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X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes
BACKGROUND: X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecul...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022384/ https://www.ncbi.nlm.nih.gov/pubmed/24721225 http://dx.doi.org/10.1186/1750-1172-9-49 |
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author | Philips, Anju K Sirén, Auli Avela, Kristiina Somer, Mirja Peippo, Maarit Ahvenainen, Minna Doagu, Fatma Arvio, Maria Kääriäinen, Helena Van Esch, Hilde Froyen, Guy Haas, Stefan A Hu, Hao Kalscheuer, Vera M Järvelä, Irma |
author_facet | Philips, Anju K Sirén, Auli Avela, Kristiina Somer, Mirja Peippo, Maarit Ahvenainen, Minna Doagu, Fatma Arvio, Maria Kääriäinen, Helena Van Esch, Hilde Froyen, Guy Haas, Stefan A Hu, Hao Kalscheuer, Vera M Järvelä, Irma |
author_sort | Philips, Anju K |
collection | PubMed |
description | BACKGROUND: X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis. METHODS & OBJECTIVES: Enrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause. RESULTS: We found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G > C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype. CONCLUSIONS: All of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations and the challenges of interpreting the results. Further functional studies are required to confirm the cause of the syndromic phenotypes associated with ZMYM3 and SYP in this study. |
format | Online Article Text |
id | pubmed-4022384 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-40223842014-05-16 X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes Philips, Anju K Sirén, Auli Avela, Kristiina Somer, Mirja Peippo, Maarit Ahvenainen, Minna Doagu, Fatma Arvio, Maria Kääriäinen, Helena Van Esch, Hilde Froyen, Guy Haas, Stefan A Hu, Hao Kalscheuer, Vera M Järvelä, Irma Orphanet J Rare Dis Research BACKGROUND: X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis. METHODS & OBJECTIVES: Enrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause. RESULTS: We found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G > C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype. CONCLUSIONS: All of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations and the challenges of interpreting the results. Further functional studies are required to confirm the cause of the syndromic phenotypes associated with ZMYM3 and SYP in this study. BioMed Central 2014-04-11 /pmc/articles/PMC4022384/ /pubmed/24721225 http://dx.doi.org/10.1186/1750-1172-9-49 Text en Copyright © 2014 Philips et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Philips, Anju K Sirén, Auli Avela, Kristiina Somer, Mirja Peippo, Maarit Ahvenainen, Minna Doagu, Fatma Arvio, Maria Kääriäinen, Helena Van Esch, Hilde Froyen, Guy Haas, Stefan A Hu, Hao Kalscheuer, Vera M Järvelä, Irma X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes |
title | X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes |
title_full | X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes |
title_fullStr | X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes |
title_full_unstemmed | X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes |
title_short | X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes |
title_sort | x-exome sequencing in finnish families with intellectual disability - four novel mutations and two novel syndromic phenotypes |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022384/ https://www.ncbi.nlm.nih.gov/pubmed/24721225 http://dx.doi.org/10.1186/1750-1172-9-49 |
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