Publications by authors named "Ingo Kurth"

103 Publications

Germline variants in DNA repair genes, including BRCA1/2, may cause familial myeloproliferative neoplasms.

Blood Adv 2021 09;5(17):3373-3376

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.

The molecular causes of myeloproliferative neoplasms (MPNs) have not yet been fully elucidated. Approximately 7% to 8% of the patients carry predisposing genetic germline variants that lead to driver mutations, which enhance JAK-STAT signaling. To identify additional predisposing genetic germline variants, we performed whole-exome sequencing in 5 families, each with parent-child or sibling pairs affected by MPNs and carrying the somatic JAK2 V617F mutation. In 4 families, we detected rare germline variants in known tumor predisposition genes of the DNA repair pathway, including the highly penetrant BRCA1 and BRCA2 genes. The identification of an underlying hereditary tumor predisposition is of major relevance for the individual patients as well as for their families in the context of therapeutic options and preventive care. Two patients with essential thrombocythemia or polycythemia vera experienced progression to acute myeloid leukemia, which may suggest a high risk of leukemic transformation in these familial MPNs. Our study demonstrates the relevance of genetic germline diagnostics in elucidating the causes of MPNs and suggests novel therapeutic options (eg, PARP inhibitors) in MPNs. Furthermore, we uncover a broader tumor spectrum upon the detection of a germline mutation in genes of the DNA repair pathway.
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http://dx.doi.org/10.1182/bloodadvances.2021004811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525218PMC
September 2021

Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability.

Eur J Hum Genet 2021 Aug 20. Epub 2021 Aug 20.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Heterozygous missense variants in the WD repeat domain 11 (WDR11) gene are associated with hypogonadotropic hypogonadism in humans. In contrast, knockout of both alleles of Wdr11 in mice results in a more severe phenotype with growth and developmental delay, features of holoprosencephaly, heart defects and reproductive disorders. Similar developmental defects known to be associated with aberrant hedgehog signaling and ciliogenesis have been found in zebrafish after Wdr11 knockdown. We here report biallelic loss-of-function variants in the WDR11 gene in six patients from three independent families with intellectual disability, microcephaly and short stature. The findings suggest that biallelic WDR11 variants in humans result in an overlapping but milder phenotype compared to Wdr11-deficient animals. However, the observed human phenotype differs significantly from dominantly inherited variants leading to hypogonadotropic hypogonadism, suggesting that recessive WDR11 variants result in a clinically distinct entity.
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http://dx.doi.org/10.1038/s41431-021-00943-5DOI Listing
August 2021

Diagnosing small fiber neuropathy in clinical practice: a deep phenotyping study.

Ther Adv Neurol Disord 2021 23;14:17562864211004318. Epub 2021 Mar 23.

Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, Würzburg, 97080, Germany.

Background And Aims: Small fiber neuropathy (SFN) is increasingly suspected in patients with pain of uncertain origin, and making the diagnosis remains a challenge lacking a diagnostic gold standard.

Methods: In this case-control study, we prospectively recruited 86 patients with a medical history and clinical phenotype suggestive of SFN. Patients underwent neurological examination, quantitative sensory testing (QST), and distal and proximal skin punch biopsy, and were tested for pain-associated gene loci. Fifty-five of these patients additionally underwent pain-related evoked potentials (PREP), corneal confocal microscopy (CCM), and a quantitative sudomotor axon reflex test (QSART).

Results: Abnormal distal intraepidermal nerve fiber density (IENFD) (60/86, 70%) and neurological examination (53/86, 62%) most frequently reflected small fiber disease. Adding CCM and/or PREP further increased the number of patients with small fiber impairment to 47/55 (85%). Genetic testing revealed potentially pathogenic gene variants in 14/86 (16%) index patients. QST, QSART, and proximal IENFD were of lower impact.

Conclusion: We propose to diagnose SFN primarily based on the results of neurological examination and distal IENFD, with more detailed phenotyping in specialized centers.
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http://dx.doi.org/10.1177/17562864211004318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283814PMC
March 2021

Unusual phenotypes in patients with a pathogenic germline variant in DICER1.

Fam Cancer 2021 Jul 31. Epub 2021 Jul 31.

Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Pathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic missense DICER1 variants in the RNase IIIb domain are linked to cause GLOW (global developmental delay, lung cysts, overgrowth, and Wilms' tumor) syndrome. Here, we report four families with germline DICER1 pathogenic variants in which one member in each family had a more complex phenotype, including skeletal findings, facial dysmorphism and developmental abnormalities. The developmental features occur with a variable expressivity and incomplete penetrance as also described for the neoplastic and dysplastic lesions associated with DICER1 variants. Whole exome sequencing (WES) was performed on all four cases and revealed no further pathogenic or likely pathogenic dominant, homozygous or compound heterozygous variants in three of them. Notably, a frameshift variant in ARID1B was detected in one patient explaining part of her phenotype. This series of patients shows that pathogenic DICER1 variants may be associated with a broader phenotypic spectrum than initially assumed, including predisposition to different tumours, skeletal findings, dysmorphism and developmental abnormalities, but genetic work up in syndromic patients should be comprehensive in order not to miss additional underlying /modifying causes.
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http://dx.doi.org/10.1007/s10689-021-00271-zDOI Listing
July 2021

Genome sequencing in families with congenital limb malformations.

