Translational Diagnostics

Pijuan, Jordi; Rodríguez-Sanz, María; Benito, Daniel Natera-de; Ortez, C.; Altimir, Arola; Osuna-López, Mireia; Roura, M.; Ugalde, Maddi; Vondel, Liedewei Van de; Reina-Castillón, Judith; Fons, Carme; Benítez, Raúl; Nascimento, A.; Hoenicka, Janet; Palau, Francesc

doi:10.1016/j.jmoldx.2020.10.006

Cited by 10 publications

(8 citation statements)

References 48 publications

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“…Our group has been an early adopter of ES in the outpatient setting, and since there are only a few studies that capture all the processes involved in the clinical implementation of NGS, we describe our program in the context of the extant literature. These literature reports can be categorized into two types: standard clinical programs (relying on clinical ES and standard practice processes) and hybrid programs (combining research ES with standard practice processes) 7–13 …”

Section: Introductionmentioning

confidence: 99%

“…In these practice settings, time‐ and resource‐intensive research activities, such as extensive personnel effort, are mostly not feasible 11,14 . Patient selection was broad, mirroring professional guidelines by the American College of Medical Genetics and Genomics (ACMG), 16 criteria that are less stringent than in hybrid programs 10,12,13 . Patient selection can influence diagnosis rates of the four clinical programs that we reviewed, one had a low threshold for utilizing ES, with a lower diagnosis rate of 25%, 3 with others that specified inclusion criteria or utilized multi‐disciplinary review boards having higher diagnosis rates of 31%–43% 8,11,14 .…”

Section: Introductionmentioning

confidence: 99%

“…standard practice processes) and hybrid programs (combining research ES with standard practice processes). [7][8][9][10][11][12][13] We reviewed four reports that outlined standard procedures for ES. 3,8,11,14,15 In these practice settings, time-and resource-intensive research activities, such as extensive personnel effort, are mostly not feasible.…”

mentioning

confidence: 99%

“…11,14 Patient selection was broad, mirroring professional guidelines by the American College of Medical Genetics and Genomics (ACMG), 16 criteria that are less stringent than in hybrid programs. 10,12,13 Patient selection can influence diagnosis rates of the four clinical programs that we reviewed, one had a low threshold for utilizing ES, with a lower diagnosis rate of 25%, 3 with others that specified inclusion criteria or utilized multi-disciplinary review boards having higher diagnosis rates of 31%-43%. 8,11,14 Substantiating this, a recent systematic review of clinical ES noted that when patients were highly selected for specific cohorts, diagnostic yield was higher (28% to 48%) than reported in standard practice (6%-24%).…”

mentioning

confidence: 99%

“…17 We reviewed four hybrid programs that published their research and clinical processes. These processes included: (a) preselecting patients with specific criteria (2/4 programs 10,13 ), (b) utilizing a multidisciplinary team of clinicians, laboratory personnel, and researchers to determine patient selection (1/4 13 ) and to review results (3/4 12,13,18 ), (c) utilizing varying bioinformatics approaches, with two programs using commercial ES with research analysis only if the commercial ES was non-diagnostic, 10,12 and two program pursuing ES analysis solely through a research pipeline. 13,18 One program also reanalyzed ES data from outside studies, 18 (d) pursuit of additional processes for diagnostic resolution: "dry laboratory" activities included case matching (two programs 12,18 ) and three programs pursuing extensive variant curation; "wet laboratory" activities included other OMICs, and functional assays.…”

mentioning

confidence: 99%

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The best of both worlds: Blending cutting‐edge research with clinical processes for a productive exome clinic

Sullivan,

Spillmann,

Schoch

et al. 2023

Clinical Genetics

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Genomic medicine has been transformed by next‐generation sequencing (NGS), inclusive of exome sequencing (ES) and genome sequencing (GS). Currently, ES is offered widely in clinical settings, with a less prevalent alternative model consisting of hybrid programs that incorporate research ES along with clinical patient workflows. We were among the earliest to implement a hybrid ES clinic, have provided diagnoses to 45% of probands, and have identified several novel candidate genes. Our program is enabled by a cost‐effective investment by the health system and is unique in encompassing all the processes that have been variably included in other hybrid/clinical programs. These include careful patient selection, utilization of a phenotype‐agnostic bioinformatics pipeline followed by manual curation of variants and phenotype integration by clinicians, close collaborations between the clinicians and the bioinformatician, pursuit of interesting variants, communication of results to patients in categories that are predicated upon the certainty of a diagnosis, and tracking changes in results over time and the underlying mechanisms for such changes. Due to its effectiveness, scalability to GS and its resource efficiency, specific elements of our paradigm can be incorporated into existing clinical settings, or the entire hybrid model can be implemented within health systems that have genomic medicine programs, to provide NGS in a scientifically rigorous, yet pragmatic setting.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The best of both worlds: Blending cutting‐edge research with clinical processes for a productive exome clinic

Sullivan,

Spillmann,

Schoch

et al. 2023

Clinical Genetics

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PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder

et al. 2021

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Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype–phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy‐number variant and whole‐exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine‐rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. Lay Summary Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD.

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CRISPR/Cas9‐based functional genomics strategy to decipher the pathogenicity of genetic variants in inherited metabolic disorders

Muñoz‐Pujol,

Ugarteburu,

Segur‐Bailach

et al. 2023

J of Inher Metab Disea

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BackgroundThe determination of the functional impact of variants of uncertain significance (VUS) is one of the major bottlenecks in the diagnostic workflow of inherited genetic diseases. To face this problem, we set up a CRISPR/Cas9‐based strategy for knock‐in cellular model generation, focusing on inherited metabolic disorders (IMDs).MethodsWe selected variants in seven IMD‐associated genes, including seven reported disease‐casing variants and four benign/likely variants. Overall, 11 knock‐in cell models were generated via homology‐directed repair in HAP1 haploid cells using CRISPR/Cas9. The functional impact of the variants was determined by analyzing the characteristic biochemical alterations of each disorder.ResultsFunctional studies performed in knock‐in cell models showed that our approach accurately distinguished the functional effect of pathogenic from non‐pathogenic variants in a reliable manner in a wide range of IMDs.ConclusionOur study provides a generic approach to assess the functional impact of genetic variants to improve IMD diagnosis and this tool could emerge as a promising alternative to invasive tests, such as muscular or skin biopsies. Although the study has been performed only in IMDs, this strategy is generic and could be applied to other genetic disorders.This article is protected by copyright. All rights reserved.

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Translational Diagnostics

Cited by 10 publications

References 48 publications

The best of both worlds: Blending cutting‐edge research with clinical processes for a productive exome clinic

The best of both worlds: Blending cutting‐edge research with clinical processes for a productive exome clinic

PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder

CRISPR/Cas9‐based functional genomics strategy to decipher the pathogenicity of genetic variants in inherited metabolic disorders

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