High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses

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dc.contributor.authorHammarsjo, Annaen_ZA
dc.contributor.authorPettersson, Mariaen_Za
dc.contributor.authorChitayat, Daviden_ZA
dc.contributor.authorHanda, Atsuhikoen_ZA
dc.contributor.authorAnderlid, Britt-Marieen_ZA
dc.contributor.authorBartocci, Marcoen_ZA
dc.contributor.authorBasel, Donalden_ZA
dc.contributor.authorBatkovskyte, Dominykaen_ZA
dc.contributor.authorBeleza-Meireles, Anaen_ZA
dc.contributor.authorConner, Peteren_ZA
dc.contributor.authorEisfeldt, Jesperen_ZA
dc.contributor.authorGirisha, Katta M.en_ZA
dc.contributor.authorHon-Yin Chung, Brianen_ZA
dc.contributor.authorHoremuzova, Evaen_ZA
dc.contributor.authorHyodo, Hironobuen_ZA
dc.contributor.authorKorņejeva, Lieneen_ZA
dc.contributor.authorLagerstedt-Robinson, Kristinaen_ZA
dc.contributor.authorLin, Angela E.en_ZA
dc.contributor.authorMagnusson, Mansen_ZA
dc.contributor.authorMoosa, Shahidaen_ZA
dc.contributor.authorNayak, Shalini S.en_ZA
dc.contributor.authorNilsson, Danielen_ZA
dc.contributor.authorOhashi, Hirofumien_ZA
dc.contributor.authorOhashi-Fukuda, Naokoen_ZA
dc.contributor.authorStranneheim, Henriken_ZA
dc.contributor.authorTaylan, Fulyaen_ZA
dc.contributor.authorTraberg, Rasaen_ZA
dc.contributor.authorVoss, Ulrikaen_ZA
dc.contributor.authorWirta, Valtterien_ZA
dc.contributor.authorNordgren, Annen_ZA
dc.contributor.authorNishimura, Genen_ZA
dc.contributor.authorLindstrand, Annaen_ZA
dc.contributor.authorGrigelioniene, Giedreen_ZA
dc.date.accessioned2023-03-20T10:21:41Zen_ZA
dc.date.available2023-03-20T10:21:41Zen_ZA
dc.date.issued2021-04en_ZA
dc.descriptionCITATION: Hammarsjö, A., Pettersson, M., Chitayat, D. et al.(2021). High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses. J Hum Genet 66, 995–1008 doi.10.1038/s10038-021-00925-xen_ZA
dc.descriptionThe original publication is available at: nature.comen_ZA
dc.description.abstractSkeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.en_ZA
dc.description.versionPublisher’s versionen_ZA
dc.format.extent14 pagesen_ZA
dc.identifier.citationHammarsjö, A., Pettersson, M., Chitayat, D. et al.(2021). High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses. J Hum Genet 66, 995–1008 doi.10.1038/s10038-021-00925-xen_ZA
dc.identifier.issn1434-5161 (print)en_ZA
dc.identifier.issn1435-232X (online)en_ZA
dc.identifier.otherdoi.10.1038/s10038-021-00925-xen_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/126683en_ZA
dc.language.isoen_ZAen_ZA
dc.publisherSpringer Nature Limiteden_ZA
dc.rights.holderAuthors retain copyrighten_ZA
dc.subjectCilia and ciliary motionen_ZA
dc.subjectMolecular diagnosisen_ZA
dc.subjectNucleotide sequenceen_ZA
dc.subjectStructural variant screeningen_ZA
dc.subjectSkeletal ciliopathiesen_ZA
dc.titleHigh diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analysesen_ZA
dc.typeArticleen_ZA
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