Cargando…

A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes

Clefts of the lip and/or palate (CL/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL/P cases and is further characterized by having lower lip...

Descripción completa

Detalles Bibliográficos
Autores principales: Al-Kurbi, Alya A., Aliyev, Elbay, AlSa’afin, Sana, Aamer, Waleed, Palaniswamy, Sasirekha, Al-Maraghi, Aljazi, Kilani, Houda, Akil, Ammira Al-Shabeeb, Stotland, Mitchell A., Fakhro, Khalid A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137688/
https://www.ncbi.nlm.nih.gov/pubmed/37107607
http://dx.doi.org/10.3390/genes14040849
_version_ 1785032526626029568
author Al-Kurbi, Alya A.
Aliyev, Elbay
AlSa’afin, Sana
Aamer, Waleed
Palaniswamy, Sasirekha
Al-Maraghi, Aljazi
Kilani, Houda
Akil, Ammira Al-Shabeeb
Stotland, Mitchell A.
Fakhro, Khalid A.
author_facet Al-Kurbi, Alya A.
Aliyev, Elbay
AlSa’afin, Sana
Aamer, Waleed
Palaniswamy, Sasirekha
Al-Maraghi, Aljazi
Kilani, Houda
Akil, Ammira Al-Shabeeb
Stotland, Mitchell A.
Fakhro, Khalid A.
author_sort Al-Kurbi, Alya A.
collection PubMed
description Clefts of the lip and/or palate (CL/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL/P cases and is further characterized by having lower lip pits. Popliteal pterygium syndrome (PPS) is a more severe form of VWS, normally characterized by orofacial clefts, lower lip pits, skin webbing, skeletal anomalies and syndactyly of toes and fingers. Both syndromes are inherited in an autosomal dominant manner, usually caused by heterozygous mutations in the Interferon Regulatory Factor 6 (IRF6) gene. Here we report the case of a two-generation family where the index presented with popliteal pterygium syndrome while both the father and sister had clinical features of van der woude syndrome, but without any point mutations detected by re-sequencing of known gene panels or microarray testing. Using whole genome sequencing (WGS) followed by local de novo assembly, we discover and validate a copy-neutral, 429 kb complex intra-chromosomal rearrangement in the long arm of chromosome 1, disrupting the IRF6 gene. This variant is copy-neutral, novel against publicly available databases, and segregates in the family in an autosomal dominant pattern. This finding suggests that missing heritability in rare diseases may be due to complex genomic rearrangements that can be resolved by WGS and de novo assembly, helping deliver answers to patients where no genetic etiology was identified by other means.
format Online
Article
Text
id pubmed-10137688
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-101376882023-04-28 A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes Al-Kurbi, Alya A. Aliyev, Elbay AlSa’afin, Sana Aamer, Waleed Palaniswamy, Sasirekha Al-Maraghi, Aljazi Kilani, Houda Akil, Ammira Al-Shabeeb Stotland, Mitchell A. Fakhro, Khalid A. Genes (Basel) Case Report Clefts of the lip and/or palate (CL/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL/P cases and is further characterized by having lower lip pits. Popliteal pterygium syndrome (PPS) is a more severe form of VWS, normally characterized by orofacial clefts, lower lip pits, skin webbing, skeletal anomalies and syndactyly of toes and fingers. Both syndromes are inherited in an autosomal dominant manner, usually caused by heterozygous mutations in the Interferon Regulatory Factor 6 (IRF6) gene. Here we report the case of a two-generation family where the index presented with popliteal pterygium syndrome while both the father and sister had clinical features of van der woude syndrome, but without any point mutations detected by re-sequencing of known gene panels or microarray testing. Using whole genome sequencing (WGS) followed by local de novo assembly, we discover and validate a copy-neutral, 429 kb complex intra-chromosomal rearrangement in the long arm of chromosome 1, disrupting the IRF6 gene. This variant is copy-neutral, novel against publicly available databases, and segregates in the family in an autosomal dominant pattern. This finding suggests that missing heritability in rare diseases may be due to complex genomic rearrangements that can be resolved by WGS and de novo assembly, helping deliver answers to patients where no genetic etiology was identified by other means. MDPI 2023-03-31 /pmc/articles/PMC10137688/ /pubmed/37107607 http://dx.doi.org/10.3390/genes14040849 Text en © 2023 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 Case Report
Al-Kurbi, Alya A.
Aliyev, Elbay
AlSa’afin, Sana
Aamer, Waleed
Palaniswamy, Sasirekha
Al-Maraghi, Aljazi
Kilani, Houda
Akil, Ammira Al-Shabeeb
Stotland, Mitchell A.
Fakhro, Khalid A.
A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes
title A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes
title_full A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes
title_fullStr A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes
title_full_unstemmed A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes
title_short A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes
title_sort complex intrachromosomal rearrangement disrupting irf6 in a family with popliteal pterygium and van der woude syndromes
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137688/
https://www.ncbi.nlm.nih.gov/pubmed/37107607
http://dx.doi.org/10.3390/genes14040849
work_keys_str_mv AT alkurbialyaa acomplexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT aliyevelbay acomplexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT alsaafinsana acomplexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT aamerwaleed acomplexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT palaniswamysasirekha acomplexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT almaraghialjazi acomplexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT kilanihouda acomplexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT akilammiraalshabeeb acomplexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT stotlandmitchella acomplexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT fakhrokhalida acomplexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT alkurbialyaa complexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT aliyevelbay complexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT alsaafinsana complexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT aamerwaleed complexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT palaniswamysasirekha complexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT almaraghialjazi complexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT kilanihouda complexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT akilammiraalshabeeb complexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT stotlandmitchella complexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes
AT fakhrokhalida complexintrachromosomalrearrangementdisruptingirf6inafamilywithpoplitealpterygiumandvanderwoudesyndromes