CMMC: FP 2020-2022 - Nürnberg, Peter | Hussain, Muhammad Sajid

Introduction

In this project, we are studying C1orf131 that we identified as a novel gene involved in intellectual disability. The protein product plays a crucial role in maintaining the structural integrity of the nucleolus. It seems to be essential for a normal brain development and function. A better understanding of the nucleolar and mitotic function of C1orf131 will shed light on the cellular processes disrupted in C1orf131-mutated individuals. Data obtained from this study will give us an unprecedented opportunity to gain new insights into the gene regulatory networks required to form an optimally functional brain.

Intellectual disability (ID) is characterized by substantial limitations in both intellectual functioning and adaptive behavior. Its worldwide prevalence is estimated to range from 1% to 3%, which casts a serious socio-economic burden on societies. Based on the inheritance patterns, ID is classified into X-linked, autosomal recessive (ARID) and dominant. We studied a Pakistani family featuring ARID and identified linkage regions with a maximum possible LOD score of 2.4 on chromosomes 1, 2, 15 and 21. Whole-exome sequencing (WES) of two affected members revealed a missense mutation (NM_152379.3;c.112G>A; p.Asp38Asn) in C1orf131 located in the linkage region on chromosome 1. The mutated residue is highly conserved and its substitution is predicted to be pathogenic by several in silico tools. Virtually nothing has been reported about C1orf131 or its protein product. Our preliminary data suggest that it is a novel nucleolar component that relocates to the chromosomal periphery during mitosis. Depletion of the protein as observed in both patient fibroblasts or cells treated with siRNA resulted in distorted nucleoli. Intriguingly, pulldown data also showed that it interacts with several nucleolar and centrosomal proteins.

Here we propose to explore the potential involvement of the C1orf131 protein in nucleolar functions and cell cycle progression and to study their impairment. We also aim to investigate its role in neurogenesis by generating single-cell RNA sequencing (scRNA-seq) data of cerebral organoids, generated from patient-derived fibroblasts via induced pluripotent stem cells (iPSC). These data will allow us to dissect the progenitor/neuronal cell ratio and progenitor-to-neuron lineage relationships. Assuming high relevance for their etiology, we are confident to elucidate yet unknown mechanisms underlying ARID and microcephaly.

Our Aims

To investigate the effects of C1orf131 mutations on nucleolar and mitotic pathways
To study the role of C1orf131 for a normal brain function with the help of
- Transcriptional profiling by scRNA-seq of human cerebral organoids derived from C1orf131-mutated cellI
- In vivo knockdown by in utero electroporation in mouse embryonic brain

Previous Work

The main focus of our research is to unravel genetic causes of neurodevelopmental disorders and to explore the consequences of the identified mutations. In the last decade, we have provided new insights into the genetic etiology of families afflicted with primary microcephaly (MCPH), microcephalic primordial dwarfism (MPD) and Filippi syndrome (FS) using state-of-the-art genetic, biochemical and cell-biological methods (Table 1). Somatic cells of a patient from a Pakistani MCPH family with a homozygous truncating frame shift mutation (c.970delC, p.Gln324Serfs*2) of CEP135 showed characteristic features of aberrant centrosomes like multiple or fragmented centrosomes along with disorganized microtubules (Figure 1A). We also found a homozygous nonsense mutation (NM_017668.2; c.658C>T, p.Arg220*) of NDE1 in an

Table 1: Progress in identifying novel disease-associated genes for neurodevelopmental disorders in recent years
No	Disorder	Gene	Consequences of the identified mutations
1	MCPH	CEP135	Centrosomal dysfunctions, multiple and fragmented centrosomes, disorganized microtubules.
2	MCPH	CDK6	Association with centrosome, depletion causes supernumerary centrosomes, disorganized microtubules.
3	MCPH	KIF14	Midbody protein, mutation triggered loss of CRIK (citron rho-interacting kinase) at the midbody that consequently impaired cytokinesis and led to apoptosis.
4	MCPH	NUP37	Component of outer rings of the nuclear pore complex (NPC), mutation altered the amount and localization of other NPCs — NUP160 and NUP133 — and decreased the number of nuclear pores.
5	MPD	PLK4	Mutation activates a novel cryptic splice acceptor site and introduces a premature termination codon. It impaired centriole biogenesis and resulted in a monopolar configuration, centriole loss and defective spindle formation.
6	FS	CKAP2L	First genetic cause of Filippi syndrome, mutation caused disorganized spindle microtubules, multipolar configurations and defects in chromosome segregation.
7	ARID	C1orf131	New ARID gene encoding a novel nucleolar protein, its depletion causes a distortion of the nucleoli.

