Scientific Publications

Novel disease gene discovered

The discovery of novel genetic disorders increasingly relies on large databases and on collaborative international efforts. CENTOGENE is proud to be part of numerous pertinent research endeavors. A recently accomplished corresponding project identified mutations in the PIGB gene as underlying a novel neuro-metabolic syndrome. The resulting study, which involved groups from ten countries, appeared in the highly prestigious American Journal of Human Genetics.

The discovery of novel genetic disorders increasingly relies on large databases and on collaborative international efforts. CENTOGENE is proud to be part of numerous pertinent research endeavors. A recently accomplished corresponding project identified mutations in the PIGB gene as underlying a novel neuro-metabolic syndrome. The resulting study, which involved groups from ten countries, appeared in the highly prestigious American Journal of Human Genetics.

Optimization of diagnostic yield

The genetic knowledge around rare hereditary diseases is rapidly increasing. Patients having received a negative diagnostic report may thus gain from a re-analysis of their exomes or genomes. A recent CENTOGENE-initiated study provided impressive evidence for this hypothesis. In a set of patients with neurodevelopmental disorders, for whom no diagnosis could be established prior to 2017, re-analysis revealed several potentially causative variants in disease genes described since. These findings were published in the June issue of Journal of Neurodevelopmental Disorders.

The genetic knowledge around rare hereditary diseases is rapidly increasing. Patients having received a negative diagnostic report may thus gain from a re-analysis of their exomes or genomes. A recent CENTOGENE-initiated study provided impressive evidence for this hypothesis. In a set of patients with neurodevelopmental disorders, for whom no diagnosis could be established prior to 2017, re-analysis revealed several potentially causative variants in disease genes described since. These findings were published in the June issue of Journal of Neurodevelopmental Disorders.

Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy

The majority of novel disease genes is currently being identified in less well-investigated consanguineous populations. Based on its corresponding global positioning, CENTOGENE has been able to contribute significantly to such research projects. The most recent example is the discovery of recessive mutations in the transcription factor PAX7 to underlie a new form of muscle disease. The findings were published in Genetics in Medicine, one of the leading journals in the field.

Disease expressivity varies widely in many genetic disorders, and identifying the underlying modifiers holds great translational potential. Based on its resources as regards technologies and samples, CENTOGENE is uniquely positioned to significantly contribute to pertinent efforts. One recent example revealed a novel modifier of disease severity and cognitive dysfunction in X-linked dystonia-parkinsonism. The results were published in the highly prestigious journal Annals of Neurology.

A homozygous frameshift variant in an alternatively spliced exon of DLG5 causes hydrocephalus and renal dysplasia

Based on the ambition to provide maximum diagnostic yield, CENTOGENE offers follow up of negative WES/WGS reports in a research setting. Recently, this approach resulted in the association of a special form of congenital hydrocephalus with bi-allelic inactivation of the DLG5 gene. The finding, which represents the definition of a novel rare disorder, was published in Clinical Genetics ahead of print on February 21st.

Utility and implications of exome sequencing in early-onset Parkinson’s disease.

Although the genetic load is high in early-onset Parkinson’s disease, thorough investigation of the genetic diagnostic yield has yet to be established. The objectives of this study were to assess variants in known genes for PD and other movement disorders and to find new candidates in 50 patients with early onset PD.

Development of an Evidence-Based Algorithm that Optimizes Sensitivity and Specificity in ES-Based Diagnostics of a Clinically Heterogeneous Patient Population

Sensitivity and specificity of NGS approaches are not well-defined, but can be estimated from applying NGS and Sanger sequencing in parallel. Utilizing this strategy, we aimed at optimizing exome sequencing (ES)-based diagnostics of a clinically diverse patient population.

Next-generation sequencing (NGS) is rapidly replacing Sanger sequencing in genetic diagnostics. Sensitivity and specificity of NGS approaches are not well-defined, but can be estimated from applying NGS and Sanger sequencing in parallel. Utilizing this strategy, we aimed at optimizing exome sequencing (ES)-based diagnostics of a clinically diverse patient population.

Evidence-Based Algorithm in ES-Based Diagnostics

Optimization of ES-based diagnostics. Next-generation sequencing (NGS) is rapidly replacing Sanger sequencing in genetic diagnostics. Sensitivity and specificity of NGS approaches are not well-defined, but can be estimated from applying NGS and Sanger sequencing in parallel.

Next-generation sequencing (NGS) is rapidly replacing Sanger sequencing in genetic diagnostics. Sensitivity and specificity of NGS approaches are not well-defined, but can be estimated from applying NGS and Sanger sequencing in parallel. Utilizing this strategy, we aimed at optimizing exome sequencing (ES)-based diagnostics of a clinically diverse patient population.

