A homozygous truncating variant in <i>CCDC186</i> in an individual with epileptic encephalopathy

Brugger, Melanie; Becker-Dettling, Fiona; Brunet, Theresa; Strom, Tim M.; Meitinger, Thomas; Lurz, Eberhard; Borggraefe, Ingo; Wagner, Matias

doi:10.1002/acn3.51260

Cited by 7 publications

(9 citation statements)

References 28 publications

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“…Fifteen genes have subsequently reached DGG status. We brie y describe a few exemplary cases below, most of which have already been published in detail elsewhere [43][44][45][46][47][48][49][50][51][52] , and provide a comprehensive list of all patients in the Supplemental Material. In SMARCA5, a gene coding for a chromatin remodeler, we identi ed de novo variants in two patients with neurodevelopmental delay and similar dysmorphic features.…”

Section: Resultsmentioning

confidence: 99%

A national diagnostic framework for patients with ultra-rare disorders: molecular genetic findings using phenotypic and sequencing data

Krawitz

2022

Preprint

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Most individuals with rare diseases first contact primary care physicians. Although efficient diagnostic routines exist for a subset of rare diseases, ultra-rare entities often require expert clinical knowledge or comprehensive genetic diagnostics, which poses structural challenges to public healthcare systems. To address these challenges, a novel structured diagnostic concept based on the presence of multidisciplinary expertise at centers for rare diseases (CRDs) that have been established at German university hospitals in recent years, was evaluated in a prospective study (TRANSLATE-NAMSE). Between January 2018 and December 2020, 5652 patients were enrolled in the study and were comprehensively assessed by multidisciplinary teams (MDTs) at ten CRDs. Exome sequencing (ES) was initiated for 268 adult and 1309 pediatric patients and partially complemented by additional molecular tests. Conclusive diagnoses were established in 494 individuals, covering 400 diagnostic-grade genes, suggesting ultra-rare disorders were enriched in this cohort. In addition, we describe 56 novel gene-phenotype associations, mainly in individuals with neurodevelopmental delay. A subcohort of 211 individuals was analyzed with the artificial intelligence–based PEDIA protocol, which integrates next-generation phenotyping on medical imaging and sequencing data. With the entire cohort data, we developed a tool to predict the diagnostic yield from the clinical features of a patient if advanced molecular testing strategies are applied.

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Section: Resultsmentioning

confidence: 99%

A national diagnostic framework for patients with ultra-rare disorders: molecular genetic findings using phenotypic and sequencing data

Krawitz

2022

Preprint

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“…CCDC186 encodes a coiled-coil domain-containing protein that is involved in the maturation of dense-core vesicles (DCVs) at the trans-Golgi network in neurons and endocrine cells [3][4][5]8]. To date, variants in CCDC186 have only been reported in two unrelated individuals presenting with failure to thrive, visual impairment, neurodevelopmental delay, hypotonia, and brain atrophy [14,15]. The patient reported by Brugger et al [15] was clinically characterized in detail, whereas the other one was reported within a large cohort study, and the main phenotypic traits were only summarized in a table format [14].…”

Section: Discussionmentioning

confidence: 99%

“…To date, variants in CCDC186 have only been reported in two unrelated individuals presenting with failure to thrive, visual impairment, neurodevelopmental delay, hypotonia, and brain atrophy [14,15]. The patient reported by Brugger et al [15] was clinically characterized in detail, whereas the other one was reported within a large cohort study, and the main phenotypic traits were only summarized in a table format [14]. Regardless of these descriptions, the association of CCDC186 mutations with this pathologic condition has not been fully established, as functional studies have not been performed in any of the two individuals reported so far.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, two patients with mutations in VPS50 with neurodevelopmental disorder and neonatal cholestasis have also been described [13]. To date, CCDC186 disease-associated variants have only been reported in one patient within a large sequencing study of 1000 cases from Saudi Arabia [14] and in a single patient presenting developmental delay, refractory epilepsy, and failure to thrive [15]. However, the association of CCDC186 deficiency with the clinical phenotype still remains unclear because of the lack of evidence about the impact of the identified variants on protein function, as well as the lack of additional clinically compatible patients that provide a comprehensive description of this new disease.…”

Section: Introductionmentioning

confidence: 99%

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Functional Evidence of CCDC186 as a New Disease-Associated Gene with Endocrine and Central Nervous System Alterations

Arrabal,

Muñoz-Pujol,

Medina Martínez

et al. 2023

IJMS

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CCDC186 protein is involved in the maturation of dense-core vesicles (DCVs) in the trans-Golgi network in neurons and endocrine cells. Mutations in genes involved in DCV regulation, other than CCDC186, have been described in patients with neurodevelopmental disorders. To date, only one patient, within a large sequencing study of 1000 cases, and a single case report with variants in CCDC186, had previously been described. However, no functional studies in any of these two cases had been performed. We identified three patients from two gypsy families, unrelated to each other, with mutations in the CCDC186 gene. Clinically, all patients presented with seizures, frontotemporal atrophy, hypomyelination, recurrent infections, and endocrine disturbances such as severe non-ketotic hypoglycemia. Low levels of cortisol, insulin, or growth hormone could only be verified in one patient. All of them had a neonatal onset and died between 7 months and 4 years of age. Whole exome sequencing identified a homozygous variant in the CCDC186 gene (c.2215C>T, p.Arg739Ter) in the index patients of both families. Protein expression studies demonstrated that CCDC186 was almost undetectable in fibroblasts and muscle tissue. These observations correlated with the transcriptomic analysis performed in fibroblasts in one of the patients, which showed a significant reduction of CCDC186 mRNA levels. Our study provides functional evidence that mutations in this gene have a pathogenic effect on the protein and reinforces CCDC186 as a new disease-associated gene. In addition, mutations in CCDC186 could explain the combined endocrine and neurologic alterations detected in our patients.

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“…A total of 17 candidate genes with high evidence are currently undergoing further investigation, mostly within the framework of international projects. A total of 17 genes (12 associated with autosomal dominant inheritance, 5 with autosomal recessive inheritance) have subsequently acquired DGG status through international cooperation [20][21][22][23][24][25][26][27][28][29][30][31][32] . In comparison with pathogenic variants in previously known disease-associated genes, the present candidate gene set showed a higher proportion of missense variants.…”

Section: Novel Diagnostic-grade Genes (Dgg) and Candidatesmentioning

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

Self Cite

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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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A homozygous truncating variant in CCDC186 in an individual with epileptic encephalopathy

Cited by 7 publications

References 28 publications

A national diagnostic framework for patients with ultra-rare disorders: molecular genetic findings using phenotypic and sequencing data

A national diagnostic framework for patients with ultra-rare disorders: molecular genetic findings using phenotypic and sequencing data

Functional Evidence of CCDC186 as a New Disease-Associated Gene with Endocrine and Central Nervous System Alterations

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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