Deciphering the molecular genetics of neurodevelopmental disorders and unraveling the functions of novel brain regulators
Neurodevelopmental disorders (NDDs) arise from disruptions in brain development. Human brain development requires precise orchestration and interplay of diverse cellular and molecular processes involving distinct cell types and defined stages over a long period. As such, brain development is highly vulnerable to genetic or environmental perturbations. Disruptions at different stages – whether in proliferation, differentiation, cellular migration, or the establishment of neural connections - can lead to a wide spectrum of cognitive, behavioral, or motor deficits.
The central focus of our research is to uncover the molecular and genetic mechanisms underlying NDDs. We have ascertained a large cohort of 860 patients, primarily from Pakistan and Yemen, manifesting known and novel syndromes of neurodevelopmental disorders like autosomal recessive primary microcephaly, intellectual disability, primordial dwarfism, and Seckel syndrome. Using state-of-the-art genomic approaches, we were able to identify disease-causing variants in several known and multiple novel genes, thus unraveling novel brain regulators. We are currently exploring the functions of these novel components in the development of the functional brain.
For several patients, the genetic causes remain elusive using short-read sequencing technologies; we therefore aim to explore the genetic determinants of these unsolved patients using long-read NGS applications.
Newly identified gene products will expand the emerging network of the involved pathways. Understanding these novel pathways will be instrumental in the development of better treatments for these disorders. In the long term, this study will improve the diagnostics of the patients and provide a solid basis for genetic counselling of affected families.
Members
Group Leader
Alumni
Dr. Faiza Aslam
Dr. Faiza Latif
Dr. Maria Asif
Dr. Arwa Khayyat
Dr. Salem Alawbathani
Dr. Abubakar Moawia
Dr. Kathrin Schrage
Dr. Emrah Kaygusuz
Dr. Ilyas Ahmed
Dr. Sandra Szczepanski
Aseel Rudaini Abdulkareem
Collaborators
Prof. Dr. Shahid Mahmood Baig, Health Services Academy (HSA), Pakistan
Prof. Dr. Uzma Abdullah, PMAS-Arid Agriculture University, Pakistan
Dr. Reem Elshafie, Kuwait Medical Genetic Center
Prof. Dr. Florence Petit, Clinique de génétique, Hôpital Jeanne de Flandre, CHU DE LILLE, Lille Cedex France
Prof. Dr. Matthias Hammerschmidt, Institute of Zoology, University of Cologne
Dr. Hans-Martin Pogoda, Institute of Zoology, University of Cologne
Dr. Hirotsugu Oda, CECAD, University of Cologne
Selected Publications
Asif, M., Khayyat, A.I.A., Alawbathani, S., Abdullah, U., Sanner, A., Georgomanolis, T., Haasters, J., Becker, K., Budde, B., Becker, C., Thiele, H., Baig, S.M., Isidoro-Garcia, M., Winter, D., Pogoda, H.M., Muhammad, S., Hammerschmidt, M., Kraft, F., Kurth, I., Martin, H.G., Wagner, M., Nurnberg, P., and Hussain, M.S. (2024). Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia. Genetics in medicine : official journal of the American College of Medical Genetics 26, 101143. https://www.ncbi.nlm.nih.gov/pubmed/38641995.
Asif, M., Abdullah, U., Nurnberg, P., Tinschert, S., and Hussain, M.S. (2023). Congenital Microcephaly: A Debate on Diagnostic Challenges and Etiological Paradigm of the Shift from Isolated/Non-Syndromic to Syndromic Microcephaly. Cells 12. https://www.ncbi.nlm.nih.gov/pubmed/36831309.
Dufour, W., Alawbathani, S., Jourdain, A.S., Asif, M., Baujat, G., Becker, C., Budde, B., Gallacher, L., Georgomanolis, T., Ghoumid, J., Hohne, W., Lyonnet, S., Ba-Saddik, I.A., Manouvrier-Hanu, S., Motameny, S., Noegel, A.A., Pais, L., Vanlerberghe, C., Wagle, P., White, S.M., Willems, M., Nurnberg, P., Escande, F., Petit, F., and Hussain,M.S. (2022). Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling. Genetics in medicine : official journal of the American College of Medical Genetics 24, 1708-1721. https://www.ncbi.nlm.nih.gov/pubmed/35583550.