MCPH patient of Yemeni origin. Primary fibroblasts of the patient showed an impaired localization pattern of the mutant protein (NudE) in form of aggregates within the nucleus as well as faint staining at the centrosomes as detected by ϒ-tubulin (Figure 1B). Investigation of CENPJ-mutated cells(NM_018451.4: c.18delC, p.Ser7Profs*2) resulted in the impairment of centriole (Figure 1C, left panel) and centrosome (Figure 1C, right panel) duplication, which depicts the role of CENP-J in centriole duplication (Figure 1C). One of our most recent findings is the identification of novel MCPH gene named KIAA0408 which encodes a novel centrosomal protein (Figure 1D).

Project Related Publications

Braun DA, Lovric S, Schapiro D, Schneider R, Marquez J, Asif M, Hussain MS, Daga A, Widmeier E, Rao J, Ashraf S, Tan W, Lusk CP, Kolb A, Jobst-Schwan T, Schmidt JM, Hoogstraten CA, Eddy K, Kitzler TM, Shril S, Moawia A, Schrage K, Khayyat AIA, Lawson JA1, Gee HY, Warejko JK, Hermle T, Majmundar AJ, Hugo H, Budde B, Motameny S, Altmüller J, Noegel AA, Fathy HM, Gale DP, Waseem SS, Khan A, Kerecuk L, Hashmi S, Mohebbi N, Ettenger R, Serdaroğlu E, Alhasan KA, Hashem M, Goncalves S, Ariceta G, Ubetagoyena M, Antonin W, Baig SM, Alkuraya FS, Shen Q, Xu H, Antignac C, Lifton RP, Mane S, Nürnberg P, Khokha MK, Hildebrandt F. Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. J Clin Invest. (2018); 128: 4313-4328.
Moawia A, Shaheen R, Rasool S, Waseem SS, Ewida N, Budde B, Kawalia A, Motameny S, Khan K, Fatima A, Jameel M, Ullah F, Akram T, Ali Z, Abdullah U, Irshad S, Höhne W, Noegel AA, Al-Owain M, Hörtnagel K, Stöbe P, Baig SM, Nürnberg P,** Alkuraya FS, Hahn A, Hussain MS. Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann Neurol. (2017); 82(4): 562-577. **Joint senior author.
Hussain MS, Battaglia, A. Szczepanski, S. Kaygusuz, E. Toliat, M.R. Sakakibara, S. Altmüller, J. Thiele, H. Nürnberg, G. Moosa, S. Yigit G, Beleggia F, Tinschert S, Clayton-Smith J, Vasudevan P, Urquhart JE, Donnai D, Fryer A, Percin F, Brancati F, Dobbie A, Smigiel R, Gillessen-Kaesbach G, Wollnik B, Noegel AA, Newman WG, Nürnberg P. Mutations in CKAP2L, the Human Ortholog of the Mouse Radmis Gene, Cause Filippi Syndrome. Am. J. Hum. Genet. (2014); 95: 622-632.
Martin, C. Ahmad, I. Klingseisen, A. Hussain, MS*. Bicknell, LS. Leitch, A. Nürnberg, G. Toliat, MR. Murray, JE. Hunt, D. Khan F, Ali Z, Tinschert S, Ding J, Keith C, Harley ME, Heyn P, Müller R, Hoffmann I, Cormier-Daire V, Dollfus H, Dupuis L, Bashamboo A, McElreavey K, Kariminejad A, Mendoza-Londono R, Moore AT, Saggar A, Schlechter C, Weleber R, Thiele H, Altmüller J, Höhne W, Hurles ME, Noegel AA, Baig SM, Nürnberg P,** Jackson AP. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nature Genetics, (2014); 46: 1283-1292. *Joint first author, **Joint senior author.
Hussain M.S, Baig S.M, Neumann S, Nürnberg G, Farooq M, Ahmad I, Wajid M, Alef T, Hennies H-C, Technau M, Altmüller J, Frommolt P, Thiele H, Noegel A.A, Nürnberg P. A Truncating Mutation of CEP135 is associated with primary microcephaly and disturbed centrosomal function. Am. J. Hum. Genet. (2012); 90: 871–878.

