Publications by authors named "Marc Sturm"

54 Publications

Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.

Neurology 2021 Mar 25;96(9):e1369-e1382. Epub 2021 Jan 25.

From the Department of Neurodegenerative Diseases (A.T., S.R., L.S., M. Synofzik), Hertie-Institute for Clinical Brain Research and Center of Neurology, and German Center for Neurodegenerative Diseases (DZNE) (A.T., S.R., L.S., M. Synofzik), University of Tübingen, Germany; MRC Centre for Neuromuscular Diseases (A.C., N.D., H.H.), Department of Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, London, UK; Department of Brain and Behaviour Sciences (A.C.), University Pavia, Italy; Department of Neurology (J.F., T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (J.F., H.J., T.K.), Bonn; Department of Neurology (H.J.), University Hospital of Heidelberg; Department of Psychiatry, Psychotherapy and Psychosomatics (A.M.H., D.R.), University of Halle, Germany; Département de Neurologie (S.M., M.A.), Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg; Department of Neurology (A.E.-L.), APHP, CHU de Bicêtre; French National Reference Center for Rare Neuropathies (NNERF) (A.E.-L.); Inserm U1195 and Paris-Sud University (A.E.-L.), Le Kremlin Bicêtre, France; Medical Faculty (S.E.), Department of Neurology, Uludag University, Bursa, Turkey; University of Zurich (V.C.S., A.A.T.); Department of Neurology (V.C.S., A.A.T.), University Hospital Zurich, Switzerland; Institute of Medical Genetics and Applied Genomics (M. Sturm, T.B.H.) and Center for Rare Diseases (T.B.H.), University of Tübingen, Germany; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (N.V.-D., H.P.); INSERM (N.V.-D., H.P.), U1258; CNRS (N.V.-D., H.P.), UMR7104, Illkirch; Université de Strasbourg (H.P.), France; Department of Neurology (B.P.v.d.W.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Neurology (M.P.), Karolinska University Hospital; Department of Clinical Neuroscience (M.P.), Karolinska Institute, Stockholm, Sweden; Department of Neurology (D.T.), Essen University Hospital, University of Duisburg-Essen, Essen; Department of Medical Statistics (R.-D.H.), RWTH Aachen University, Germany; Department of Neurology (J.G.), Hospital Universitario Miguel Servet. Zaragoza, Spain; Department of Neurology (M. Strupp), University Hospital, and German Center for Vertigo and Balance Disorders (M.Strupp), Ludwig Maximilians University, Munich, Germany; Neurology Service (G.M.), Hospital Unversitario Central de Asturias (HUCA), SESPA, Oviedo, Spain; Department of Neurosciences and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Institute of Genetics and Molecular and Cellular Biology (M.A.), INSERM-U964/CNRS-UMR7104, University of Strasbourg, Illkirch; Strasbourg Federation of Translational Medicine (M.A.), University of Strasbourg, Strasbourg, France; Service of Neurology (J.I.), University Hospital "Marqués de Valdecilla (IDIVAL)," University of Cantabria, "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)," Santander, Spain; and Suna and Inan Kıraç Foundation (A.N.B.), Neurodegeneration Research Laboratory, KUTTAM, Koç University School of Medicine, Istanbul, Turkey.

Objective: To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).

Methods: Multimodal repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia.

Results: Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression.

Conclusions: RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials.

Classification Of Evidence: This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.
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http://dx.doi.org/10.1212/WNL.0000000000011528DOI Listing
March 2021

Bi-allelic truncating mutations in VWA1 cause neuromyopathy.

Brain 2021 Jan 18. Epub 2021 Jan 18.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.

The von Willebrand Factor A domain containing 1 protein, encoded by VWA1, is an extracellular matrix protein expressed in muscle and peripheral nerve. It interacts with collagen VI and perlecan, two proteins that are affected in hereditary neuromuscular disorders. Lack of VWA1 is known to compromise peripheral nerves in a Vwa1 knock-out mouse model. Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder. We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent. Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature.
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http://dx.doi.org/10.1093/brain/awaa418DOI Listing
January 2021

Intermediate phenotype of ATP13A2 mutation in two Chilean siblings: Towards a continuum between parkinsonism and hereditary spastic paraplegia.