Asif, M., Kaygusuz, E., Shinawi, M., Nickelsen, A., Hsieh, T.C., Wagle, P., Budde, B.S., Hochscherf, J., Abdullah, U., Honing, S., Nienberg, C., Lindenblatt, D., Noegel, A.A., Altmuller, J., Thiele, H., Motameny, S., Fleischer, N., Segal, I., Pais, L., Tinschert, S., Samra, N.N., Savatt, J.M., Rudy, N.L., De Luca, C., Italian Undiagnosed Diseases, N., Paola, F., White, S.M., Krawitz, P., Hurst, A.C.E., Niefind, K., Jose, J., Brancati, F., Nurnberg, P., and Hussain, M.S. (2022). De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway. HGG Adv 3, 100111. https://www.ncbi.nlm.nih.gov/pubmed/35571680.
Iqbal, M., Maroofian, R., Cavdarli, B., Riccardi, F., Field, M., Banka, S., Bubshait, D.K., Li, Y., Hertecant, J., Baig, S.M., Dyment, D., Efthymiou, S., Abdullah, U., Makhdoom, E.U.H., Ali, Z., Scherf de Almeida, T., Molinari, F., Mignon-Ravix, C., Chabrol, B., Antony, J., Ades, L., Pagnamenta, A.T., Jackson, A., Douzgou, S., Genomics England Research, C., Beetz, C., Karageorgou, V., Vona, B., Rad, A., Baig, J.M., Sultan, T., Alvi, J.R., Maqbool, S., Rahman, F., Toosi, M.B., Ashrafzadeh, F., Imannezhad, S., Karimiani, E.G., Sarwar, Y., Khan, S., Jameel, M., Noegel, A.A., Budde, B., Altmuller, J., Motameny, S., Hohne, W., Houlden, H., Nurnberg, P., Wollnik, B., Villard, L., Alkuraya, F.S., Osmond, M., Hussain, M.S.**, and Yigit, G. (2021). Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies. Genetics in medicine : official journal of the American College of Medical Genetics. https://www.ncbi.nlm.nih.gov/pubmed/34244665.
Farooq, M., Lindbaek, L., Krogh, N., Doganli, C., Keller, C., Monnich, M., Goncalves, A.B., Sakthivel, S., Mang, Y., Fatima, A., Andersen, V.S., Hussain, M.S., Eiberg, H., Hansen, L., Kjaer, K.W., Gopalakrishnan, J., Pedersen, L.B., Mollgard, K., Nielsen, H., Baig, S.M., Tommerup, N., Christensen, S.T., and Larsen, L.A. (2020). RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis. Nature communications 11, 5816. https://www.ncbi.nlm.nih.gov/pubmed/33199730.
Kinfe, T.M., Asif, M., Chakravarthy, K.V., Deer, T.R., Kramer, J.M., Yearwood, T.L., Hurlemann, R., Hussain, M.S., Motameny, S., Wagle, P., Nurnberg, P., Gravius, S., Randau, T., Gravius, N., Chaudhry, S.R., and Muhammad, S. (2019). Unilateral L4-dorsal root ganglion stimulation evokes pain relief in chronic neuropathic postsurgical knee pain and changes of inflammatory markers: part II whole transcriptome profiling. J Transl Med 17, 205. https://www.ncbi.nlm.nih.gov/pubmed/31217010.
Braun, D.A., Lovric, S., Schapiro, D., Schneider, R., Marquez, J., Asif, M., Hussain, M.S., Daga, A., Widmeier, E., Rao, J., Ashraf, S., Tan, W., Lusk, C.P., Kolb, A., Jobst-Schwan, T., Schmidt, J.M., Hoogstraten, C.A., Eddy, K., Kitzler, T.M., Shril, S., Moawia, A., Schrage, K., Khayyat, A.I.A., Lawson, J.A., Gee, H.Y., Warejko, J.K., Hermle, T., Majmundar, A.J., Hugo, H., Budde, B., Motameny, S., Altmuller, J., Noegel, A.A., Fathy, H.M., Gale, D.P., Waseem, S.S., Khan, A., Kerecuk, L., Hashmi, S., Mohebbi, N., Ettenger, R., Serdaroglu, E., Alhasan, K.A., Hashem, M., Goncalves, S., Ariceta, G., Ubetagoyena, M., Antonin, W., Baig, S.M., Alkuraya, F.S., Shen, Q., Xu, H., Antignac, C., Lifton, R.P., Mane, S., Nurnberg, P., Khokha, M.K., and Hildebrandt, F. (2018). Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. J Clin Invest 128, 4313-4328. http://www.ncbi.nlm.nih.gov/pubmed/30179222.