Hum Genet 2021 Aug 22;140(8):1229-1239. Epub 2021 Jun 22.

Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.
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http://dx.doi.org/10.1007/s00439-021-02295-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263393PMC
August 2021

Swarm Learning for decentralized and confidential clinical machine learning.

Nature 2021 06 26;594(7862):265-270. Epub 2021 May 26.

Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.

Fast and reliable detection of patients with severe and heterogeneous illnesses is a major goal of precision medicine. Patients with leukaemia can be identified using machine learning on the basis of their blood transcriptomes. However, there is an increasing divide between what is technically possible and what is allowed, because of privacy legislation. Here, to facilitate the integration of any medical data from any data owner worldwide without violating privacy laws, we introduce Swarm Learning-a decentralized machine-learning approach that unites edge computing, blockchain-based peer-to-peer networking and coordination while maintaining confidentiality without the need for a central coordinator, thereby going beyond federated learning. To illustrate the feasibility of using Swarm Learning to develop disease classifiers using distributed data, we chose four use cases of heterogeneous diseases (COVID-19, tuberculosis, leukaemia and lung pathologies). With more than 16,400 blood transcriptomes derived from 127 clinical studies with non-uniform distributions of cases and controls and substantial study biases, as well as more than 95,000 chest X-ray images, we show that Swarm Learning classifiers outperform those developed at individual sites. In addition, Swarm Learning completely fulfils local confidentiality regulations by design. We believe that this approach will notably accelerate the introduction of precision medicine.
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http://dx.doi.org/10.1038/s41586-021-03583-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189907PMC
June 2021

C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation.

J Clin Invest 2021 06;131(12)

Department of Pediatrics, Medical Faculty.

BACKGROUNDDeciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell's function and its pathophysiology.METHODSWhole-exome sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene.RESULTSWe identified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, the patients showed signs of respiratory chain defects, and a CRISPR/Cas9-KO cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of periodic acid-Schiff-positive (PAS-positive) material in tissues from affected individuals, together with decreased glycogen branching enzyme 1 (GBE1) activity, indicated an additional impact of C2orf69 on glycogen metabolism.CONCLUSIONSOur study identifies C2orf69 as an important regulator of human mitochondrial function and suggests that this gene has additional influence on other metabolic pathways.
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http://dx.doi.org/10.1172/JCI143078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203463PMC
June 2021

The difficulty to model Huntington's disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells.

Sci Rep 2021 03 25;11(1):6934. Epub 2021 Mar 25.

Institute of Physiology, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-clamp experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-clamp experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.
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http://dx.doi.org/10.1038/s41598-021-85656-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994641PMC
March 2021

Alveolar capillary dysplasia without misalignment of pulmonary veins, hyperinflammation, megalocornea and overgrowth - Association with a homozygous 2bp-insertion in LTBP2?

Eur J Med Genet 2021 Jun 22;64(6):104209. Epub 2021 Mar 22.

Department of Pediatrics, RWTH Aachen University Hospital, Aachen, Germany.

We present a male infant with alveolar capillary dysplasia without misalignment of pulmonary veins, hyperinflammation, megalocornea and macrosomia/macrocephaly at birth. Whole-exome sequencing revealed a homozygous 2bp-insertion in the latent transforming growth factor-beta binding protein 2 (LTBP2) (c.278_279dup, p.(Ser94Glyfs*187)). So far, LTBP2-variants have been frequently reported with an eye-restricted phenotype including primary congenital glaucoma and megalocornea/microspherphakia and ectopia lentis with/without secondary glaucoma. Hitherto reported systemic phenotypes showed, among others, features as tall stature, finger anomalies, high-arched palate and cardiovascular anomalies. The main pathophysiological finding of our patient was an alveolar capillary dysplasia (with pulmonary arterial hypertension and right ventricular impairment but without misalignment of pulmonary veins) resulting in almost continuous oxygen demand and prolonged dependence on mechanical ventilation. He died of respiratory failure at the age of seven months. This patient may extend the LTBP2-related phenotype with resulting diagnostic implications.
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http://dx.doi.org/10.1016/j.ejmg.2021.104209DOI Listing
June 2021

Balance between macrophage migration inhibitory factor and sCD74 predicts outcome in patients with acute decompensation of cirrhosis.