Publications 2022 until 10/2022

Asif M, Kaygusuz E, Shinawi M, Nickelsen A, Hsieh TC, Wagle P, Budde BS, Hochscherf J, Abdullah U, Honing S, Nienberg C, Lindenblatt D, Noegel AA, Altmuller J, Thiele H, Motameny S, Fleischer N, Segal I, Pais L, Tinschert S, Samra NN, Savatt JM, Rudy NL, De Luca C, Italian Undiagnosed Diseases N, Paola F, White SM, Krawitz P, Hurst ACE, Niefind K, Jose J, Brancati F, Nurnberg P, and Hussain MS (2022). De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway. HGG Adv3, 100111. doi:10.1016/j.xhgg.2022.100111.

Dufour W, Alawbathani S, Jourdain AS, Asif M, Baujat G, Becker C, Budde B, Gallacher L, Georgomanolis T, Ghoumid J, Hohne W, Lyonnet S, Ba-Saddik IA, Manouvrier-Hanu S, Motameny S, Noegel AA, Pais L, Vanlerberghe C, Wagle P, White SM, Willems M, Nurnberg P, Escande F, Petit F, and Hussain MS (2022). Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling. Genet Med. doi:10.1016/j.gim.2022.04.022.

Neitzel H, Varon R, Chughtai S, Dartsch J, Dutrannoy-Tonsing V, Nurnberg P, Nurnberg G, Schweiger M, Digweed M, Hildebrand G, Hackmann K, Holtgrewe M, Sarioglu N, Schulze B, Horn D, and Sperling K (2022). Transmission ratio distortion of mutations in the master regulator of centriole biogenesis PLK4. Hum Genet. doi:10.1007/s00439-022-02461-w.

Schmidt J, Schreiber G, Altmuller J, Thiele H, Nurnberg P, Li Y, Kaulfuss S, Funke R, Wilken B, Yigit G, and Wollnik B (2022). Familial cleft tongue caused by a unique translation initiation codon variant in TP63. Eur J Hum Genet30, 211-218. doi:10.1038/s41431-021-00967-x.

Wong KM, Jepsen WM, Efthymiou S, Salpietro V, Sanchez-Castillo M, Yip J, Kriouile Y, Diegmann S, Dreha-Kulaczewski S, Altmuller J, Thiele H, Nurnberg P, Toosi MB, Akhondian J, Ghayoor Karimiani E, Hummel-Abmeier H, Huppke B, Houlden H, Gartner J, Maroofian R, and Huppke P (2022). Mutations in TAF8 cause a neurodegenerative disorder. Brain. doi:10.1093/brain/awac154.

Hauke J, Harter P, Ernst C, Burges A, Schmidt S, Reuss A, Borde J, De Gregorio N, Dietrich D, El-Balat A, Kayali M, Gevensleben H, Hilpert F, Altmuller J, Heimbach A, Meier W, Schoemig-Markiefka B, Thiele H, Kimmig R, Nurnberg P, Kast K, Richters L, Sehouli J, Schmutzler RK, and Hahnen E (2022). Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in BRCA1/2: results of the observational AGO-TR1 study (NCT02222883). J Med Genet59, 248-252. doi:10.1136/jmedgenet-2020-107353.