Parkinsonism Relat Disord 2020 12 6;81:45-47. Epub 2020 Oct 6.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, Cologne, Germany; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2020.10.004DOI Listing
December 2020

Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia.

Am J Hum Genet 2020 08 23;107(2):364-373. Epub 2020 Jul 23.

Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany. Electronic address:

We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413886PMC
August 2020

Genetic Architecture of Parkinson's Disease in the Indian Population: Harnessing Genetic Diversity to Address Critical Gaps in Parkinson's Disease Research.

Front Neurol 2020 18;11:524. Epub 2020 Jun 18.

Department of Neurology, G. B. Pant Institute of Medical Education and Research, New Delhi, India.

Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our "hub-spoke" model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.
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http://dx.doi.org/10.3389/fneur.2020.00524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323575PMC
June 2020

De novo mutations in FBRSL1 cause a novel recognizable malformation and intellectual disability syndrome.

Hum Genet 2020 Nov 18;139(11):1363-1379. Epub 2020 May 18.

Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.

We report truncating de novo variants in specific exons of FBRSL1 in three unrelated children with an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. The function of FBRSL1 is largely unknown. Interestingly, mutations in the FBRSL1 paralogue AUTS2 lead to an intellectual disability syndrome (AUTS2 syndrome). We determined human FBRSL1 transcripts and describe protein-coding forms by Western blot analysis as well as the cellular localization by immunocytochemistry stainings. All detected mutations affect the two short N-terminal isoforms, which show a ubiquitous expression in fetal tissues. Next, we performed a Fbrsl1 knockdown in Xenopus laevis embryos to explore the role of Fbrsl1 during development and detected craniofacial abnormalities and a disturbance in neurite outgrowth. The aberrant phenotype in Xenopus laevis embryos could be rescued with a human N-terminal isoform, while the long isoform and the N-terminal isoform containing the mutation p.Gln163* isolated from a patient could not rescue the craniofacial defects caused by Fbrsl1 depletion. Based on these data, we propose that the disruption of the validated N-terminal isoforms of FBRSL1 at critical timepoints during embryogenesis leads to a hitherto undescribed complex neurodevelopmental syndrome.
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http://dx.doi.org/10.1007/s00439-020-02175-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519918PMC
November 2020

Pontocerebellar hypoplasia type 11: Does the genetic defect determine timing of cerebellar pathology?

Eur J Med Genet 2020 Jul 28;63(7):103938. Epub 2020 Apr 28.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076, Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076, Tübingen, Germany. Electronic address:

Pontocerebellar hypoplasia (PCH) comprises a clinically and genetically heterogeneous group of disorders characterized by hypoplasia and degeneration of the cerebellum and ventral pons. To date at least 18 different clinical subtypes of PCH associated with pathogenic variants in 19 different genes have been described. Only recently, bi-allelic variants in TBC1D23 have been reported as the underlying molecular defect in seven index cases with a suspected non-degenerative form of PCH, PCH type 11 (PCH11). We used exome sequencing to investigate an individual with global developmental delay, ataxia, seizures, and progressive PCH. Brain volume was evaluated over a disease course of 14 years using volumetric magnetic resonance imaging (MRI). Volume alterations were compared to age-matched controls as well as data from children with PCH2. We identified a homozygous frameshift variant in exon 9 of 18 of TBC1D23 predicting a loss of protein function. Brain morphometry revealed a pattern of pontine, brain stem, and supratentorial volume loss similar to PCH2 patients although less pronounced. Intriguingly, cerebral MRI findings at the age of 1 and 15 years clearly showed progressive atrophy of the cerebellum, especially the hemispheres. In four of the cases reported in the literature cerebellar hemispheres could be evaluated on the MRIs displayed, they also showed atrophic foliae. While pontine hypoplasia and pronounced microcephaly are in line with previous reports on PCH11, our observations of clearly postnatal atrophy of the cerebellum argues for a different pathomechanism than in the other forms of PCH and supports the hypothesis that TBC1D23 deficiency predominantly interferes with postnatal rather than with prenatal cerebellar development.
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http://dx.doi.org/10.1016/j.ejmg.2020.103938DOI Listing
July 2020

First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery.