JHEP Rep 2021 Apr 17;3(2):100221. Epub 2020 Dec 17.

Department of Internal Medicine III, RWTH Aachen University Hospital, Aachen, Germany.

Background & Aims: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine and an important regulator of innate immune responses. We hypothesised that serum concentrations of MIF are associated with disease severity and outcome in patients with decompensated cirrhosis and acute-on-chronic liver failure (ACLF).

Methods: Circulating concentrations of MIF and its soluble receptor CD74 (sCD74) were determined in sera from 292 patients with acute decompensation of cirrhosis defined as new onset or worsening of ascites requiring hospitalisation. Of those, 78 (27%) had ACLF. Short-term mortality was assessed 90 days after inclusion.

Results: Although serum concentrations of MIF and sCD74 did not correlate with liver function parameters or ACLF, higher MIF (optimum cut-off >2.3 ng/ml) and lower concentrations of sCD74 (optimum cut-off <66.5 ng/ml) both indicated poorer 90-day transplant-free survival in univariate analyses (unadjusted hazard ratio [HR] 2.01 [1.26-3.22];  = 0.004 for MIF; HR 0.59 [0.38-0.92];  = 0.02 for sCD74) and after adjustment in multivariable models. Higher MIF concentrations correlated with surrogates of systemic inflammation (white blood cells,  = 0.005; C-reactive protein,  = 0.05) and were independent of genetic MIF promoter polymorphisms. Assessment of MIF plasma concentrations in portal venous blood and matched blood samples from the right atrium in a second cohort of patients undergoing transjugular intrahepatic portosystemic shunt insertion revealed a transhepatic MIF gradient with higher concentrations in the right atrial blood.

Conclusions: Serum concentrations of MIF and its soluble receptor CD74 predict 90-day transplant-free survival in patients with acute decompensation of cirrhosis. This effect was independent of liver function and genetic predispositions, but rather reflected systemic inflammation. Therefore, MIF and sCD74 represent promising prognostic markers beyond classical scoring systems in patients at risk of ACLF.

Lay Summary: Inflammatory processes contribute to the increased risk of death in patients with cirrhosis and ascites. We show that patients with high serum levels of the inflammatory cytokine macrophage migration inhibitory factor (MIF) alongside low levels of its binding receptor sCD74 in blood indicate an increased mortality risk in patients with ascites. The cirrhotic liver is a relevant source of elevated circulating MIF levels.
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http://dx.doi.org/10.1016/j.jhepr.2020.100221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890204PMC
April 2021

Assessing the impact of pain-linked Nav1.7 variants: An example of two variants with no biophysical effect.

Channels (Austin) 2021 12;15(1):208-228

Institute of Physiology, RWTH Aachen University Hospital , Aachen, Germany.

Mutations in the voltage-gated sodium channel Nav1.7 are linked to human pain. The Nav1.7/N1245S variant was described before in several patients suffering from primary erythromelalgia and/or olfactory hypersensitivity. We have identified this variant in a pain patient and a patient suffering from severe and life-threatening orthostatic hypotension. In addition, we report a female patient suffering from muscle pain and carrying the Nav1.7/E1139K variant. We tested both Nav1.7 variants by whole-cell voltage-clamp recordings in HEK293 cells, revealing a slightly enhanced current density for the N1245S variant when co-expressed with the β1 subunit. This effect was counteracted by an enhanced slow inactivation. Both variants showed similar voltage dependence of activation and steady-state fast inactivation, as well as kinetics of fast inactivation, deactivation, and use-dependency compared to WT Nav1.7. Finally, homology modeling revealed that the N1245S substitution results in different intramolecular interaction partners. Taken together, these experiments do not point to a clear pathogenic effect of either the N1245S or E1139K variant and suggest they may not be solely responsible for the patients' pain symptoms. As discussed previously for other variants, investigations in heterologous expression systems may not sufficiently mimic the pathophysiological situation in pain patients, and single nucleotide variants in other genes or modulatory proteins are necessary for these specific variants to show their effect. Our findings stress that biophysical investigations of ion channel mutations need to be evaluated with care and should preferably be supplemented with studies investigating the mutations in their context, ideally in human sensory neurons.
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http://dx.doi.org/10.1080/19336950.2020.1870087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833769PMC
December 2021

The genetic landscape of axonal neuropathies in the middle-aged and elderly: Focus on .

Neurology 2020 12 3;95(24):e3163-e3179. Epub 2020 Nov 3.

