AutoCaSc: Prioritizing candidate genes for neurodevelopmental disorders

Lieberwirth, Johann; Büttner, Benjamin; Klöckner, Chiara; Platzer, Konrad; Popp, Bernt; Jamra, Rami Abou

doi:10.1002/humu.24451

Cited by 7 publications

(3 citation statements)

References 51 publications

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“…Recently, a patient with a NRXN3 missense variant of uncertain significance (p.Arg39Cys) and a neurodevelopmental disorder was described [ 65 ]. Additionally, a microdeletion of 7177 base pairs (79176037–79183213) affecting NRXN3 was detected in four patients; two of them were sisters in a Saudi epilepsy cohort [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Case Report—An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions

Feichtinger

Preisel

Brugger

et al. 2023

Genes

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Background: Heterozygous, large-scale deletions at 14q24.3-31.1 affecting the neurexin-3 gene have been associated with neurodevelopmental disorders such as autism. Both “de novo” occurrences and inheritance from a healthy parent suggest incomplete penetrance and expressivity, especially in autism spectrum disorder. NRXN3 encodes neurexin-3, a neuronal cell surface protein involved in cell recognition and adhesion, as well as mediating intracellular signaling. NRXN3 is expressed in two distinct isoforms (alpha and beta) generated by alternative promoters and splicing. MM/Results: Using exome sequencing, we identified a monoallelic frameshift variant c.159_160del (p.Gln54AlafsTer50) in the NRXN3 beta isoform (NM_001272020.2) in a 5-year-old girl with developmental delay, autism spectrum disorder, and behavioral issues. This variant was inherited from her mother, who did not have any medical complaints. Discussion: This is the first detailed report of a loss-of-function variant in NRXN3 causing an identical phenotype, as reported for heterozygous large-scale deletions in the same genomic region, thereby confirming NRXN3 as a novel gene for neurodevelopmental disorders with autism.

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Section: Discussionmentioning

confidence: 99%

Case Report—An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions

Feichtinger

Preisel

Brugger

et al. 2023

Genes

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“…These genes differ from ‘candidate genes’, which are only reported in large screening cohorts. If a gene could not be reliably associated with an NDD phenotype, we used an in-house tool to score NDD candidate variants (AutoCaSc 15 ; https://autocasc.uni-leipzig.de/).…”

Section: Methodsmentioning

confidence: 99%

Re-evaluation and Re-analysis of 152 research exomes five years after the initial report reveals clinically relevant changes in 20%

Bartolomaeus

Hentschel

Jamra

et al. 2022

Preprint

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Iterative re-analysis of NGS results is not well investigated for published research cohorts of rare diseases. We revisited a cohort of 152 consanguineous families with developmental disorders (NDD) reported five years ago. We re-evaluated all reported variants according to diagnostic classification guidelines or our candidate gene scoring system (AutoCaSc) and systematically scored the validity of gene-disease associations. Sequencing data was re-processed using an up-to-date pipeline for case-level re-analysis. In 30/152 (20%) families, we identified a clinically relevant change. Thirteen previously reported (likely) pathogenic variants were re-classified as VUS/benign. In three cases, the gene-disease association (TSEN15, NAPB, and FAR1) validity was judged as limited. We identified 12 new disease causing variants. Two previously reported variants were missed by our updated pipeline due to alignment or reference issues. Our results support the need to re-evaluate screening studies, not only the negative cases but including supposedly solved ones. This also applies in a diagnostic setting. We highlight that the complexity of computational re-analysis for old data should be weighed against the decreasing re-testing costs. Since extensive re-analysis per case is beyond the resources of most institutions, we recommend a screening procedure that would quickly identify the majority (83%) of new variants.

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“…78,79 Variants with a high likelihood of being disease-causing, e.g., those with loss of function or high pathogenicity scores, or those that had arisen de novo, were shared through MME in order to identify similar patients. 80,81 Statistical Analyses All statistical analyses were conducted in R (version 4.1.2). 82 Proportions were tested using a two-sided Fisher's exact test.…”

Section: Es Data-processing Pipelinementioning

confidence: 99%

Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings

Schmidt

Danyel

Grundmann

et al. 2023

Preprint

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Most individuals with rare diseases initially consult their primary care physician. For a subset of rare diseases, efficient diagnostic pathways are available. However, ultra-rare diseases often require both expert clinical knowledge and comprehensive genetic diagnostics, which poses structural challenges for public healthcare systems. To address these challenges within Germany, a novel structured diagnostic concept, based on multidisciplinary expertise at established university hospital centers for rare diseases (CRDs), was evaluated in the three year prospective study TRANSLATE NAMSE. A key goal of TRANSLATE NAMSE was to assess the clinical value of exome sequencing (ES) in the ultra-rare disease population. The aims of the present study were to perform a systematic investigation of the phenotypic and molecular genetic data of TRANSLATE NAMSE patients who had undergone ES in order to determine the yield of both ultra-rare diagnoses and novel gene-disease associations; and determine whether the complementary use of machine learning and artificial intelligence (AI) tools improved diagnostic effectiveness and efficiency. ES was performed for 1,577 patients (268 adult and 1,309 pediatric). Molecular genetic diagnoses were established in 499 patients (74 adult and 425 pediatric). A total of 370 distinct molecular genetic causes were established. The majority of these concerned known disorders, most of which were ultra-rare. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were delineated, mainly in individuals with neurodevelopmental disorders. To determine the likelihood that ES will lead to a molecular diagnosis in a given patient, based on the respective clinical features only, we developed a statistical framework called YieldPred. The genetic data of a subcohort of 224 individuals that also gave consent to the computer-assisted analysis of their facial images were processed with the AI tool Prioritization of Exome Data by Image Analysis (PEDIA) and showed superior performance in variant prioritization. The present analyses demonstrated that the novel structured diagnostic concept facilitated the identification of ultra-rare genetic disorders and novel gene-disease associations on a national level and that the machine learning and AI tools improved diagnostic effectiveness and efficiency for ultra-rare genetic disorders.

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AutoCaSc: Prioritizing candidate genes for neurodevelopmental disorders

Cited by 7 publications

References 51 publications

Case Report—An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions

Case Report—An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions

Re-evaluation and Re-analysis of 152 research exomes five years after the initial report reveals clinically relevant changes in 20%

Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings

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