{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:45:38Z","timestamp":1791049538237,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T00:00:00Z","timestamp":1620864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Koeln Fortune Program, Faculty of Medicine, University of Cologne","award":["project No. 381\/2020"],"award-info":[{"award-number":["project No. 381\/2020"]}]},{"DOI":"10.13039\/501100010221","name":"Higher Education Commision, Pakistan","doi-asserted-by":"publisher","award":["EUHM, SSW"],"award-info":[{"award-number":["EUHM, SSW"]}],"id":[{"id":"10.13039\/501100010221","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009983","name":"Center for Molecular Medicine Cologne, University of Cologne","doi-asserted-by":"publisher","award":["Projects 38-RP and C12; 2635\/8029\/01 and 2635\/8326\/01"],"award-info":[{"award-number":["Projects 38-RP and C12; 2635\/8029\/01 and 2635\/8326\/01"]}],"id":[{"id":"10.13039\/501100009983","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic\u2014microcephaly primary hereditary (MCPH)\u2014and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome (n = 2). In addition to homozygous causal variants in ASPM or CENPJ, we discovered additional heterozygous modifier variants in WDR62, CEP63, RAD50 and PCNT\u2014genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel CENPJ variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional PCNT variant. We show that the CENPJ missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment.<\/jats:p>","DOI":"10.3390\/genes12050731","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T11:10:06Z","timestamp":1620904206000},"page":"731","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ"],"prefix":"10.3390","volume":"12","author":[{"given":"Ehtisham Ul Haq","family":"Makhdoom","sequence":"first","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad 38000, Pakistan"},{"name":"Neurochemicalbiology and Genetics Laboratory (NGL), Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syeda Seema","family":"Waseem","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad 38000, Pakistan"},{"name":"Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7168-8266","authenticated-orcid":false,"given":"Uzma","family":"Abdullah","sequence":"additional","affiliation":[{"name":"University Institute of Biochemistry and Biotechnology (UIBB), PMAS-Arid Agriculture University, Rawalpindi 46000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9090-7789","authenticated-orcid":false,"given":"Ghulam","family":"Hussain","sequence":"additional","affiliation":[{"name":"Neurochemicalbiology and Genetics Laboratory (NGL), Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Asif","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9385-4168","authenticated-orcid":false,"given":"Birgit","family":"Budde","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"H\u00f6hne","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrid","family":"Tinschert","sequence":"additional","affiliation":[{"name":"Zentrum Medizinische Genetik, Medizinische Universit\u00e4t, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5962-2101","authenticated-orcid":false,"given":"Saadia Maryam","family":"Saadi","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hammad","family":"Yousaf","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zafar","family":"Ali","sequence":"additional","affiliation":[{"name":"Centre for Biotechnology and Microbiology, University of Swat, Swat 19130, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambrin","family":"Fatima","sequence":"additional","affiliation":[{"name":"Department of Biological and Biomedical Sciences, Aga Khan University, Karachi 74000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6984-8526","authenticated-orcid":false,"given":"Emrah","family":"Kaygusuz","sequence":"additional","affiliation":[{"name":"Bilecik \u015eeyh Edebali University, Molecular Biology and Genetics, G\u00fcl\u00fcmbe Campus, Bilecik 11230, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4743-7387","authenticated-orcid":false,"given":"Ayaz","family":"Khan","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Jameel","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3207-4074","authenticated-orcid":false,"given":"Sheraz","family":"Khan","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5334-403X","authenticated-orcid":false,"given":"Muhammad","family":"Tariq","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9015-3179","authenticated-orcid":false,"given":"Iram","family":"Anjum","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Kinnaird College for Women, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Altm\u00fcller","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Thiele","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"H\u00f6ning","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahid Mahmood","family":"Baig","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad 38000, Pakistan"},{"name":"Department of Biological and Biomedical Sciences, Aga Khan University, Karachi 74000, Pakistan"},{"name":"Pakistan Science Foundation (PSF), 1- Constitution Avenue, G-5\/2, Islamabad 44000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7228-428X","authenticated-orcid":false,"given":"Peter","family":"N\u00fcrnberg","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1353-8809","authenticated-orcid":false,"given":"Muhammad Sajid","family":"Hussain","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1055\/s-0037-1602820","article-title":"Diagnostic approach to primary microcephaly","volume":"48","year":"2017","journal-title":"Neuropediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.spen.2007.07.003","article-title":"Microcephaly syndromes","volume":"14","author":"Abuelo","year":"2007","journal-title":"Semin. 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