From the Friedrich-Baur-Institute (J.S., B.S.-W., M.W.), Department of Neurology, LMU Munich, Germany; DNA Laboratory (P.L., P.S.), Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic; Neuromuscular Unit (D.K., A.K.), Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland; Dr. John T. Macdonald Foundation Department of Human Genetics (L.A., A.R., S.Z.), John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, FL; Neurogenetics Group (J.B., T.D., P.D.J.), Center for Molecular Neurology, University of Antwerp; Institute Born-Bunge (J.B., T.D., P.D.J.), University of Antwerp; Neuromuscular Reference Centre (J.B., P.D.J.), Department of Neurology, Antwerp University Hospital, Belgium; Department of Clinical Chemistry and Laboratory Medicine (C.B.), Jena University Hospital; Centogene AG (C.B.), Rostock, Germany; Department of Medical Genetics (G.J.B., H.H.), Telemark Hospital Trust, Skien, Norway; Neurology Department (D.B., A.L., J. Weishaupt), Ulm University, Germany; Department of Neurology (J.D., D. Walk), University of Minnesota, Minneapolis; Department of Neurology (L.D.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Sleep Medicine and Neuromuscular Diseases (B.D., A.S., P.Y.), University of Münster; Institute of Human Genetics (K.E., I.K.), Medical Faculty, RWTH Aachen University, Germany; Sydney Medical School (M.E., M.K., G.N.), Concord Hospital, Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, Australia; Department of Orthopaedics and Trauma Surgery (C.F., K.K., D. Weinmann, R.W., S.T., M.A.-G.), Medical University of Vienna, Austria; AP-HP (T.S.), Institut de Myologie, Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France, G-H Pitié-Salpêtrière, Paris, France; Department of Neurology (D.N.H.), University of Rochester, NY; Department of Clinical Neurosciences (R.H.), University of Cambridge School of Clinical Medicine, UK; Department of Neurology (S.I.), Konventhospital der Barmherzigen Brüder Linz; Karl Chiari Lab for Orthopaedic Biology (K.K., D. Weinmann, S.T.), Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Austria; Stanford Center for Undiagnosed Diseases (J.N.K.), Stanford, CA; Undiagnosed Diseases Network (UDN) (J.N.K., S.Z.); Centre for Medical Research (N.G.L., R.O., G.Ravenscroft), University of Western Australia, Nedlands; Harry Perkins Institute of Medical Research (N.G.L., R.O., G. Ravenscroft), Nedlands; Neurogenetic Unit (P.J.L.), Royal Perth Hospital, Perth, Australia; Department of Neurology (W.N.L., J. Wanschitz), Medical University of Innsbruck, Austria; Department of Neurosciences and Behavior (W.M.), Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; Department of Neurology (S.P.), Hannover Medical School, Germany; Department of Clinical and Experimental Medicine (G. Ricci), University of Pisa, Italy; Institute of Human Genetics (S.R.-S.), Medical University of Innsbruck, Austria; Department of Neurodegenerative Diseases Hertie-Institute for Clinical Brain Research and Center of Neurology (L.S., R.S., M.S.), University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (L.S., R.S., M.S.), Tübingen, Germany; AP-HP (B.F.), Laboratoire de génétique moléculaire, pharmacogénétique et hormonologie, Hôpital de Bicêtre; Le Kremlin-Bicêtre, France; Institute of Human Genetics (T.M.S.), Helmholtz Zentrum Munich-German Research Center for Environmental Health, Neuherberg; Institute for Human Genetics (T.M.S.), Technical University Munich; and Institut für Klinische Genetik (J. Wagner), Technische Universität Dresden, Medizinische Fakultät Carl Gustav Carus, Germany.

Objective: To test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years.

Methods: We recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and single-gene sequencing (n = 104). We further queried WES repositories for variants and measured blood levels of the -encoded protein neprilysin.

Results: In the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of variants was often consistent with an incompletely penetrant autosomal-dominant trait and less frequently with autosomal-recessive inheritance.

Conclusions: A detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, by variants in either CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.
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http://dx.doi.org/10.1212/WNL.0000000000011132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836667PMC
December 2020

Need for a precise molecular diagnosis in Beckwith-Wiedemann and Silver-Russell syndrome: what has to be considered and why it is important.

J Mol Med (Berl) 2020 10 24;98(10):1447-1455. Epub 2020 Aug 24.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, D-52074, Aachen, Germany.