Eur J Hum Genet 2020 08 25;28(8):1034-1043. Epub 2020 Mar 25.

Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

A high rate of consanguinity leads to a high prevalence of autosomal recessive disorders in inbred populations. One example of inbred populations is the Arab communities in Israel and the Palestinian Authority. In the Palestinian Authority in particular, due to limited access to specialized medical care, most patients do not receive a genetic diagnosis and can therefore neither receive genetic counseling nor possibly specific treatment. We used whole-exome sequencing as a first-line diagnostic tool in 83 Palestinian and Israeli Arab families with suspected neurogenetic disorders and were able to establish a probable genetic diagnosis in 51% of the families (42 families). Pathogenic, likely pathogenic or highly suggestive candidate variants were found in the following genes extending and refining the mutational and phenotypic spectrum of these rare disorders: ACO2, ADAT3, ALS2, AMPD2, APTX, B4GALNT1, CAPN1, CLCN1, CNTNAP1, DNAJC6, GAMT, GPT2, KCNQ2, KIF11, LCA5, MCOLN1, MECP2, MFN2, MTMR2, NT5C2, NTRK1, PEX1, POLR3A, PRICKLE1, PRKN, PRX, SCAPER, SEPSECS, SGCG, SLC25A15, SPG11, SYNJ1, TMCO1, and TSEN54. Further, this cohort has proven to be ideal for prioritization of new disease genes. Two separately published candidate genes (WWOX and PAX7) were identified in this study. Analyzing the runs of homozygosity (ROHs) derived from the Exome sequencing data as a marker for the rate of inbreeding, revealed significantly longer ROHs in the included families compared with a German control cohort. The total length of ROHs correlated with the detection rate of recessive disease-causing variants. Identification of the disease-causing gene led to new therapeutic options in four families.
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http://dx.doi.org/10.1038/s41431-020-0609-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382450PMC
August 2020

Genetic basis of neurodevelopmental disorders in 103 Jordanian families.

Clin Genet 2020 04 1;97(4):621-627. Epub 2020 Mar 1.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.
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http://dx.doi.org/10.1111/cge.13720DOI Listing
April 2020

Single Molecule Molecular Inversion Probes for High Throughput Germline Screenings in Dystonia.

Front Neurol 2019 18;10:1332. Epub 2019 Dec 18.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

This study's aim was to investigate a large cohort of dystonia patients for pathogenic and rare variants in the gene, making use of a new, cost-efficient enrichment technology for NGS-based screening. Single molecule Molecular Inversion Probes (smMIPs) were used for targeted enrichment and sequencing of all protein coding exons and exon-intron boundaries of the gene in 373 dystonia patients and six positive controls with known variants. Additionally, a rare-variant association study was performed. One patient (0.3%) was compound heterozygous and 21 others were carriers of variants of unknown significance (VUS) in the gene. Although mutations in sporadic dystonia patients are not common, exclusion of pathogenic variants is crucial to recognize a potential tumor predisposition syndrome. SmMIPs produced similar results as routinely used NGS-based approaches. Our results underline the importance of implementing in the routine genetic testing of dystonia patients and confirm the reliability of smMIPs and their usability for germline screenings in rare neurodegenerative conditions.
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http://dx.doi.org/10.3389/fneur.2019.01332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930228PMC
December 2019

Novel Variants in Patients with Intellectual Disability.

Mol Syndromol 2019 Jul 3;10(4):195-201. Epub 2019 Apr 3.

Institute of Medical Genetics and Applied Genomics, Hertie Institute for Clinical Brain Research, Tübingen, Germany.

