Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome

Żemojtel, Tomasz; Köhler, Sebastian; Mackenroth, Luisa; Jäger, Marten; Hecht, Jochen; Krawitz, Peter; Graul‐Neumann, Luitgard; Doelken, Sandra C.; Ehmke, Nadja; Spielmann, Malte; Øien, Nancy Christine; Schweiger, Michal R.; Krüger, Ulrike; Frommer, Götz; Fischer, Björn; Kornak, Uwe; Flöttmann, Ricarda; Ardeshirdavani, Amin; Moreau, Yves; Lewis, Suzanna; Haendel, Melissa; Smedley, Damian; Horn, Denise; Mundlos, Stefan; Robinson, Peter N.

doi:10.1126/scitranslmed.3009262

Cited by 233 publications

(244 citation statements)

References 69 publications

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“…Subsequently, the analysis was extended to include those genes listed in the HPO database associated with optic atrophy (primarily syndromic) and again the results were negative. Therefore, the whole exome was subsequently analyzed using the phenotype-driven strategy for exome prioritization of human Mendelian disease genes (15,16). Notably, a heterozygous p.R468C (c.1402C>T) mutation was identified in exon 11 of the AFG3L2 gene.…”

Section: Discussionmentioning

confidence: 99%

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Colavito¹,

Maritan²,

Suppiej³

et al. 2017

Biomedical Reports

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Abstract.Autosomal dominant optic atrophy (DOA) is the most frequent form of hereditary optic atrophy, a disease presenting with considerable inter-and intra-familial clinical variability. Although a number of mutations in different genes are now known to cause DOA, many cases remain undiagnosed. In an attempt to identify the underlying genetic defect, whole exome sequencing was performed in a 19-year-old male that had been affected by isolated DOA since childhood. The exome sequencing revealed a pathogenic mutation (p.R468C, c.1402C>T) in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene, a gene known to be associated with spinocerebellar ataxia. The patient did not show any signs other than DOA. Thus, the result demonstrates the possibility that mutations in the AFG3L2 gene may be a cause of isolated autosomal DOA. IntroductionAutosomal dominant optic atrophy (DOA) is a disorder that results from the degeneration of the optic nerve fibers (1). It is one of the most prevalent forms of inherited optic neuropathies, which are genetic conditions affecting the retinal ganglion cells whose axons constitute the optic nerve (2). DOA is an important cause of inherited visual failure and occurs equally among males and females (1). Its prevalence is estimated to be 1 per 30,000 worldwide with higher frequencies in Denmark (1 per 10,000) due to a founder effect (3). It is generally diagnosed during childhood and is characterized by loss of visual acuity, dyschromatopsia, visual field defects and optic nerve pallor with optic disc excavation (4).The majority of DOA cases (80%) are isolated (non-syndromic) while the remaining (20%) are syndromic (2). DOA that presents clinically as an isolated optic neuropathy is caused by mutations in OPA1, mitochondrial dynamin like GTPase (OPA1) (4), OPA3, outer mitochondrial membrane lipid metabolism regulator (OPA3; also associated with cataracts) (5), aconitase 2 (ACO2) (6) and transmembrane protein 126A (TMEM126A) (7) genes, while syndromic DOA forms show greater genetic heterogeneity (8). To date, 224 genes associated with optic atrophy are listed in the Human Phenotype Ontology (HPO) database, the majority presenting with neurological symptoms, such as ataxia, mental retardation and spastic paraplegia (9). Increasing evidence also indicates that other genes, in addition to yet unidentified genes, are involved (10). Yet, despite these advancements, more than half of DOA patients still await a genetic diagnosis (11). This shortcoming may be overcome using whole exome sequencing, which has the potential to define the molecular diagnosis of patients presenting with a negative result for mutations in the OPA1, OPA3, ACO2 and TMEM126A genes.In the current study, the exome of an Italian patient affected by isolated DOA was analyzed. By combining exome sequencing with phenotype-driven variant analysis, a heterozygous mutation was identified in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene. Notably, the p.R468C (c.1402C>T) mutation was recently described in a family ex...

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Section: Discussionmentioning

confidence: 99%

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Colavito¹,

Maritan²,

Suppiej³

et al. 2017

Biomedical Reports

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“…[1][2][3][4] These developments have been paired with discussions surrounding the ethics and protocols for reporting incidental findings and unclassified variants (UV). [5][6][7][8][9][10][11] To further develop these concepts the Genetic Services Quality Committee of the European Society of Human Genetics (ESHG) hosted a meeting with invited participants representing laboratory specialists, clinical geneticists, lawyers, ethicists, patient groups and bioinformaticians on June 11th 2013 in Paris.…”

Section: Linical Next Generation Sequencing (Ngs) Is Being Implementedmentioning

confidence: 99%

Towards a European consensus for reporting incidental findings during clinical NGS testing

et al. 2015

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“…48 These discoveries are critically dependent on new statistical methods that exploit the power of HPO-based patient coding together with genotypes obtained by sequencing. 84,106,107 To discover which genes are pertinent to the remaining IPDs, screening of large case collections will be essential. The small number of reported independent cases in the majority of IPDs and the lack of discovery in SPD to date indicate that extremely large collections are needed to bring together adequate numbers of unrelated index cases with a shared genetic basis.…”

Section: Human Phenotype Ontologymentioning

confidence: 99%

Inherited platelet disorders: toward DNA-based diagnosis

Lentaigne

Freson

Laffan

et al. 2016

Blood

118

100

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Variations in platelet number, volume, and function are largely genetically controlled, and many loci associated with platelet traits have been identified by genome-wide association studies (GWASs).1 The genome also contains a large number of rare variants, of which a tiny fraction underlies the inherited diseases of humans. Research over the last 3 decades has led to the discovery of 51 genes harboring variants responsible for inherited platelet disorders (IPDs). However, the majority of patients with an IPD still do not receive a molecular diagnosis. Alongside the scientific interest, molecular or genetic diagnosis is important for patients. There is increasing recognition that a number of IPDs are associated with severe pathologies, including an increased risk of malignancy, and a definitive diagnosis can inform prognosis and care. In this review, we give an overview of these disorders grouped according to their effect on platelet biology and their clinical characteristics. We also discuss the challenge of identifying candidate genes and causal variants therein, how IPDs have been historically diagnosed, and how this is changing with the introduction of high-throughput sequencing. Finally, we describe how integration of large genomic, epigenomic, and phenotypic datasets, including whole genome sequencing data, GWASs, epigenomic profiling, protein–protein interaction networks, and standardized clinical phenotype coding, will drive the discovery of novel mechanisms of disease in the near future to improve patient diagnosis and management.

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Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome

Cited by 233 publications

References 69 publications

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Towards a European consensus for reporting incidental findings during clinical NGS testing

Inherited platelet disorders: toward DNA-based diagnosis

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