromosomal region 22q11.2, which is well acknowledged to result in DiGeorge heart failure syndrome when deleted, but results in a variable neurodevelopmental disorder with no cardiological problems when duplicated-a similar hypothesis may be instigated. Loss of function variants in SH3KBP1 are most commonly detected in patients with IMD61, but findings on two families with intellectual disability and large duplications encompassing SH3KBP1, EIF1AX, and RPS6KA3 genes indicate a possible role for SH3KBP1 in addition to that of RPS6KA3 [44,45]. Limited data hinder further explanation on how phenotypic findings may be attributed to duplications which call for additional assessments and studies [42].…”

Section: Discussionmentioning

confidence: 99%

Germline CNV Detection through Whole-Exome Sequencing (WES) Data Analysis Enhances Resolution of Rare Genetic Diseases

Tilemis

Marinakis

Veltra

et al. 2023

Genes

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Whole-Exome Sequencing (WES) has proven valuable in the characterization of underlying genetic defects in most rare diseases (RDs). Copy Number Variants (CNVs) were initially thought to escape detection. Recent technological advances enabled CNV calling from WES data with the use of accurate and highly sensitive bioinformatic tools. Amongst 920 patients referred for WES, 454 unresolved cases were further analysed using the ExomeDepth algorithm. CNVs were called, evaluated and categorized according to ACMG/ClinGen recommendations. Causative CNVs were identified in 40 patients, increasing the diagnostic yield of WES from 50.7% (466/920) to 55% (506/920). Twenty-two CNVs were available for validation and were all confirmed; of these, five were novel. Implementation of the ExomeDepth tool promoted effective identification of phenotype-relevant and/or novel CNVs. Among the advantages of calling CNVs from WES data, characterization of complex genotypes comprising both CNVs and SNVs minimizes cost and time to final diagnosis, while allowing differentiation between true or false homozygosity, as well as compound heterozygosity of variants in AR genes. The use of a specific algorithm for calling CNVs from WES data enables ancillary detection of different types of causative genetic variants, making WES a critical first-tier diagnostic test for patients with RDs.

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“…They lack the typical craniofacial and musculoskeletal phenotype of Coffin-Lowry syndrome. 15 3.4 | GK (Xp21.1)…”

Section: Rps6ka3 (Xp213)mentioning

confidence: 99%

“…They cause a phenotype with normal growth, mild to moderate impairment of cognitive function, speech impairment, attention deficit and hyperactivity (Table 3). They lack the typical craniofacial and musculoskeletal phenotype of Coffin‐Lowry syndrome 15 …”

Section: Duplications Of Xlid Genesmentioning

confidence: 99%

Clinical findings in individuals with duplication of genes associated with X‐linked intellectual disability

Sahajpal,

Ziats,

Chaubey

et al. 2023

Clinical Genetics

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Duplication of all genes associated with X‐linked intellectual disability (XLID) have been reported but the majority of the duplications include more than one XLID gene. It is exceptional for whole XLID gene duplications to cause the same phenotype as sequence variants or deletions of the same gene. Duplication of PLP1, the gene associated with Pelizaeus‐Merzbacher syndrome, is the most notable duplication of this type. More commonly, duplication of XLID genes results in very different phenotypes than sequence alterations or deletions. Duplication of MECP2 is widely recognized as a duplication of this type, but a number of others exist. The phenotypes associated with gene duplications are often milder than those caused by deletions and sequence variants. Among some duplications that are clinically significant, marked skewing of X‐inactivation in female carriers has been observed. This report describes the phenotypic consequences of duplication of 22 individual XLID genes, of which 10 are described for the first time.

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Spectrum of X-linked intellectual disabilities and psychiatric symptoms in a family harbouring a Xp22.12 microduplication encompassing the RPS6KA3 gene

Cited by 5 publications

References 34 publications

Breakpoint junction analysis for complex genomic rearrangements with the caldera volcano‐like pattern

Breakpoint junction analysis for complex genomic rearrangements with the caldera volcano‐like pattern

Germline CNV Detection through Whole-Exome Sequencing (WES) Data Analysis Enhances Resolution of Rare Genetic Diseases

Clinical findings in individuals with duplication of genes associated with X‐linked intellectual disability

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