Molecular diagnostic testing of the 11p15.5-associated imprinting disorders Silver-Russell and Beckwith-Wiedemann syndrome (SRS, BWS) is challenging due to the broad spectrum of molecular defects and their mosaic occurrence. Additionally, the decision on the molecular testing algorithm is hindered by their clinical heterogeneity. However, the precise identification of the type of defect is often a prerequisite for the clinical management and genetic counselling. Four major molecular alterations (epimutations, uniparental disomies, copy number variants, single nucleotide variants) have been identified, but their frequencies vary between SRS and BWS. Due to their molecular aetiology, epimutations in both disorders as well as upd(11)pat in BWS are particular prone to mosaicism which might additionally complicate the interpretation of testing results. We report on our experience of molecular analysis in a total cohort of 1448 patients referred for diagnostic testing of BWS and SRS, comprising a dataset from 737 new patients and from 711 cases from a recent study. Though the majority of positively tested patients showed the expected molecular results, we identified a considerable number of clinically unexpected molecular alterations as well as not yet reported changes and discrepant mosaic distributions. Additionally, the rate of multilocus imprinting disturbances among the patients with epimutations and uniparental diploidies could be further specified. Altogether, these cases show that comprehensive testing strategies have to be applied in diagnostic testing of SRS and BWS. The precise molecular diagnosis is required as the basis for a targeted management (e.g. ECG (electrocardiogram) and tumour surveillance in BWS, growth treatment in SRS). The molecular diagnosis furthermore provides the basis for genetic counselling. However, it has to be considered that recurrence risk calculation is determined by the phenotypic consequences of each molecular alteration and mechanism by which the alteration arose. KEY MESSAGES: The detection rates for the typical molecular defects of Beckwith-Wiedemann syndrome or Silver-Russell syndrome (BWS, SRS) are lower in routine cohorts than in clinically well-characterised ones. A broad spectrum of (unexpected) molecular alterations in both disorders can be identified. Multilocus imprinting disturbances (MLID) are less frequent in SRS than expected. The frequency of MLID and uniparental diploidy in BWS is confirmed. Mosaicism is a diagnostic challenge in BWS and SRS. The precise determination of the molecular defects affecting is the basis for a targeted clinical management and genetic counselling.
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http://dx.doi.org/10.1007/s00109-020-01966-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524824PMC
October 2020

Gain-of-function mutation in SCN11A causes itch and affects neurogenic inflammation and muscle function in Scn11a+/L799P mice.

PLoS One 2020 20;15(8):e0237101. Epub 2020 Aug 20.

Institute of Physiology 1/Neurophysiology, University Hospital - Friedrich Schiller University Jena, Jena, Germany.

Mutations in the genes encoding for voltage-gated sodium channels cause profound sensory disturbances and other symptoms dependent on the distribution of a particular channel subtype in different organs. Humans with the gain-of-function mutation p.Leu811Pro in SCN11A (encoding for the voltage-gated Nav1.9 channel) exhibit congenital insensitivity to pain, pruritus, self-inflicted injuries, slow healing wounds, muscle weakness, Charcot-like arthropathies, and intestinal dysmotility. As already shown, knock-in mice (Scn11a+/L799P) carrying the orthologous mutation p.Leu799Pro replicate reduced pain sensitivity and show frequent tissue lesions. In the present study we explored whether Scn11a+/L799P mice develop also pruritus, muscle weakness, and changes in gastrointestinal transit time. Furthermore, we analyzed morphological and functional differences in nerves, skeletal muscle, joints and small intestine from Scn11a+/L799P and Scn11a+/+ wild type mice. Compared to Scn11a+/+ mice, Scn11a+/L799P mice showed enhanced scratching bouts before skin lesions developed, indicating pruritus. Scn11a+/L799P mice exhibited reduced grip strength, but no disturbances in motor coordination. Skeletal muscle fiber types and joint architecture were unaltered in Scn11a+/L799P mice. Their gastrointestinal transit time was unaltered. The small intestine from Scn11a+/L799P showed a small shift towards less frequent peristaltic movements. Similar proportions of lumbar dorsal root ganglion neurons from Scn11a+/L799P and Scn11a+/+ mice were calcitonin gene-related peptide (CGRP-) positive, but isolated sciatic nerves from Scn11a+/L799P mice exhibited a significant reduction of the capsaicin-evoked release of CGRP indicating reduced neurogenic inflammation. These data indicate important Nav1.9 channel functions in several organs in both humans and mice. They support the pathophysiological relevance of increased basal activity of Nav1.9 channels for sensory abnormalities (pain and itch) and suggest resulting malfunctions of the motor system and of the gastrointestinal tract. Scn11a+/L799P mice are suitable to investigate the role of Nav1.9, and to explore the pathophysiological changes and mechanisms which develop as a consequence of Nav1.9 hyperactivity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237101PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440628PMC
October 2020

Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles.

Brain 2020 08;143(8):2406-2420

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy.
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http://dx.doi.org/10.1093/brain/awaa206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447519PMC
August 2020

Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder.

Brain 2020 08;143(8):2437-2453

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.
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http://dx.doi.org/10.1093/brain/awaa204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447524PMC
August 2020

Inherited cases of CNOT3-associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies.