Asif M, Mocanu ID, Abdullah U, Hohne W, Altmuller J, Makhdoom EUH, Thiele H, Baig SM, Nurnberg P, Graul-Neumann L, and Hussain MS (2022). A novel missense variant of SCN4A co-segregates with congenital essential tremor in a consanguineous Kurdish family. Am J Med Genet A 188, 1251-1258. doi:10.1002/ajmg.a.62610.

Gonenc, II, Elcioglu NH, Martinez Grijalva C, Aras S, Grossmann N, Praulich I, Altmuller J, Kaulfuss S, Li Y, Nurnberg P, Burfeind P, Yigit G, and Wollnik B (2022). Phenotypic spectrum of BLM- and RMI1-related Bloom syndrome. Clin Genet 101, 559-564. doi:10.1111/cge.14125.

Tschernoster N, Erger F, Walsh PR, McNicholas B, Fistrek M, Habbig S, Schumacher AL, Folz-Donahue K, Kukat C, Toliat MR, Becker C, Thiele H, Kavanagh D, NurnbergP, Beck BB, and Altmuller J (2022). Unraveling Structural Rearrangements of the CFH Gene Cluster in Atypical Hemolytic Uremic Syndrome Patients Using Molecular Combing and Long-Fragment Targeted Sequencing. J Mol Diagn 24, 619-631. doi:10.1016/j.jmoldx.2022.02.006.

Tschernoster N, Erger F, Walsh PR, McNicholas B, Fistrek M, Habbig S, Schumacher L, Folz-Donahue K, Kukat C, Toliat MR, Becker C, Thiele H, Kavanagh D, Nurnberg P, Beck B, and Altmuller J (2022). None Fits All: Unraveling Structural Rearrangements of the CFH Gene Cluster in Atypical Hemolytic Uremic Syndrome Patients Using Molecular Combing and Long-Fragment Targeted Sequencing. J Mol Diagn. doi:10.1016/j.jmoldx.2022.02.006.

Publications 2021

Asif M, Mocanu ID, Abdullah U, Hohne W, Altmuller J, Makhdoom EUH, Thiele H, Baig SM, Nurnberg P, Graul-Neumann L, and Hussain MS (2021). A novel missense variant of SCN4A co-segregates with congenital essential tremor in a consanguineous Kurdish family. Am J Med Genet A. doi:10.1002/ajmg.a.62610.

Bamborschke D, Ozdemir O, Kreutzer M, Motameny S, Thiele H, Kribs A, Dotsch J, Altmuller J, Nurnberg P, and Cirak S (2021). Ultra-rapid emergency genomic diagnosis of Donahue syndrome in a preterm infant within 17 hours. Am J Med Genet A185, 90-96. doi:10.1002/ajmg.a.61917.

Daimaguler HS, Akpulat U, Ozdemir O, Yis U, Gungor S, Talim B, Diniz G, Baydan F, Thiele H, Altmuller J, Nurnberg P, and Cirak S (2021). Clinical and genetic characterization of PYROXD1-related myopathy patients from Turkey. Am J Med Genet A185, 1678-1690. doi:10.1002/ajmg.a.62148.

Gizak A, Diegmann S, Dreha-Kulaczewski S, Wisniewski J, Duda P, Ohlenbusch A, Huppke B, Henneke M, Hohne W, Altmuller J, Thiele H, Nurnberg P, Rakus D, Gartner J, and Huppke P (2021). A novel remitting leukodystrophy associated with a variant in FBP2. Brain Commun3, fcab036. doi:10.1093/braincomms/fcab036.

Iqbal M, Maroofian R, Cavdarli B, Riccardi F, Field M, Banka S, Bubshait DK, Li Y, Hertecant J, Baig SM, Dyment D, Efthymiou S, Abdullah U, Makhdoom EUH, Ali Z, Scherf de Almeida T, Molinari F, Mignon-Ravix C, Chabrol B, Antony J, Ades L, Pagnamenta AT, Jackson A, Douzgou S, Genomics England Research C, Beetz C, Karageorgou V, Vona B, Rad A, Baig JM, Sultan T, Alvi JR, Maqbool S, Rahman F, Toosi MB, Ashrafzadeh F, Imannezhad S, Karimiani EG, Sarwar Y, Khan S, Jameel M, Noegel AA, Budde B, Altmuller J, Motameny S, Hohne W, Houlden H, Nurnberg P, Wollnik B, Villard L, Alkuraya FS, Osmond M, Hussain MS, and Yigit G (2021). Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies. Genet Med23, 2138-2149. doi:10.1038/s41436-021-01260-4.

