Rasool, Sajida, Baig, Jamshaid Mahmood, Moawia, Abubakar, Ahmad, Ilyas, Iqbal, Maria, Waseem, Syeda Seema, Asif, Maria, Abdullah, Uzma, Makhdoom, Ehtisham Ul Haq, Kaygusuz, Emrah, Zakaria, Muhammad, Ramzan, Shafaq, ul Haque, Saif, Mir, Asif, Anjum, Iram ORCID: 0000-0002-9015-3179, Fiaz, Mehak, Ali, Zafar, Tariq, Muhammad, Saba, Neelam, Hussain, Wajid, Budde, Birgit, Irshad, Saba, Noegel, Angelika Anna, Hoening, Stefan, Baig, Shahid Mahmood, Nuernberg, Peter and Hussain, Muhammad Sajid (2020). An update of pathogenic variants in ASPM, WDR62, CDK5RAP2, STIL, CENPJ, and CEP135 underlying autosomal recessive primary microcephaly in 32 consanguineous families from Pakistan. Mol. Genet. Genom. Med., 8 (9). HOBOKEN: WILEY. ISSN 2324-9269

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Abstract

Background: Primary microcephaly (MCPH) is a congenital neurodevelopmental disorder manifesting as small brain and intellectual disability. It underlies isolated reduction of the cerebral cortex that is reminiscent of early hominids which makes it suitable model disease to study the hominin-specific volumetric expansion of brain. Mutations in 25 genes have been reported to cause this disorder. Although majority of these genes were discovered in the Pakistani population, still a significant proportion of these families remains uninvestigated. Methods: We studied a cohort of 32 MCPH families from different regions of Pakistan. For disease gene identification, genome-wide linkage analysis, Sanger sequencing, gene panel, and whole-exome sequencing were performed. Results: By employing these techniques individually or in combination, we were able to discern relevant disease-causing DNA variants. Collectively, 15 novel mutations were observed in five different MCPH genes; ASPM (10), WDR62 (1), CDK5RAP2 (1), STIL (2), and CEP135 (1). In addition, 16 known mutations were also verified. We reviewed the literature and documented the published mutations in six MCPH genes. Intriguingly, our cohort also revealed a recurrent mutation, c.7782_7783delGA;p.(Lys2595Serfs*6), of ASPM reported worldwide. Drawing from this collective data, we propose two founder mutations, ASPM:c.9557C>G;p. (Ser3186*) and CENPJ:c.18delC;p.(Ser7Profs*2), in the Pakistani population. Conclusions: We discovered novel DNA variants, impairing the function of genes indispensable to build a proper functioning brain. Our study expands the mutational spectra of known MCPH genes and also provides supporting evidence to the pathogenicity of previously reported mutations. These novel DNA variants will be helpful for the clinicians and geneticists for establishing reliable diagnostic strategies for MCPH families.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rasool, SajidaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Jamshaid MahmoodUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moawia, AbubakarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahmad, IlyasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iqbal, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waseem, Syeda SeemaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Asif, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdullah, UzmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Makhdoom, Ehtisham Ul HaqUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaygusuz, EmrahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zakaria, MuhammadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramzan, ShafaqUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
ul Haque, SaifUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mir, AsifUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anjum, IramUNSPECIFIEDorcid.org/0000-0002-9015-3179UNSPECIFIED
Fiaz, MehakUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ali, ZafarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tariq, MuhammadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saba, NeelamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussain, WajidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Budde, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Irshad, SabaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noegel, Angelika AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoening, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Shahid MahmoodUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussain, Muhammad SajidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-326209
DOI: 10.1002/mgg3.1408
Journal or Publication Title: Mol. Genet. Genom. Med.
Volume: 8
Number: 9
Date: 2020
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 2324-9269
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROTEIN-TRUNCATING MUTATIONS; GENETIC-HETEROGENEITYMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/32620

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