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Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ
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 addition...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153008/ https://www.ncbi.nlm.nih.gov/pubmed/34068194 http://dx.doi.org/10.3390/genes12050731 |
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author | Makhdoom, Ehtisham Ul Haq Waseem, Syeda Seema Iqbal, Maria Abdullah, Uzma Hussain, Ghulam Asif, Maria Budde, Birgit Höhne, Wolfgang Tinschert, Sigrid Saadi, Saadia Maryam Yousaf, Hammad Ali, Zafar Fatima, Ambrin Kaygusuz, Emrah Khan, Ayaz Jameel, Muhammad Khan, Sheraz Tariq, Muhammad Anjum, Iram Altmüller, Janine Thiele, Holger Höning, Stefan Baig, Shahid Mahmood Nürnberg, Peter Hussain, Muhammad Sajid |
author_facet | Makhdoom, Ehtisham Ul Haq Waseem, Syeda Seema Iqbal, Maria Abdullah, Uzma Hussain, Ghulam Asif, Maria Budde, Birgit Höhne, Wolfgang Tinschert, Sigrid Saadi, Saadia Maryam Yousaf, Hammad Ali, Zafar Fatima, Ambrin Kaygusuz, Emrah Khan, Ayaz Jameel, Muhammad Khan, Sheraz Tariq, Muhammad Anjum, Iram Altmüller, Janine Thiele, Holger Höning, Stefan Baig, Shahid Mahmood Nürnberg, Peter Hussain, Muhammad Sajid |
author_sort | Makhdoom, Ehtisham Ul Haq |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8153008 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81530082021-05-27 Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ Makhdoom, Ehtisham Ul Haq Waseem, Syeda Seema Iqbal, Maria Abdullah, Uzma Hussain, Ghulam Asif, Maria Budde, Birgit Höhne, Wolfgang Tinschert, Sigrid Saadi, Saadia Maryam Yousaf, Hammad Ali, Zafar Fatima, Ambrin Kaygusuz, Emrah Khan, Ayaz Jameel, Muhammad Khan, Sheraz Tariq, Muhammad Anjum, Iram Altmüller, Janine Thiele, Holger Höning, Stefan Baig, Shahid Mahmood Nürnberg, Peter Hussain, Muhammad Sajid Genes (Basel) Article 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. MDPI 2021-05-13 /pmc/articles/PMC8153008/ /pubmed/34068194 http://dx.doi.org/10.3390/genes12050731 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Makhdoom, Ehtisham Ul Haq Waseem, Syeda Seema Iqbal, Maria Abdullah, Uzma Hussain, Ghulam Asif, Maria Budde, Birgit Höhne, Wolfgang Tinschert, Sigrid Saadi, Saadia Maryam Yousaf, Hammad Ali, Zafar Fatima, Ambrin Kaygusuz, Emrah Khan, Ayaz Jameel, Muhammad Khan, Sheraz Tariq, Muhammad Anjum, Iram Altmüller, Janine Thiele, Holger Höning, Stefan Baig, Shahid Mahmood Nürnberg, Peter Hussain, Muhammad Sajid Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ |
title | Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ |
title_full | Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ |
title_fullStr | Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ |
title_full_unstemmed | Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ |
title_short | Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ |
title_sort | modifier genes in microcephaly: a report on wdr62, cep63, rad50 and pcnt variants exacerbating disease caused by biallelic mutations of aspm and cenpj |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153008/ https://www.ncbi.nlm.nih.gov/pubmed/34068194 http://dx.doi.org/10.3390/genes12050731 |
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