Kargapolova Y, Rehimi R, Kayserili H, Bruhl J, Sofiadis K, Zirkel A, Palikyras S, Mizi A, Li Y, Yigit G, Hoischen A, Frank S, Russ N, Trautwein J, van Bon B, Gilissen C, Laugsch M, Gusmao EG, Josipovic N, Altmuller J, Nurnberg P, Langst G, Kaiser FJ, Watrin E, Brunner H, Rada-Iglesias A, Kurian L, Wollnik B, Bouazoune K, and Papantonis A (2021). Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology. Nat Commun12, 3014. doi:10.1038/s41467-021-23327-1.

Keller N, Paketci C, Altmueller J, Fuhrmann N, Wunderlich G, Schrank B, Unver O, Yilmaz S, Boostani R, Karimiani EG, Motameny S, Thiele H, Nurnberg P, Maroofian R, Yis U, Wirth B, and Karakaya M (2021). Genomic variants causing mitochondrial dysfunction are common in hereditary lower motor neuron disease. Hum Mutat42, 460-472. doi:10.1002/humu.24181.

Waseem SS, Moawia A, Budde B, Tariq M, Khan A, Ali Z, Khan S, Iqbal M, Malik NA, Haque SU, Altmüller J, Thiele H, Hussain MS, Cirak S, Baig SM, Nürnberg P (2021). A Homozygous AKNA Frameshift Variant Is Associated with Microcephaly in a Pakistani Family. Genes (Basel)12. doi: 10.3390/genes12101494.

Makhdoom EUH, Waseem SS, Iqbal M, Abdullah U, Hussain G, Asif M, Budde B, Hohne W, Tinschert S, Saadi SM, Yousaf H, Ali Z, Fatima A, Kaygusuz E, Khan A, Jameel M, Khan S, Tariq M, Anjum I, Altmuller J, Thiele H, Honing S, Baig SM, Nurnberg P, and Hussain MS (2021). Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ. Genes (Basel)12. doi:10.3390/genes12050731.

Ramzan S, Tennstedt S, Tariq M, Khan S, Noor Ul Ayan H, Ali A, Munz M, Thiele H, Korejo AA, Mughal AR, Jamal SZ, Nurnberg P, Baig SM, Erdmann J, and Ahmad I (2021). A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family. Genes (Basel)12. doi:10.3390/genes12081282.

Rosswog C, Bartenhagen C, Welte A, Kahlert Y, Hemstedt N, Lorenz W, Cartolano M, Ackermann S, Perner S, Vogel W, Altmuller J, Nurnberg P, Hertwig F, Gohring G, Lilienweiss E, Stutz AM, Korbel JO, Thomas RK, Peifer M, and Fischer M (2021). Chromothripsis followed by circular recombination drives oncogene amplification in human cancer. Nat Genet53, 1673-1685. doi:10.1038/s41588-021-00951-7.

Schmidt J, Schreiber G, Altmuller J, Thiele H, Nurnberg P, Li Y, Kaulfuss S, Funke R, Wilken B, Yigit G, and Wollnik B (2021). Familial cleft tongue caused by a unique translation initiation codon variant in TP63. Eur J Hum Genet. doi:10.1038/s41431-021-00967-x.

Schmidt J, Goergens J, Pochechueva T, Kotter A, Schwenzer N, Sitte M, Werner G, Altmuller J, Thiele H, Nurnberg P, Isensee J, Li Y, Muller C, Leube B, Reinhardt HC, Hucho T, Salinas G, Helm M, Jachimowicz RD, Wieczorek D, Kohl T, Lehnart SE, Yigit G, and Wollnik B (2021). Biallelic variants in YRDC cause a developmental disorder with progeroid features. Hum Genet140, 1679-1693. doi:10.1007/s00439-021-02347-3.

