Scientific Publications

FAHN/SPG35: a narrow phenotypic spectrum across disease classifications

Major problems with rare diseases are related to the paucity and the heterogeneity of scientific publications. Standardized large-scale data compilation is one approach to overcome these issues. CENTOGENE meticulously curates consented clinical and genetic observation, and openly shares such internal knowledge with academic partners. The recent characterization of the ultra-rare FAHN-related disorder represents a pertinent example; it was published in the June 2019 issue of Brain.

Major problems with rare diseases are related to the paucity and the heterogeneity of scientific publications. Standardized large-scale data compilation is one approach to overcome these issues. CENTOGENE meticulously curates consented clinical and genetic observation, and openly shares such internal knowledge with academic partners. The recent characterization of the ultra-rare FAHN-related disorder represents a pertinent example; it was published in the June 2019 issue of Brain.

Genotype Phenotype Correlation in a New Fabry-Disease-Causing Mutation

Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by α-galactosidase A deficiency leading to intracellular glycosphingolipid accumulation. FD manifestation is multisystem, and can differ depending on disease-related genetic variants.

The interpretation of missense variants in a disease context is challenging, especially for variants that have never been reported before. In metabolic disorders, the potential of biochemical analyses for assisting in variant classification is increasingly recognized. CENTOGENE therefore combined genetic, enzymatic and metabolic testing into a single approach termed CentoMetabolic®.

A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism

X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT)n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP.

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.

Identification of PKD1 and PKD2 gene variants in a cohort of 125 Asian Indian patients of ADPKD

CENTOGENE considers its global positioning a key aspect for generating truly novel knowledge. The company’s involvement in a recent large-scale epidemiological study in India nicely exemplifies the success of this approach. Upon genetic screening of Indian patients with chronic liver disease, many pathogenic PKD1 variants were shown to be specific to this under-investigated ethnic group. The findings were published ahead of print in Journal of Human Genetics on February 28th.

CENTOGENE considers its global positioning a key aspect for generating truly novel knowledge. The company’s involvement in a recent large-scale epidemiological study in India nicely exemplifies the success of this approach. Upon genetic screening of Indian patients with chronic liver disease, many pathogenic PKD1 variants were shown to be specific to this under-investigated ethnic group. The findings were published ahead of print in Journal of Human Genetics on February 28th.

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.

Assessment of Cardiac Involvement in Fabry Disease (FD) with Native T1 Mapping

Mass-spectrometry based quantification of biomarkers is a routine step in the diagnostic workup of many diseases at CENTOGENE. Read more about our recent research.

Mass-spectrometry based quantification of biomarkers is a routine step in the diagnostic workup of many diseases at CENTOGENE. In addition, these well-established tools are increasingly being utilized in research settings. A recent example involved the Fabry Disease (FD)-specific biomarker Lyso-Gb3. Scientists including CENTOGENE’s CEO Prof. A. Rolfs showed that sub-clinical cardiac involvement in FD is accurately reflected by plasma-based Lyso-Gb3 values.

Prodromal substantia nigra sonography undermines suggested association between substrate accumulation and the risk for GBA‐related Parkinson’s disease

Parkinson’s disease (PD) and Gaucher disease are amongst the primary research foci at Centogene. As both conditions may be caused by mutations in the GBA gene, a common pathomechanism is widely assumed. Based on a combination of several approaches, an international team of GBA experts involving Centogene researchers now questioned this hypothesis. The findings, which strongly impact on therapeutic considerations for GBA-related PD, were recently published in the European Journal of Neurology

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.

Clinical, biomarker and genetic spectrum of Niemann-Pick type C in Egypt

Niemann-Pick type C (NPC) is an autosomal recessive condition which is caused by bi-allelic variants in either NPC1 (95% of patients) or NPC2 (5%). It manifests with mainly neurological symptoms. Sphingomyelin Lyso-SM-509 has recently been proposed as a potential NPC biomarker.

Role of ANO3 mutations in dystonia: A large-scale mutational screening study

Newly suggested gene-disease associations need confirmatory follow-up by large-scale epidemiological studies; CENTOGENE actively engages in pertinent research projects. A recent example addressed the hypothetical link between ANO3 and movement disorders. Screening of >1,000 patients revealed strong support of a pathogenic role for heterozygous ANO3 missense variants in Parkinson’s disease and dystonia. The findings were published ahead of print in Parkinsonism & Related Disorders ahead of print on January 2nd.

Newly suggested gene-disease associations need confirmatory follow-up by large-scale epidemiological studies; CENTOGENE actively engages in pertinent research projects. A recent example addressed the hypothetical link between ANO3 and movement disorders. Screening of >1,000 patients revealed strong support of a pathogenic role for heterozygous ANO3 missense variants in Parkinson’s disease and dystonia. The findings were published ahead of print in Parkinsonism & Related Disorders ahead of print on January 2nd.

Genetic Variants in the NALCN–UNC80–UNC79 Ion Channel

Genetic variants in components of the NALCN–UNC80–UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies). Find more information on our website.

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the “NALCN channelosome”, consisting of multiple proteins including UNC80 and UNC79.

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.

HTRA2 Defect: a Recognizable Inborn Error of Metabolism

HTRA2 defect: inborn error of metabolism. Neonatal-onset movement disorders, especially in combination with seizures, are rare and often related to mitochondrial disorders. 3-methylglutaconic aciduria (3-MGA-uria) is a marker for mitochondrial dysfunction.

Neonatal-onset movement disorders, especially in combination with seizures, are rare and often related to mitochondrial disorders. 3-methylglutaconic aciduria (3-MGA-uria) is a marker for mitochondrial dysfunction. In particular, consistently elevated urinary excretion of 3-methylglutaconic acid is the hallmark of a small but growing group of inborn errors of metabolism (IEM) due to defective phospholipid remodeling or mitochondrial membrane-associated disorders (mutations in TAZ, SERAC1, OPA3, CLPB, DNAJC19, TMEM70, TIMM50).

A Variant in NUDT2 Causes a Recessive Neurodevelopmental Disorder

A variant in NUDT2 causes a neurodevelopmental disorder. A recent study on 337 patients with various forms of intellectual disability proposed the homozygous nonsense variant c.34C>T (p.Arg12*) in NUDT2 to underlie global developmental delay in 2 affected sisters.

A recent study on 337 patients with various forms of intellectual disability proposed the homozygous nonsense variant c.34C>T (p.Arg12*) in NUDT2 to underlie global developmental delay in 2 affected sisters.