The First Missense Pathogenic Variant in the KAT6A Gene

CENTOGENE published results of another successful collaborative study in the highly ranked Journal of Human Genetics titled: “A KAT6A variant in a family with autosomal dominantly inherited microcephaly and developmental delay.”

CENTOGENE published results of another successful collaborative study in the highly ranked Journal of Human Genetics titled: “A KAT6A variant in a family with autosomal dominantly inherited microcephaly and developmental delay.”

Unmet Needs in Human Genomic Variant Interpretation

The quality and the precision of a final diagnosis do not consist solely of correct variant classification and clinical interpretation. Diagnosis begins at the preanalytical level, and all subsequent interpretation can produce either a negative or a positive effect.

The quality and the precision of a final diagnosis do not consist solely of correct variant classification and clinical interpretation. Diagnosis begins at the preanalytical level, and all subsequent interpretation can produce either a negative or a positive effect, depending on the quality of the “wet-bench” preparation.

Novel Homozygous PCK1 Mutation

A novel homozygous PCK1 mutation was detected in all in this study affected individuals. Whole exome sequencing was performed. Read more!

Clinical and laboratory data were collected from three Finnish patients including a sibling pair and another unrelated child with unexplained childhood hypoglycemia. Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis. Exome sequencing was performed for the patients and their parents. A novel homozygous PCK1 c.925GNA (p.G309R) mutation was detected in all affected individuals.

Novel GNB1 Mutations Disrupt Assembly and Function of G Protein Heterotrimers and Cause Global Developmental Delay in Humans

Using exome sequencing, we identified 14 different novel variants in GNB1 in 16 pediatric patients. Read more in our latest scientific articles!

Global developmental delay (GDD), often accompanied by intellectual disability, seizures and other features is a severe, clinically and genetically highly heterogeneous childhood-onset disorder. In cases where genetic causes have been identified, de-novo mutations in neuronally expressed genes are a common scenario. These mutations can be best identified by exome sequencing of parent-offspring trios. De novo mutations in the guanine nucleotide-binding protein, beta 1 (GNB1) gene, encoding the Gβ1 subunit of heterotrimeric G proteins, have recently been identified as a novel genetic cause of GDD.

Clinical Exome Sequencing – Results from 2819 Samples Reflecting 1000 Families

A study was conducted using WES to identify underlying pathogenic variants, or likely pathogenic variants, in 1,000 diagnostic cases from 54 different countries. Read more!

A study was conducted using whole exome sequencing (WES) to identify underlying pathogenic variants, or likely pathogenic variants, in 1,000 diagnostic cases from 54 different countries. Patients selected displayed a wide variety in the number, nature and severity of symptoms. Clinical information given by the requesting physicians was translated to HPO terms and WES was performed on patient samples according to standardized settings.

Guidelines for Diagnostic Next-Generation Sequencing

Here we present guidelines for the evaluation and validation of next-generation sequencing applications for the diagnosis of genetic disorders. Read more!

The work was performed by a group of laboratory geneticists and bioinformaticians, and discussed with clinical geneticists, industry and patients’ representatives, and other stakeholders in the field of human genetics. The statements that were written during the elaboration of the guidelines are presented here.

Novel GNB1 Missense Mutation in a Patient with Generalized Dystonia, Hypotonia, and Intellectual Disability

Exome sequencing of a 15-year-old German girl and her unaffected parents revealed a heterozygous heterozygous de novo mutation in GNB1. Read more!

Recently, exome sequencing has extended our knowledge of genetic causes of developmental delay through identification of de novo, germline mutations in the guanine nucleotide-binding protein, beta 1 (GNB1) in 13 patients with neurodevelopmental disability and a wide range of additional symptoms and signs including hypotonia in 11 and seizures in 10 of the patients. Limb/arm dystonia was found in 2 patients.

Whole Exome Sequencing in a Rare Disease: A Patient with Anomalous Left Coronary Artery from the Pulmonary Artery (Bland-White-Garland Syndrome)

We report the results of the first whole exome sequencing (WES) of an ALCAPA patient who has been followed for 8 years. Read more!

Anomalous origin of left coronary artery from pulmonary artery (ALCAPA), also known as the Bland-White-Garland syndrome, is a rare congenital abnormality, with an incidence of 1 in 300,000 live births. Herein we report the results of the first whole exome sequencing (WES) of an ALCAPA patient who has been followed for 8 years; his clinical course was described previously elsewhere (Türkmen et al., 2014).