Intellectual disability (ID) occurs in approximately 1% of the population. Over the last years, broad sequencing approaches such as whole exome sequencing (WES) substantially contributed to the definition of the molecular defects underlying nonsyndromic ID. Pathogenic variants in , which encodes the human immunodeficiency virus type I enhancer binding protein 2, have recently been reported as a cause of ID, developmental delay, behavioral disorders, and dysmorphic features. HIVEP2 serves as a transcriptional factor regulating NF-ĸB and diverse genes that are essential in neural development. To date, only 8 patients with pathogenic de novo nonsense or frameshift variants and 1 patient with a pathogenic missense variant in have been reported. By WES, we identified 2 novel truncating variants, c.6609_6616delTGAGGGTC (p.Glu2204*) and c.6667C>T (p.Arg2223*), in 2 young adults presenting with developmental delay and mild ID without any dysmorphic features, systemic malformations, or behavioral issues.
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http://dx.doi.org/10.1159/000499060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738162PMC
July 2019

Deep-intronic variants in CNGB3 cause achromatopsia by pseudoexon activation.

Hum Mutat 2020 01 30;41(1):255-264. Epub 2019 Sep 30.

Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.

Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients' phenotype. Forty-seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic alleles. In a second step, in silico prediction tools were used to filter out those variants with little odds of being deleterious. This left three variants that were analyzed using heterologous splicing assays. Variant c.1663-1205G>A, found in 14 subjects, and variant c.1663-2137C>T, found in two subjects, were indeed shown to exert a splicing defect by causing pseudoexon insertion into the transcript. Subsequent screening of further unsolved CNGB3 subjects identified four additional cases harboring the c.1663-1205G>A variant which makes it the eighth most frequent CNGB3 variant in our cohort. Compound heterozygosity could be validated in ten cases. Our study demonstrates that whole gene sequencing can be a powerful approach to identify the second pathogenic allele in patients apparently harboring only one disease-causing variant.
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http://dx.doi.org/10.1002/humu.23920DOI Listing
January 2020

variants in cause sporadic early-onset progressive sensorimotor neuropathy.

J Med Genet 2020 04 22;57(4):283-288. Epub 2019 Aug 22.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

Background: Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in in three unrelated patients with intermediate CMT.

Methods: We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in oocytes.

Results: We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in oocytes showed a significant reduction in potassium influx for both changes.

Conclusion: Our findings expand the genotypic and phenotypic spectrum associated with variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.
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http://dx.doi.org/10.1136/jmedgenet-2019-106273DOI Listing
April 2020

Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women.

BMC Cancer 2019 Aug 8;19(1):787. Epub 2019 Aug 8.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

Background: Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon.

Methods: We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways.

Results: Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00-27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05.

Conclusions: To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results.
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http://dx.doi.org/10.1186/s12885-019-5946-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686546PMC
August 2019

KCNC1-related disorders: new de novo variants expand the phenotypic spectrum.

Ann Clin Transl Neurol 2019 07 7;6(7):1319-1326. Epub 2019 Jun 7.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

A recurrent de novo missense variant in KCNC1, encoding a voltage-gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic-clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant-negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.
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http://dx.doi.org/10.1002/acn3.50799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649617PMC
July 2019

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

Genet Med 2019 11 16;21(11):2521-2531. Epub 2019 May 16.

CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada.

Purpose: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established.

Methods: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease.

Results: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration.

Conclusion: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
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http://dx.doi.org/10.1038/s41436-019-0532-zDOI Listing
November 2019

Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma.

Genome Med 2019 04 30;11(1):28. Epub 2019 Apr 30.

Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, D-72076, Tübingen, Germany.

Background: Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs.

Methods: In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data.

Results: The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somatic mutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignant melanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations.

Conclusions: This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignant melanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.
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http://dx.doi.org/10.1186/s13073-019-0636-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492406PMC
April 2019

Homozygous TBC1 domain-containing kinase (TBCK) mutation causes a novel lysosomal storage disease - a new type of neuronal ceroid lipofuscinosis (CLN15)?

Acta Neuropathol Commun 2018 12 27;6(1):145. Epub 2018 Dec 27.