Clin Genet 2020 10 19;98(4):408-412. Epub 2020 Aug 19.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

De novo pathogenic variants in CNOT3 have recently been reported in a developmental delay disorder (intellectual developmental disorder with speech delay, autism, and dysmorphic facies [IDDSADF, OMIM: #618672]). The patients present with a variable degree of developmental delay and behavioral problems. To date, all reported disease-causing variants occurred de novo and no parent-child transmission was observed. We report for the first time autosomal dominant transmissions of the CNOT3-associated developmental disorder in two unrelated families. The clinical characteristics in our patients match the IDDSADF features reported so far and suggest substantial variability of the phenotype within the same family.
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http://dx.doi.org/10.1111/cge.13819DOI Listing
October 2020

Long-read sequencing to understand genome biology and cell function.

Int J Biochem Cell Biol 2020 09 3;126:105799. Epub 2020 Jul 3.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany. Electronic address:

Determining the sequence of DNA and RNA molecules has a huge impact on the understanding of cell biology and function. Recent advancements in next-generation short-read sequencing (NGS) technologies, drops in cost and a resolution down to the single-cell level shaped our current view on genome structure and function. Third-generation sequencing (TGS) methods further complete the knowledge about these processes based on long reads and the ability to analyze DNA or RNA at single molecule level. Long-read sequencing provides additional possibilities to study genome architecture and the composition of highly complex regions and to determine epigenetic modifications of nucleotide bases at a genome-wide level. We discuss the principles and advancements of long-read sequencing and its applications in genome biology.
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http://dx.doi.org/10.1016/j.biocel.2020.105799DOI Listing
September 2020

Genetic testing in inherited endocrine disorders: joint position paper of the European reference network on rare endocrine conditions (Endo-ERN).

Orphanet J Rare Dis 2020 06 8;15(1):144. Epub 2020 Jun 8.

Department of Paediatrics and Adolescent Medicine, Division of Paediatric Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany.

Background: With the development of molecular high-throughput assays (i.e. next generation sequencing), the knowledge on the contribution of genetic and epigenetic alterations to the etiology of inherited endocrine disorders has massively expanded. However, the rapid implementation of these new molecular tools in the diagnostic settings makes the interpretation of diagnostic data increasingly complex.

Main Body: This joint paper of the ENDO-ERN members aims to overview chances, challenges, limitations and relevance of comprehensive genetic diagnostic testing in rare endocrine conditions in order to achieve an early molecular diagnosis. This early diagnosis of a genetically based endocrine disorder contributes to a precise management and helps the patients and their families in their self-determined planning of life. Furthermore, the identification of a causative (epi)genetic alteration allows an accurate prognosis of recurrence risks for family planning as the basis of genetic counselling. Asymptomatic carriers of pathogenic variants can be identified, and prenatal testing might be offered, where appropriate.

Conclusions: The decision on genetic testing in the diagnostic workup of endocrine disorders should be based on their appropriateness to reliably detect the disease-causing and -modifying mutation, their informational value, and cost-effectiveness. The future assessment of data from different omic approaches should be embedded in interdisciplinary discussions using all available clinical and molecular data.
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http://dx.doi.org/10.1186/s13023-020-01420-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278165PMC
June 2020

Differential diagnosis of vacuolar myopathies in the NGS era.

Brain Pathol 2020 09 15;30(5):877-896. Epub 2020 Jun 15.

Institute of Neuropathology, RWTH Aachen University, Aachen, Germany.

Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non-inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late-onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr-caveolinopathy and of limb-girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.
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http://dx.doi.org/10.1111/bpa.12864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017999PMC
September 2020

A novel homozygous splice-site mutation in the SPTBN4 gene causes axonal neuropathy without intellectual disability.

Eur J Med Genet 2020 Apr 16;63(4):103826. Epub 2019 Dec 16.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Mutations in spectrin beta non-erythrocytic 4 (SPTBN4) have been linked to congenital hypotonia, intellectual disability and motor neuropathy. Here we report on two siblings with a homozygous splice-site mutation in the SPTBN4 gene, lacking previously reported features of the disorder such as seizures, feeding difficulties, respiratory difficulties or profound intellectual disability. Our findings indicate that muscular hypotonia, myopathic facies with ptosis and axonal neuropathy can be the core clinical features in the SPTBN4 disorder and suggest that SPTBN4 mutation analysis should be considered in infants with marked axonal neuropathy.
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http://dx.doi.org/10.1016/j.ejmg.2019.103826DOI Listing
April 2020

Novel Pathogenic Variants in a Cassette Exon of in Patients With Cerebral Cavernous Malformations.

Front Neurol 2019 20;10:1219. Epub 2019 Nov 20.

Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.

