Makhdoom, Ehtisham Ul Haq, Waseem, Syeda Seema, Iqbal, Maria, Abdullah, Uzma ORCID: 0000-0002-7168-8266, Hussain, Ghulam, Asif, Maria, Budde, Birgit, Hoehne, Wolfgang, Tinschert, Sigrid, Saadi, Saadia Maryam ORCID: 0000-0001-5962-2101, Yousaf, Hammad, Ali, Zafar ORCID: 0000-0002-2389-3337, Fatima, Ambrin, Kaygusuz, Emrah, Khan, Ayaz, Jameel, Muhammad, Khan, Sheraz, Tariq, Muhammad ORCID: 0000-0002-5334-403X, Anjum, Iram, Altmueller, Janine, Thiele, Holger, Hoening, Stefan, Baig, Shahid Mahmood, Nuernberg, Peter and Hussain, Muhammad Sajid (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, 12 (5). BASEL: MDPI. ISSN 2073-4425

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Abstract

Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic-microcephaly primary hereditary (MCPH)-and 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-genes 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Makhdoom, Ehtisham Ul HaqUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waseem, Syeda SeemaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iqbal, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdullah, UzmaUNSPECIFIEDorcid.org/0000-0002-7168-8266UNSPECIFIED
Hussain, GhulamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Asif, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Budde, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tinschert, SigridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saadi, Saadia MaryamUNSPECIFIEDorcid.org/0000-0001-5962-2101UNSPECIFIED
Yousaf, HammadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ali, ZafarUNSPECIFIEDorcid.org/0000-0002-2389-3337UNSPECIFIED
Fatima, AmbrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaygusuz, EmrahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, AyazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jameel, MuhammadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, SherazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tariq, MuhammadUNSPECIFIEDorcid.org/0000-0002-5334-403XUNSPECIFIED
Anjum, IramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoening, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Shahid MahmoodUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussain, Muhammad SajidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-599056
DOI: 10.3390/genes12050731
Journal or Publication Title: Genes
Volume: 12
Number: 5
Date: 2021
Publisher: MDPI
Place of Publication: BASEL
ISSN: 2073-4425
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROTEIN; CENTROSOME; COMPLEX; HETEROGENEITY; CDK5RAP2; CPAPMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59905

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