Department of Neuropathology, Philipps University and University Hospital of Marburg, Baldingerstrasse, 35043, Marburg, Germany.

Homozygous mutation of TBC1 domain-containing kinase (TBCK) is the cause of a very recently defined severe childhood disorder, which is characterized by severe hypotonia, global developmental delay, intellectual disability, epilepsy, characteristic facies and premature death. The link between TBCK loss of function and symptoms in patients with TBCK deficiency disorder (TBCK-DD) remains elusive. Here we demonstrate for the first time the histopathological characteristics of TBCK deficiency consisting of 1) a widespread and massive accumulation of lipofuscin storage material in neurons of the central nervous system without notable neuronal degeneration, 2) storage deposits in few astrocytes, 3) carbohydrate-rich deposits in brain, spleen and liver and 4) vacuolated lymphocytes. Biochemical examinations ruled out more than 20 known lysosomal storage diseases. These investigations strikingly uncover TBCK-DD as a novel type of lysosomal storage disease which is characterized by different storage products rather than one specific type of accumulated material. Due to the clear predominance of intraneuronal lipofuscin storage material and the characteristic clinical presentation we propose to classify this disease as a new subtype of neuronal ceroid lipofuscinosis (CLN15). Our results and previous reports suggest an autophagosomal-lysosomal dysfunction caused by enhanced mTORC1-mediated autophagosome formation and reduced Rab-mediated autophagosome-lysosome fusion, thus disclosing potential novel targets for therapeutic approaches in TBCK-DD.
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http://dx.doi.org/10.1186/s40478-018-0646-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307319PMC
December 2018

Loss of NFAT2 expression results in the acceleration of clonal evolution in chronic lymphocytic leukemia.

J Leukoc Biol 2019 03 17;105(3):531-538. Epub 2018 Dec 17.

Department of Oncology, Hematology and Immunology, University of Tübingen, Tübingen, Germany.

Chronic lymphocytic leukemia (CLL) can be defined as a clonal expansion of B cells with stereotypic BCRs. Somatic hypermutation of the BCR heavy chains (IGVH) defines a subgroup of patients with a better prognosis. In up to 10% of CLL cases, a transformation to an aggressive B cell lymphoma (Richter's syndrome) with a dismal prognosis can be observed over time. NFAT proteins are transcription factors originally identified in T cells, which also play an important role in B cells. The TCL1 transgenic mouse is a well-accepted model of CLL. Upon B cell-specific deletion of NFAT2, TCL1 transgenic mice develop a disease resembling human Richter's syndrome. Whereas TCL1 B cells exhibit tonic anergic BCR signaling characteristic of human CLL, loss of NFAT2 expression leads to readily activated BCRs indicating different BCR usage with altered downstream signaling. Here, we analyzed BCR usage in wild-type and TCL1 transgenic mice with and without NFAT2 deletion employing conventional molecular biology techniques and next-generation sequencing (NGS). We demonstrate that the loss of NFAT2 in CLL precipitates the selection of unmutated BCRs and the preferential usage of certain VDJ recombinations, which subsequently results in the accelerated development of oligoclonal disease.
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http://dx.doi.org/10.1002/JLB.2AB0218-076RRDOI Listing
March 2019

Understanding the role of genetic variability in LRRK2 in Indian population.

Mov Disord 2019 04 28;34(4):496-505. Epub 2018 Nov 28.

Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.

Background: Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations.

Objectives: To resolve the role of LRRK2 in the Indian population.

Methods: We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene.

Results: We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity.

Conclusions: Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27558DOI Listing
April 2019

Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity.

Breast Cancer Res 2018 08 7;20(1):87. Epub 2018 Aug 7.

Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.

Background: Breast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-like phenotype do not harbor detectable causative germline TP53 variants. Yet, no systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilling Li-Fraumeni(-like) clinical diagnostic criteria.

Methods: To specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germline variants.

Results: We identified 13 pathogenic or likely pathogenic germline variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in established hereditary breast cancer susceptibility genes (i.e., PALB2, CHEK2, ATM). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibility to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A/p14, and RUNX1).