Autosomal dominant cerebral cavernous malformation (CCM) represents a genetic disorder with a high mutation detection rate given that stringent inclusion criteria are used and copy number variation analyses are part of the diagnostic workflow. Pathogenic variants in either (), or () can be identified in 87-98% of CCM families with at least two affected individuals. However, the interpretation of novel sequence variants in the 5'-region of remains challenging as there are various alternatively spliced transcripts and different transcription start sites. Comprehensive genetic and clinical data of CCM2 patients with variants in cassette exons that are either skipped or included into alternative transcripts in the splicing process can significantly facilitate clinical variant interpretation. We here report novel pathogenic variants in exon 3 and the adjacent donor splice site, describe the natural history of CCM disease in mutation carriers and provide further evidence for the classification of the amino acids encoded by the nucleotides of this cassette exon as a critical region within CCM2. Finally, we illustrate the advantage of a combined single nucleotide and copy number variation detection approach in NGS-based // gene panel analyses which can significantly reduce diagnostic turnaround time.
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http://dx.doi.org/10.3389/fneur.2019.01219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879547PMC
November 2019

Paroxysmal tonic upgaze: A heterogeneous clinical condition responsive to carbonic anhydrase inhibition.

Eur J Paediatr Neurol 2020 Mar 20;25:181-186. Epub 2019 Nov 20.

Division of Neuropediatrics and Social Pediatrics, Dept. of Pediatrics, University Hospital RWTH Aachen, Germany.

Background: Paroxysmal tonic upgaze (PTU), defined as an involuntary upward movement of the eyes, has been considered as a benign phenomenon but may also be associated with ataxia and developmental delay.

Methods: We report eight children with PTU; six of them also exhibiting symptoms of ataxia and/or developmental delay. Treatment with carbonic anhydrase inhibition was offered to children with persisting and/or severe forms.

Results: Whole-exome sequencing and genome-wide array analysis (n = 7) did not reveal mutations in the three known genes associated with PTU (CACNA1A, GRID2, SEPSECS), whereas by MLPA a heterozygous deletion of exon 31 of the CACNA1A gene could be detected in one patient, her mother and two further family members. Further exome and array analysis showed no recurrent variants in potentially novel PTU-related genes in more than one patient. A de novo variant at a highly conserved position in the SIM1 gene was detected in one patient, for which a pathogenic effect could be speculated. Carbonic anhydrase inhibition was started in five children and proved at least partially effective in all of them.

Conclusion: Irrespective of the clinical background and the molecular basic mechanism of PTU, therapeutic carbonic anhydrase inhibition was effective in all five children (acetazolamide, n = 3; sultiame, n = 2) who received this treatment.
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http://dx.doi.org/10.1016/j.ejpn.2019.11.002DOI Listing
March 2020

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3.

Nat Commun 2019 10 29;10(1):4919. Epub 2019 Oct 29.

Department of Neurology-centre de référence des epilepsies rares, University Hospital of Strasbourg, 1 Avenue Molière, 67200, Strasbourg, France.

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
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http://dx.doi.org/10.1038/s41467-019-12763-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820781PMC
October 2019

Germline Mutations Predispose to Pediatric Medulloblastoma.

J Clin Oncol 2020 01 14;38(1):43-50. Epub 2019 Oct 14.

RWTH Aachen University, Aachen, Germany.

Purpose: The identification of a heritable tumor predisposition often leads to changes in management and increased surveillance of individuals who are at risk; however, for many rare entities, our knowledge of heritable predisposition is incomplete.

Methods: Families with childhood medulloblastoma, one of the most prevalent childhood malignant brain tumors, were investigated to identify predisposing germline mutations. Initial findings were extended to genomes and epigenomes of 1,044 medulloblastoma cases from international multicenter cohorts, including retrospective and prospective clinical studies and patient series.

Results: We identified heterozygous germline mutations in the G protein-coupled receptor 161 () gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). mutations were exclusively associated with the sonic hedgehog medulloblastoma (MB) subgroup and accounted for 5% of infant MB cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at in all affected MB tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MB tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of deficiency and the primary mechanism for biallelic inactivation of in affected MB tumors.

Conclusion: Here, we describe a novel brain tumor predisposition syndrome that is caused by germline mutations and characterized by MB in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline mutations.
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http://dx.doi.org/10.1200/JCO.19.00577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943973PMC
January 2020

A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain.

Front Neurosci 2019 3;13:918. Epub 2019 Sep 3.

Department of Neurology, Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, United States.