Sprute R, Jergas H, Olmez A, Alawbathani S, Karasoy H, Dafsari HS, Becker K, Daimaguler HS, Nurnberg P, Muntoni F, Topaloglu H, Uyanik G, and Cirak S (2021). Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations. Am J Med Genet A185, 344-354. doi:10.1002/ajmg.a.61951.

Theobald SJ, Simonis A, Georgomanolis T, Kreer C, Zehner M, Eisfeld HS, Albert MC, Chhen J, Motameny S, Erger F, Fischer J, Malin JJ, Grab J, Winter S, Pouikli A, David F, Boll B, Koehler P, Vanshylla K, Gruell H, Suarez I, Hallek M, Fatkenheuer G, Jung N, Cornely OA, Lehmann C, Tessarz P, Altmuller J, Nurnberg P, Kashkar H, Klein F, Koch M, and Rybniker J (2021). Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19. EMBO Mol Med13, e14150. doi:10.15252/emmm.202114150.

Warnat-Herresthal S, Schultze H, Shastry KL, Manamohan S, Mukherjee S, Garg V, Sarveswara R, Handler K, Pickkers P, Aziz NA, Ktena S, Tran F, Bitzer M, Ossowski S, Casadei N, Herr C, Petersheim D, Behrends U, Kern F, Fehlmann T, Schommers P, Lehmann C, Augustin M, Rybniker J, Altmuller J, Mishra N, Bernardes JP, Kramer B, Bonaguro L, Schulte-Schrepping J, De Domenico E, Siever C, Kraut M, Desai M, Monnet B, Saridaki M, Siegel CM, Drews A, Nuesch-Germano M, Theis H, Heyckendorf J, Schreiber S, Kim-Hellmuth S, Study C-A, Nattermann J, Skowasch D, Kurth I, Keller A, Bals R, Nurnberg P, Riess O, Rosenstiel P, Netea MG, Theis F, Mukherjee S, Backes M, Aschenbrenner AC, Ulas T, Deutsche C-OI, Breteler MMB, Giamarellos-Bourboulis EJ, Kox M, Becker M, Cheran S, Woodacre MS, Goh EL, and Schultze JL (2021). Swarm Learning for decentralized and confidential clinical machine learning. Nature594, 265-270. doi:10.1038/s41586-021-03583-3.

Young N, Asif M, Jackson M, Fernandez-Mayoralas DM, de la Pena MJ, Calleja-Perez B, Alvarez S, Hunter-Featherstone E, Noegel AA, Hohne W, Nurnberg P, Obara B, Hussain MS, Karakesisoglou I, and Fernandez-Jaen A (2021). Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism. Genes (Basel)12. doi:10.3390/genes12091294.

Publications 2020

Balogh E, Chandler JC, Varga M, Tahoun M, Menyhard DK, Schay G, Goncalves T, Hamar R, Legradi R, Szekeres A, Gribouval O, Kleta R, Stanescu H, Bockenhauer D, Kerti A, Williams H, Kinsler V, Di WL, Curtis D, Kolatsi-Joannou M, Hammid H, Szocs A, Perczel K, Maka E, Toldi G, Sava F, Arrondel C, Kardos M, Fintha A, Hossain A, D'Arco F, Kaliakatsos M, Koeglmeier J, Mifsud W, Moosajee M, Faro A, Javorszky E, Rudas G, Saied MH, Marzouk S, Kelen K, Gotze J, Reusz G, Tulassay T, Dragon F, Mollet G, Motameny S, Thiele H, Dorval G, Nurnberg P, Perczel A, Szabo AJ, Long DA, Tomita K, Antignac C, Waters AM, and Tory K (2020). Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis. Proc Natl Acad Sci U S A 117, 15137-47.