Conclusions: Our study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoallelic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-like) syndrome lacking TP53 variants in coding regions.
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http://dx.doi.org/10.1186/s13058-018-1011-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081832PMC
August 2018

Novel WNT1 mutations in children with osteogenesis imperfecta: Clinical and functional characterization.

Bone 2018 09 20;114:144-149. Epub 2018 Jun 20.

Shandong Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, Jinan 250062, China; School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan 250200, China. Electronic address:

Introduction: Biallelic mutations in WNT1 can give rise to a rare form of moderate to severe OI. Here we report on 12 children (age 2 to 16 years; 5 girls) with biallelic WNT1 mutations.

Methods: Genomic DNA was analyzed either by targeted next-generation sequencing or Sanger sequencing. Mutations were modeled on the WNT1 protein structure. The in vitro functional effect of WNT1 mutations on WNT signaling was assessed in HEK293 cells using the topflash reporter assay system.

Results: All patients had lower extremity deformities and vertebral compression fractures. Seven individuals had upper extremity deformities. Intellectual development appeared normal in 11 children, but was clearly impaired in a 3-year old boy. Ptosis was noted in 7 patients. Height z-scores varied widely, from -7.2 to +1.5. A total of 11 disease-causing WNT1 variants (7 missense mutations, 4 mutations leading to premature termination codons) were identified, of which 9 were novel. Three-dimensional protein modeling suggested that each of the missense mutations led to structural modifications. Functional in vitro studies revealed that all observed missense mutations led to decreased ability of WNT1 to induce WNT signaling via the canonical WNT pathway.

Conclusions: The reported biallelic WNT1 variants cause loss of WNT1 function and lead to a severe bone fragility phenotype with conspicuous involvement of the spine.
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http://dx.doi.org/10.1016/j.bone.2018.06.018DOI Listing
September 2018

Isolated PREPL deficiency associated with congenital myasthenic syndrome-22.

Klin Padiatr 2018 09 18;230(5):281-283. Epub 2018 Jun 18.

Department of General Pediatrics, Heinrich-Heine-University, Duesseldorf, Germany.

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http://dx.doi.org/10.1055/a-0605-3659DOI Listing
September 2018

De novo FBXO11 mutations are associated with intellectual disability and behavioural anomalies.

Hum Genet 2018 May 23;137(5):401-411. Epub 2018 May 23.

Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.

Intellectual disability (ID) has an estimated prevalence of 1.5-2%. In most affected individuals, its genetic basis remains unclear. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that a large proportion of sporadic ID cases results from de novo mutations. Here, we present two unrelated individuals with similar clinical features and deleterious de novo variants in FBXO11 detected by WES. Individual 1, a 14-year-old boy, has mild ID as well as mild microcephaly, corrected cleft lip and alveolus, hyperkinetic disorder, mild brain atrophy and minor facial dysmorphism. WES detected a heterozygous de novo 1 bp insertion in the splice donor site of exon 3. Individual 2, a 3-year-old boy, showed ID and pre- and postnatal growth retardation, postnatal mild microcephaly, hyperkinetic and restless behaviour, as well as mild dysmorphism. WES detected a heterozygous de novo frameshift mutation. While ten individuals with ID and de novo variants in FBXO11 have been reported as part of larger studies, only one of the reports has some additional clinical data. Interestingly, the latter individual carries the identical mutation as our individual 2 and also displays ID, intrauterine growth retardation, microcephaly, behavioural anomalies, and dysmorphisms. Thus, we confirm deleterious de novo mutations in FBXO11 as a cause of ID and start the delineation of the associated clinical picture which may also comprise postnatal microcephaly or borderline small head size and behavioural anomalies.
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http://dx.doi.org/10.1007/s00439-018-1892-1DOI Listing
May 2018

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Am J Hum Genet 2017 Dec 30;101(6):985-994. Epub 2017 Nov 30.

Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812889PMC
December 2017

Clinical and genetic characteristics of sporadic adult-onset degenerative ataxia.

