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

TitleHigh diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses
Authors
Issue Date2021
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/jhg/index.html
Citation
Journal of Human Genetics, 2021, Epub 2021-04-20 How to Cite?
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.
DescriptionHybrid open access
Persistent Identifierhttp://hdl.handle.net/10722/299155
ISSN
2023 Impact Factor: 2.6
2023 SCImago Journal Rankings: 1.148
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHammarsjo, A-
dc.contributor.authorPettersson, M-
dc.contributor.authorChitayat, D-
dc.contributor.authorHanda, A-
dc.contributor.authorAnderlid, BM-
dc.contributor.authorBartocci, M-
dc.contributor.authorBasel, D-
dc.contributor.authorBatkovskyte, D-
dc.contributor.authorBeleza-Meireles, A-
dc.contributor.authorConner, P-
dc.contributor.authorEisfeldt, J-
dc.contributor.authorGirisha, KM-
dc.contributor.authorChung, BHY-
dc.contributor.authorHoremuzova, E-
dc.contributor.authorHyodo, H-
dc.contributor.authorKornejeva, L-
dc.contributor.authorLagerstedt-Robinson, K-
dc.contributor.authorLin, AE-
dc.contributor.authorMagnusson, M-
dc.contributor.authorMoosa, S-
dc.contributor.authorNayak, SS-
dc.contributor.authorNilsson, D-
dc.contributor.authorOhashi, H-
dc.contributor.authorOhashi-Fukuda, N-
dc.contributor.authorStranneheim, H-
dc.contributor.authorTaylan, F-
dc.contributor.authorTraberg, R-
dc.contributor.authorVoss, U-
dc.contributor.authorWirta, V-
dc.contributor.authorNordgren, A-
dc.contributor.authorNishimura, G-
dc.contributor.authorLindstrand, A-
dc.contributor.authorGrigelioniene, G-
dc.date.accessioned2021-04-28T02:26:55Z-
dc.date.available2021-04-28T02:26:55Z-
dc.date.issued2021-
dc.identifier.citationJournal of Human Genetics, 2021, Epub 2021-04-20-
dc.identifier.issn1434-5161-
dc.identifier.urihttp://hdl.handle.net/10722/299155-
dc.descriptionHybrid open access-
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.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/jhg/index.html-
dc.relation.ispartofJournal of Human Genetics-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleHigh diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses-
dc.typeArticle-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.authorityChung, BHY=rp00473-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s10038-021-00925-x-
dc.identifier.scopuseid_2-s2.0-85104884788-
dc.identifier.hkuros322295-
dc.identifier.volumeEpub 2021-04-20-
dc.identifier.isiWOS:000641214100001-
dc.publisher.placeUnited Kingdom-

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