Moawia, A., Shaheen, R., Rasool, S., Waseem, S.S., Ewida, N., Budde, B., Kawalia, A., Motameny, S., Khan, K., Fatima, A., Jameel, M., Ullah, F., Akram, T., Ali, Z., Abdullah, U., Irshad, S., Hohne, W., Noegel, A.A., Al-Owain, M., Hortnagel, K., Stobe, P., Baig, S.M., Nurnberg, P., Alkuraya, F.S., Hahn, A., and Hussain, M.S.** (2017). Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann Neurol 82, 562-577. http://www.ncbi.nlm.nih.gov/pubmed/28892560.
Szczepanski, S., Hussain, M.S.*, Sur, I., Altmuller, J., Thiele, H., Abdullah, U., Waseem, S.S., Moawia, A., Nurnberg, G., Noegel, A.A., Baig, S.M., and Nurnberg, P. (2016). A novel homozygous splicing mutation of CASC5 causes primary microcephaly in a large Pakistani family. Hum Genet 135, 157-170. https://www.ncbi.nlm.nih.gov/pubmed/26621532.
Hussain, M.S., Battaglia, A., Szczepanski, S., Kaygusuz, E., Toliat, M.R., Sakakibara, S., Altmuller, J., Thiele, H., Nurnberg, G., Moosa, S., Yigit, G., Beleggia, F., Tinschert, S., Clayton-Smith, J., Vasudevan, P., Urquhart, J.E., Donnai, D., Fryer, A., Percin, F., Brancati, F., Dobbie, A., Smigiel, R., Gillessen-Kaesbach, G., Wollnik, B., Noegel, A.A., Newman, W.G., and Nurnberg, P. (2014). Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome. Am J Hum Genet 95, 622-632. https://www.ncbi.nlm.nih.gov/pubmed/25439729.
Martin, C.A., Ahmad, I., Klingseisen, A., Hussain, M.S.*, Bicknell, L.S., Leitch, A., Nurnberg, G., Toliat, M.R., Murray, J.E., Hunt, D., Khan, F., Ali, Z., Tinschert, S., Ding, J., Keith, C., Harley, M.E., Heyn, P., Muller, R., Hoffmann, I., Cormier-Daire, V., Dollfus, H., Dupuis, L., Bashamboo, A., McElreavey, K., Kariminejad, A., Mendoza-Londono, R., Moore, A.T., Saggar, A., Schlechter, C., Weleber, R., Thiele, H., Altmuller, J., Hohne, W., Hurles, M.E., Noegel, A.A., Baig, S.M., Nurnberg, P., and Jackson, A.P. (2014). Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet 46, 1283-1292. https://www.ncbi.nlm.nih.gov/pubmed/25344692.
Hussain, M.S., Baig, S.M., Neumann, S., Peche, V.S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T.N., Fatima, A., Malik, N.A., Ahmad, I., Altmuller, J., Frommolt, P., Thiele, H., Hohne, W., Yigit, G., Wollnik, B., Neubauer, B.A., Nurnberg, P., and Noegel, A.A. (2013). CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly. Hum Mol Genet 22, 5199-5214. https://www.ncbi.nlm.nih.gov/pubmed/23918663.
Hussain, M.S., Baig, S.M., Neumann, S., Nurnberg, G., Farooq, M., Ahmad, I., Alef, T., Hennies, H.C., Technau, M., Altmuller, J., Frommolt, P., Thiele, H., Noegel, A.A., and Nurnberg, P. (2012). A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am J Hum Genet 90, 871-878. https://www.ncbi.nlm.nih.gov/pubmed/22521416.
*Shared first author
**Shared corresponding author