A Novel and Mosaic WDR45 Nonsense Variant Causes Beta-Propeller Protein-Associated Neurodegeneration Identified Through Whole Exome Sequencing and X chromosome Heterozygosity Analysis

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dc.authoridZeliha Görmez / 0000-0001-9519-2647
dc.authorscopusidZeliha Görmez / 26025606000
dc.authorwosidZeliha Görmez / A-9557-2013
dc.contributor.authorAkcakaya, Nihan Hande
dc.contributor.authorSalman, Barış
dc.contributor.authorGörmez, Zeliha
dc.contributor.authorArgüden, Yelda Tarkan
dc.contributor.authorÇırakoğlu, Ayşe
dc.contributor.authorÇakmur, Raif
dc.contributor.authorÇolakoğlu, Berril Dönmez
dc.contributor.authorHacıhanefioğlu, Seniha
dc.contributor.authorÖzbek, Uğur
dc.contributor.authorYapıcı, Zuhal
dc.contributor.authorİşeri, Sibel Aylin Uğur
dc.date.accessioned2020-08-30T20:06:58Z
dc.date.available2020-08-30T20:06:58Z
dc.date.issued2019
dc.departmentİstinye Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Yazılım Mühendisliği Bölümüen_US
dc.descriptionArguden, Yelda Tarkan/0000-0002-5405-3365; Ozbek, Ugur/0000-0001-5319-0547; Akcakaya, Nihan Hande/0000-0001-8414-4017en_US
dc.description.abstractBeta-propeller protein-associated neurodegeneration (BPAN) is an X-linked rare dominant disorder of autophagy. The role of WDR45 has been implicated in BPAN almost exclusively in females possibly due to male lethality. Characterization of distinctive clinical manifestations and potentially the complex genetic determinants in rare male patients remain crucial for deciphering BPAN and other X-linked dominant diseases. We performed whole exome sequencing (WES) followed by segregation analysis and identified a novel nonsense and mosaic variant in WDR45, namely NM_007075.3:c.873C>G; p.(Tyr291*) in an affected male at the age of 34. His biphasic medical history was compatible with BPAN, which was characterized by delayed psychomotor development, intellectual disability, and progression into dystonia parkinsonism in his twenties. The variant had an apparently mosaic pattern both in whole exome and Sanger sequencing findings. In order to figure out if mosaicism was restricted to this variant or related to a chromosomal level mosaicism, we used our in-house WES data from 129 unrelated individuals to calculate the threshold values of male and female X chromosome heterozygosity (XcHet) in WES data for our pipeline. A background level of heterozygous variants on X chromosome excluding the pseudoautosomal loci is an observed phenomenon in WES analysis and this level has been used as a quality measure. Herein, we suggest utilization of this measure for detection of digital anomalies of the X chromosome in males by potentially observing a higher XcHet value than the threshold value. This approach has revealed a variant level mosaicism in the affected male, which was further supported with cytogenetic analyses.en_US
dc.description.sponsorshipScientific Research Projects Coordination Unit of Istanbul UniversityIstanbul University [TDK-2017-26646]en_US
dc.description.sponsorshipThis study was funded by the Scientific Research Projects Coordination Unit of Istanbul University, Project Number TDK-2017-26646.en_US
dc.identifier.citationAkcakaya, N. H., Salman, B., Gormez, Z., Arguden, Y. T., Cirakoglu, A., Cakmur, R., … Iseri, S. A. U. (2019). A Novel and Mosaic WDR45 Nonsense Variant Causes Beta-Propeller Protein-Associated Neurodegeneration Identified Through Whole Exome Sequencing and X chromosome Heterozygosity Analysis. NEUROMOLECULAR MEDICINE, 21(1), 54–59. https://doi.org/10.1007/s12017-018-08522-6en_US
dc.identifier.doi10.1007/s12017-018-08522-6en_US
dc.identifier.endpage59en_US
dc.identifier.issn1535-1084en_US
dc.identifier.issn1559-1174en_US
dc.identifier.issue1en_US
dc.identifier.pmid30612247en_US
dc.identifier.scopus2-s2.0-85059577739en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage54en_US
dc.identifier.urihttps://doi.org/10.1007/s12017-018-08522-6
dc.identifier.urihttps://hdl.handle.net/20.500.12713/665
dc.identifier.volume21en_US
dc.identifier.wosWOS:000458670800006en_US
dc.identifier.wosqualityQ3en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.institutionauthorGörmez, Zelihaen_US
dc.language.isoenen_US
dc.publisherHumana Press Incen_US
dc.relation.ispartofNeuromolecular Medicineen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectWdr45en_US
dc.subjectMosaicismen_US
dc.subjectWhole Exome Sequencingen_US
dc.subjectX Chromosome Heterozygosityen_US
dc.subjectBpanen_US
dc.titleA Novel and Mosaic WDR45 Nonsense Variant Causes Beta-Propeller Protein-Associated Neurodegeneration Identified Through Whole Exome Sequencing and X chromosome Heterozygosity Analysisen_US
dc.typeArticleen_US

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