Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families
Objective: Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias. Method: Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all kno...
| Autores: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Tipo de documento: | Artículo |
| Estado: | Published version |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/126828 |
| Acceso en línea: | https://hdl.handle.net/2445/126828 |
| Nivel de acceso: | Acceso abierto |
| Palabra clave: | Paraplegia Malalties hereditàries Genetic disorders |
| _version_ | 1878729643592253440 |
|---|---|
| author | Soehn, Anne S. |
| author2 | Rattay, Tim W. Beck-Wödl, Stefanie Schäferhoff, Karin Monk, Dave Nicholas Döbler-Neumann, Marion Hörtnagel, Konstanze Schlüter, Agatha Ruiz, Montserrat Pujol Onofre, Aurora Züchner, Stephan Riess, Olaf Schüle, Rebecca Bauer, Peter Schöls, Ludger |
| author2_role | author author author author author author author author author author author author author author |
| author_browse | Bauer, Peter Beck-Wödl, Stefanie Döbler-Neumann, Marion Hörtnagel, Konstanze Monk, Dave Nicholas Pujol Onofre, Aurora Rattay, Tim W. Riess, Olaf Ruiz, Montserrat Schlüter, Agatha Schäferhoff, Karin Schöls, Ludger Schüle, Rebecca Soehn, Anne S. Züchner, Stephan |
| author_facet | Soehn, Anne S. Rattay, Tim W. Beck-Wödl, Stefanie Schäferhoff, Karin Monk, Dave Nicholas Döbler-Neumann, Marion Hörtnagel, Konstanze Schlüter, Agatha Ruiz, Montserrat Pujol Onofre, Aurora Züchner, Stephan Riess, Olaf Schüle, Rebecca Bauer, Peter Schöls, Ludger |
| author_role | author |
| collection | Recercat. Dipósit de la Recerca de Catalunya |
| description | Objective: Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias. Method: Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all known hereditary spastic paraplegia genes. Results: Segregation analysis revealed in all cases only one parent as a heterozygous mutation carrier whereas the other parent did not carry FA2H mutations. A macro deletion within FA2H, which could have caused a hemizygous genotype, was excluded by multiplex ligation-dependent probe amplification in all cases. Finally, a microsatellite array revealed uniparental disomy (UPD) in all 4 families leading to homozygous FA2H mutations. UPD was confirmed by microarray analyses and methylation profiling. Conclusion: UPD has rarely been described as causative mechanism in neurodegenerative diseases. Of note, we identified this mode of inheritance in 4 families with the rare diagnosis of spastic paraplegia type 35 (SPG35). Since UPD seems to be a relevant factor in SPG35 and probably additional autosomal recessive diseases, we recommend segregation analysis especially in nonconsanguineous homozygous index cases to unravel UPD as mutational mechanism. This finding may bear major repercussion for genetic counseling, given the markedly reduced risk of recurrence for affected families. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_0c0beaedb4a10d38128df35cb4d15826 |
| institution | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| instname_str | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:recercat.cat:2445/126828 |
| publishDate | 2016 |
| publishDateSort | 2016 |
| publisher | Lippincott Williams & Wilkins |
| publisherStr | Lippincott Williams & Wilkins |
| reponame_str | Recercat. Dipósit de la Recerca de Catalunya |
| spelling | Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families Soehn, Anne S. Rattay, Tim W. Beck-Wödl, Stefanie Schäferhoff, Karin Monk, Dave Nicholas Döbler-Neumann, Marion Hörtnagel, Konstanze Schlüter, Agatha Ruiz, Montserrat Pujol Onofre, Aurora Züchner, Stephan Riess, Olaf Schüle, Rebecca Bauer, Peter Schöls, Ludger Paraplegia Malalties hereditàries Genetic disorders Objective: Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias. Method: Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all known hereditary spastic paraplegia genes. Results: Segregation analysis revealed in all cases only one parent as a heterozygous mutation carrier whereas the other parent did not carry FA2H mutations. A macro deletion within FA2H, which could have caused a hemizygous genotype, was excluded by multiplex ligation-dependent probe amplification in all cases. Finally, a microsatellite array revealed uniparental disomy (UPD) in all 4 families leading to homozygous FA2H mutations. UPD was confirmed by microarray analyses and methylation profiling. Conclusion: UPD has rarely been described as causative mechanism in neurodegenerative diseases. Of note, we identified this mode of inheritance in 4 families with the rare diagnosis of spastic paraplegia type 35 (SPG35). Since UPD seems to be a relevant factor in SPG35 and probably additional autosomal recessive diseases, we recommend segregation analysis especially in nonconsanguineous homozygous index cases to unravel UPD as mutational mechanism. This finding may bear major repercussion for genetic counseling, given the markedly reduced risk of recurrence for affected families. Lippincott Williams & Wilkins https://hdl.handle.net/2445/126828 |
| spellingShingle | Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families Soehn, Anne S. Paraplegia Malalties hereditàries Genetic disorders |
| status_str | publishedVersion |
| title | Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families |
| title_full | Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families |
| title_fullStr | Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families |
| title_full_unstemmed | Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families |
| title_short | Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families |
| title_sort | Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families |
| topic | Paraplegia Malalties hereditàries Genetic disorders |
| topic_facet | Paraplegia Malalties hereditàries Genetic disorders |
| url | https://hdl.handle.net/2445/126828 |