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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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