Voltage-gated sodium channel Nav1.9 is a threshold channel that regulates action potential firing. Nav1.9 is preferentially expressed in myenteric neurons, and small-diameter dorsal root ganglion (DRG) and trigeminal ganglion neurons including nociceptors. Recent studies have demonstrated a monogenic Mendelian link of Nav1.9 to human pain disorders. Gain-of-function variants in Nav1.9, which cause smaller depolarizations of RMP, have been identified in patients with familial episodic pain type 3 (FEPS3) and the more common pain disorder small fiber neuropathy. To explore the phenotypic spectrum of Nav1.9 channelopathy, here we report a new Nav1.9 mutation, N816K, in a child with early-onset episodic pain in both legs, episodic abdominal pain, and chronic constipation. Sequencing of further selected pain genes was normal. N816K alters a residue at the N-terminus of loop 2, proximal to the cytoplasmic terminus of transmembrane segment 6 in domain II. Voltage-clamp recordings demonstrate that Nav1.9-N816K significantly increases current density and hyperpolarizes voltage-dependence of activation by 10 mV, enabling a larger window current. Current-clamp recordings in DRG neurons shows that N816K channels depolarize RMP of small DRG neurons by 7 mV, reduce current threshold of firing an action potential and render DRG neurons hyperexcitable. Taken together these data demonstrate gain-of-function attributes of the newly described N816K mutation at the channel and cellular levels, which are consistent with a pain phenotype in the carrier of this mutation.
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http://dx.doi.org/10.3389/fnins.2019.00918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733892PMC
September 2019

Genetic Variants in the Promoter Region of the Macrophage Migration Inhibitory Factor are Associated with the Severity of Hepatitis C Virus-Induced Liver Fibrosis.

Int J Mol Sci 2019 Jul 31;20(15). Epub 2019 Jul 31.

Department of Internal Medicine III, RWTH Aachen University Hospital, 52074 Aachen, Germany.

Two polymorphisms in the promoter region of macrophage migration inhibitory factor (MIF) - rs755622 and rs5844572 - exhibit prognostic relevance in inflammatory diseases. The aim of this study was to investigate a correlation between these MIF promoter polymorphisms and the severity of hepatitis C virus (HCV)-induced liver fibrosis. Our analysis included two independent patient cohorts with HCV-induced liver fibrosis (504 and 443 patients, respectively). The genotype of the single nucleotide polymorphism (SNP) -173 G/C and the repeat number of the microsatellite polymorphism -794 CATT were determined in DNA samples and correlated with fibrosis severity. In the first cohort, homozygous carriers of the C allele in the rs755622 had lower fibrosis stages compared to heterozygous carriers or wild types (1.25 vs. 2.0 vs. 2.0; = 0.03). Additionally, ≥7 microsatellite repeats were associated with lower fibrosis stages (
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http://dx.doi.org/10.3390/ijms20153753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696142PMC
July 2019

Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia.

Exp Neurol 2019 10 24;320:112958. Epub 2019 May 24.

John van Geest Centre for Brain Repair, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK; Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK. Electronic address:

We identified a homozygous missense mutation in the gene encoding NAD synthesizing enzyme NMNAT2 in two siblings with childhood onset polyneuropathy with erythromelalgia. No additional homozygotes for this rare allele, which leads to amino acid substitution T94M, were present among the unaffected relatives tested or in the 60,000 exomes of the ExAC database. For axons to survive, axonal NMNAT2 activity has to be maintained above a threshold level but the T94M mutation confers a partial loss of function both in the ability of NMNAT2 to support axon survival and in its enzymatic properties. Electrophysiological tests and histological analysis of sural nerve biopsies in the patients were consistent with loss of distal sensory and motor axons. Thus, it is likely that NMNAT2 mutation causes this pain and axon loss phenotype making this the first disorder associated with mutation of a key regulator of Wallerian-like axon degeneration in humans. This supports indications from numerous animal studies that the Wallerian degeneration pathway is important in human disease and raises important questions about which other human phenotypes could be linked to this gene.
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http://dx.doi.org/10.1016/j.expneurol.2019.112958DOI Listing
October 2019

Contribution of GRB10 to the prenatal phenotype in Silver-Russell syndrome? Lessons from 7p12 copy number variations.

Eur J Med Genet 2019 Jul 14;62(7):103671. Epub 2019 May 14.

Institute of Human Genetics, University Hospital, Technical University Aachen (RWTH), Aachen, Germany.

The growth factor binding protein 10 (GRB10) has been suggested as a candidate gene for Silver-Russell syndrome because of its localization in 7p12, its imprinting status, data from mice models and its putative role in growth. Based on a new patient with normal growth carrying a GRB10 deletion affecting the paternal allele and data from the literature, we conclude that the heterogeneous clinical findings in patients with copy number variations (CNVs) of GRB10 gene depend on the size and the gene content of the CNV. However, evidence from mouse and human cases indicate a growth suppressing role of GRB10 in prenatal development. As a result, an increase of active maternal GRB10 copies, e.g. by maternal uniparental disomy of chromosome 7 or duplications of the region results in intrauterine growth retardation. In contrast, a defective GRB10 copy might result in prenatal overgrowth, whereas the paternal GRB10 allele is not required for proper prenatal growth.
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http://dx.doi.org/10.1016/j.ejmg.2019.103671DOI Listing
July 2019
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