Novel Compound Heterozygous Mutation in TRAPPC9 Gene: The Relevance of Whole Genome Sequencing

Álvarez-Mora, María Isabel; Corominas, Jordi; Gilissen, Christian; Sánchez, Aurora; Madrigal, Irene; Rodríguez‐Revenga, Laia

doi:10.3390/genes12040557

Cited by 18 publications

(14 citation statements)

References 30 publications

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“…In our cohort, WGS was applied to 12 out of the 57 patients which remain undiagnosed, identifying only causative variants in 1 of the patients (Table 1 ). This patient (patient 31) was found to carry a missense variant and an intragenic deletion of 90 Kb, not detected neither by CMA nor WES [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic yield of next-generation sequencing in 87 families with neurodevelopmental disorders

Álvarez-Mora

Sánchez

Rodríguez‐Revenga

et al. 2022

Orphanet J Rare Dis

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Background Neurodevelopmental disorders (NDDs) are a group of heterogeneous conditions, which include mainly intellectual disability, developmental delay (DD) and autism spectrum disorder (ASD), among others. These diseases are highly heterogeneous and both genetic and environmental factors play an important role in many of them. The introduction of next generation sequencing (NGS) has lead to the detection of genetic variants in several genetic diseases. The main aim of this report is to discuss the impact and advantages of the implementation of NGS in the diagnosis of NDDs. Herein, we report diagnostic yields of applying whole exome sequencing in 87 families affected by NDDs and additional data of whole genome sequencing (WGS) from 12 of these families. Results The use of NGS technologies allowed identifying the causative gene alteration in approximately 36% (31/87) of the families. Among them, de novo mutation represented the most common cause of genetic alteration found in 48% (15/31) of the patients with diagnostic mutations. The majority of variants were located in known neurodevelopmental disorders genes. Nevertheless, some of the diagnoses were made after the use of GeneMatcher tools which allow the identification of additional patients carrying mutations in THOC2, SETD1B and CHD9 genes. Finally the use of WGS only allowed the identification of disease causing variants in 8% (1/12) of the patients in which previous WES failed to identify a genetic aetiology. Conclusion NGS is more powerful in identifying causative pathogenic variant than conventional algorithms based on chromosomal microarray as first-tier test. Our results reinforce the implementation of NGS as a first-test in genetic diagnosis of NDDs.

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Section: Discussionmentioning

confidence: 99%

“…Analysis of cases that underwent NGS has been previously described [10][11][12][13][14][15]. Briefly, allelic variants with MAF > 0.03 in any of the databases used (GnomAD, ExAC and 1000Genomes) and minimal coverage lower than 20% were discarded.…”

Section: Sequencing and Bioinformatics Pipelinementioning

confidence: 99%

Diagnostic yield of next-generation sequencing in 87 families with neurodevelopmental disorders

Álvarez-Mora

Sánchez

Rodríguez‐Revenga

et al. 2022

Orphanet J Rare Dis

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“…TRAPPC9 is the main component of TRAPP complex type II, also knows as TRAPII, which facilitates endoplasmic reticulum (ER)-to-Golgi vesicular transport, the transport within the Golgi, and the transport between Golgi and endosomes [19]. Biallelic loss-of-function mutations have been observed with intellectual disability, along with variable clinical co-segregation of obesity, hypoplastic corpus callosum, microcephaly, behavioral changes, and dysmorphic features [19][20][21]. The clinical features of the reported families have been summarized in Supplementary Table 2.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing of Pakistani Consanguineous Families Identified Pathogenic Variants in Genes of Intellectual Disability

Asif

Anayat

Tariq

et al. 2022

Genes

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Intellectual disability (ID) is a condition of significant limitation of cognitive functioning and adaptive behavior, with 50% of etiology attributed to genetic predisposition. We recruited two consanguineous Pakistani families manifesting severe ID and developmental delay. The probands were subjected to whole exome sequencing (WES) and variants were further prioritized based on population frequency, predicted pathogenicity and functional relevance. The WES data analysis identified homozygous pathogenic variants in genes MBOAT7 and TRAPPC9. The pathogenicity of the variants was supported by co-segregation analysis and in silico tool. The findings of this study expand mutation spectrum and provide additional evidence to the role of MBOAT7 and TRAPPC9 in causation of ID.

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“…Nowadays new technologies, such as whole exome (WES) and whole genome sequencing (WGS), have become more efficient and inexpensive such that it is ongoing a debate for choosing the proper first-tier diagnostic test ( Srivastava et al, 2019 ; Alvarez-Mora et al, 2021 ; Arteche-Lopez et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs

et al. 2021

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Neurodevelopmental disorders (NDDs) are a heterogeneous class of brain diseases, with a complex genetic basis estimated to account for up to 50% of cases. Nevertheless, genetic diagnostic yield is about 20%. Array-comparative genomic hybridization (array-CGH) is an established first-level diagnostic test able to detect pathogenic copy number variants (CNVs), however, most identified variants remain of uncertain significance (VUS). Failure of interpretation of VUSs may depend on various factors, including complexity of clinical phenotypes and inconsistency of genotype-phenotype correlations. Indeed, although most NDD-associated CNVs are de novo, transmission from unaffected parents to affected children of CNVs with high risk for NDDs has been observed. Moreover, variability of genetic components overlapped by CNVs, such as long non-coding genes, genomic regions with long-range effects, and additive effects of multiple CNVs can make CNV interpretation challenging. We report on 12 patients with complex phenotypes possibly explained by complex genetic mechanisms, including involvement of antisense genes and boundaries of topologically associating domains. Eight among the 12 patients carried two CNVs, either de novo or inherited, respectively, by each of their healthy parents, that could additively contribute to the patients’ phenotype. CNVs overlapped either known NDD-associated or novel candidate genes (PTPRD, BUD13, GLRA3, MIR4465, ABHD4, and WSCD2). Bioinformatic enrichment analyses showed that genes overlapped by the co-occurring CNVs have synergistic roles in biological processes fundamental in neurodevelopment. Double CNVs could concur in producing deleterious effects, according to a two-hit model, thus explaining the patients’ phenotypes and the incomplete penetrance, and variable expressivity, associated with the single variants. Overall, our findings could contribute to the knowledge on clinical and genetic diagnosis of complex forms of NDD.

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Novel Compound Heterozygous Mutation in TRAPPC9 Gene: The Relevance of Whole Genome Sequencing

Cited by 18 publications

References 30 publications

Diagnostic yield of next-generation sequencing in 87 families with neurodevelopmental disorders

Diagnostic yield of next-generation sequencing in 87 families with neurodevelopmental disorders

Whole-Exome Sequencing of Pakistani Consanguineous Families Identified Pathogenic Variants in Genes of Intellectual Disability

Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs

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