Budde BS, Aly MA, Mohamed MR, Bress A, Altmuller J, Motameny S, Kawalia A, Thiele H, Konrad K, Becker C, Toliat MR, Nurnberg G, Sayed EAF, Mohamed ES, Pfister M, and Nurnberg P (2020). Comprehensive molecular analysis of 61 Egyptian families with hereditary nonsyndromic hearing loss. Clin Genet 10.1111/cge.13754.

Ding C, Scicluna BP, Stroo I, Yang J, Roelofs JJ, de Boer OJ, de Vos AF, Nurnberg P, Revenko AS, Crosby J, Van't Veer C, and van der Poll T (2020). Prekallikrein inhibits innate immune signaling in the lung and impairs host defense during pneumosepsis in mice. J Pathol 250, 95-106.

Erger F, Norling D, Borchert D, Leenen E, Habbig S, Wiesener MS, Bartram MP, Wenzel A, Becker C, Toliat MR, Nurnberg P, Beck BB, and Altmuller J (2020). cfNOMe - A single assay for comprehensive epigenetic analyses of cell-free DNA. Genome Med 12, 54.

Farooq M, Lindbæk L, Krogh N, Doganli C, Keller C, Mönnich M, Gonçalves AB, Sakthivel S, Mang Y, Fatima A, Andersen VS, Hussain MS, Eiberg H, Hansen L, Kjaer KW, Gopalakrishnan J, Pedersen LB, Møllgård K, Nielsen H, Baig SM, Tommerup N, Christensen ST, Larsen LA (2020). RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis. Nat Commun11, 5816. doi: 10.1038/s41467-020-19658-0.Bamborschke D, Daimagüler HS, Hahn A, Hussain MS, Nürnberg P, Cirak S (2020). Mutation in CEP135 causing primary microcephaly and subcortical heterotopia. Am J Med Genet A182, 2450-2453. doi: 10.1002/ajmg.a.61762.

Farooq M, Lindbaek L, Krogh N, Doganli C, Keller C, Monnich M, Goncalves AB, Sakthivel S, Mang Y, Fatima A, Andersen VS, Hussain MS, Eiberg H, Hansen L, Kjaer KW, Gopalakrishnan J, Pedersen LB, Mollgard K, Nielsen H, Baig SM, Tommerup N, Christensen ST, and Larsen LA (2020). RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis. Nat Commun 11, 5816. doi:10.1038/s41467-020-19658-0.

Hauke J, Harter P, Ernst C, Burges A, Schmidt S, Reuss A, Borde J, De Gregorio N, Dietrich D, El-Balat A, Kayali M, Gevensleben H, Hilpert F, Altmuller J, Heimbach A, Meier W, Schoemig-Markiefka B, Thiele H, Kimmig R, Nurnberg P, Kast K, Richters L, Sehouli J, Schmutzler RK, and Hahnen E (2020). Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in BRCA1/2: results of the observational AGO-TR1 study (NCT02222883). Journal of medical genetics 10.1136/jmedgenet-2020-107353.

Karsak M, Glebov K, Scheffold M, Bajaj T, Kawalia A, Karaca I, Rading S, Kornhuber J, Peters O, Diez-Fairen M, Frolich L, Hull M, Wiltfang J, Scherer M, Riedel-Heller S, Schneider A, Heneka MT, Fliessbach K, Sharaf A, Thiele H, Lennarz M, Jessen F, Maier W, Kubisch C, Ignatova Z, Nurnberg P, Pastor P, Walter J, and Ramirez A (2020). A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2. Hum Mutat 41, 169-81.

Lessel I, Chen MJ, Luttgen S, Arndt F, Fuchs S, Meien S, Thiele H, Jones JR, Shaw BR, Crossman DK, Nurnberg P, Korf BR, Kubisch C, and Lessel D (2020). Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies. Hum Genet 139, 483-98.

Niestroj LM, Perez-Palma E, Howrigan DP, Zhou Y, Cheng F, Saarentaus E, Nurnberg P, Stevelink R, Daly MJ, Palotie A, Lal D, and Epi C (2020). Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects. Brain 143, 2106-18.

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