Neurology 2017 Sep 9;89(10):1043-1049. Epub 2017 Aug 9.

From the Department of Neurology (I.G., T.K.), University Hospital of Bonn; German Center for Neurodegenerative Diseases (DZNE) (I.G., H.J., B.P., T.K.), Bonn; Institute of Medical Genetics and Applied Genomics (F.H., M.S.) and Department of Neurodegenerative Diseases (L.S., M.S.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Department of Neurology (H.J.), Heidelberg University Hospital; Department of Neurology (S.V.), Otto-von-Guericke University Magdeburg; German Center for Neurodegenerative Diseases (DZNE) (S.V., J.M.), Magdeburg; German Center for Neurodegenerative Diseases (DZNE) (L.S., M.S.), Tübingen, Germany; Department of Neurology (C.T., I.M.W.), Oslo University Hospital; Faculty of Medicine (C.T.), Institute of Clinical Medicine, University of Oslo, Norway; Department of Neurology (S.B., A.E.), Medical University Innsbruck, Austria; Department of Neurology (B.v.d.W., J.v.G.), Radboud University Medical Center, Nijmegen, Netherlands; Department of Neurology (C.K., A.D.), University of Rostock; German Center for Neurodegenerative Diseases (DZNE) (C.K., A.D.), Rostock; Department of Neurology (J.-S.K.), University of Frankfurt; Department of Neurology (D.T.), Essen University Hospital, University of Duisburg-Essen, Germany; Institute of Neurology (G.S.), Catholic University of Sacred Heart; SPInal REhabilitation Lab (SPIRE) (M.M.), Fondazione Santa Lucia, IRCCS, Rome, Italy; Department of Neurology (T.K., C.N.), Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich; German Center for Neurodegenerative Diseases (DZNE) (T.K., C.N.), Munich; Munich Cluster for Systems Neurology (SyNergy) (T.K.), Munich; Department of Neurology (C.G.), University Medical Center Hamburg-Eppendorf (UKE), Germany; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University, Naples, Italy; Centogene AG (P.B.), Rostock, Germany; Pierre Louis Institute of Epidemiology and Public Health (S.T.d.M.), Pierre and Marie Curie University (UPMC); and AP-HP (S.T.d.M.), Biostatistics Unit, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

Objective: To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations.

Methods: The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing.

Results: The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, < 0.0001) and disease duration (0.22 ± 0.06 per additional year, = 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made.

Conclusions: Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort.

Clinicaltrialsgov Registration: NCT02701036.
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http://dx.doi.org/10.1212/WNL.0000000000004311DOI Listing
September 2017

Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.

Brain 2017 06;140(6):1561-1578

Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.
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http://dx.doi.org/10.1093/brain/awx095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402316PMC
June 2017

A comprehensive quality control workflow for paired tumor-normal NGS experiments.

Bioinformatics 2017 Jun;33(11):1721-1722

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

Summary: Quality control (QC) is an important part of all NGS data analysis stages. Many available tools calculate QC metrics from different analysis steps of single sample experiments (raw reads, mapped reads and variant lists). Multi-sample experiments, as sequencing of tumor-normal pairs, require additional QC metrics to ensure validity of results. These multi-sample QC metrics still lack standardization. We therefore suggest a new workflow for QC of DNA sequencing of tumor-normal pairs. With this workflow well-known single-sample QC metrics and additional metrics specific for tumor-normal pairs can be calculated. The segmentation into different tools offers a high flexibility and allows reuse for other purposes. All tools produce qcML, a generic XML format for QC of -omics experiments. qcML uses quality metrics defined in an ontology, which was adapted for NGS.

Availability And Implementation: All QC tools are implemented in C ++ and run both under Linux and Windows. Plotting requires python 2.7 and matplotlib. The software is available under the 'GNU General Public License version 2' as part of the ngs-bits project: https://github.com/imgag/ngs-bits.

Contact: christopher.schroeder@med.uni-tuebingen.de.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btx032DOI Listing
June 2017