High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases

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dc.authoridBeltran, Sergi/0000-0002-2810-3445
dc.authoridGao, Fei/0009-0005-1647-2146
dc.authoridMatalonga, Leslie/0000-0003-0807-2570
dc.authoridHorvath, Rita/0000-0002-9841-170X
dc.authoridYilmaz, Elmasnur/0000-0001-9711-0203
dc.authoridHoulden, Henry/0000-0002-2866-7777
dc.authoridOktay, Yavuz/0000-0002-0158-2693
dc.authorwosidKALAFATCILAR POLAT, Ayşe İpek/A-9714-2016
dc.authorwosidBeltran, Sergi/I-3408-2015
dc.authorwosidHoulden, Henry J/C-1532-2008
dc.authorwosidGao, Fei/JWA-3373-2024
dc.authorwosidOktay, Yavuz/G-4794-2015
dc.contributor.authorKurul, Semra Hiz
dc.contributor.authorOktay, Yavuz
dc.contributor.authorTopf, Ana
dc.contributor.authorSzabo, Nora Zs
dc.contributor.authorGungor, Serdal
dc.contributor.authorYaramis, Ahmet
dc.contributor.authorSonmezler, Ece
dc.date.accessioned2024-08-04T20:52:04Z
dc.date.available2024-08-04T20:52:04Z
dc.date.issued2022
dc.departmentİnönü Üniversitesien_US
dc.description.abstractConsanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms. We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two per cent of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations. This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%). We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialized bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity.en_US
dc.description.sponsorshipTUBITAK (The Scientific and Technological Research Council of Turkey) [216S771]; Turkish Academy of Sciences' Young Investigator award, TUBA-GEB_IP (2017); Wellcome Trust [212219/Z/18/Z]; UK NIHR from the Medical Research Council Mitochondrial Biology Unit [MC_UU_00015/9]; Leverhulme Trust [RPG-2018-408]; MRC research grant [MR/S035699/1]; Alzheimer's Society Project Grant [AS-PG-18b-022]; NIHR Cambridge Biomedical Research Centre [BRC-1215-20014]; European Research Council [309548]; Wellcome Investigator Award [109915/Z/15/Z]; Medical Research Council (UK) [MR/N025431/1]; Wellcome Trust Pathfinder Scheme [201064/Z/16/Z]; Newton Fund [UK/Turkey] [MR/N027302/1]; Lily Foundation; Stoneygate Trust; Evelyn Trust; Addenbrookes Charitable Trust [G100142]; Canadian Institutes of Health Research [FDN-167281]; Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C); Canada Foundation for Innovation [CFI-JELF 38412]; Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health) [950-232279]; National Human Genome Research Institute; National Eye Institute; National Heart, Lung and Blood Institute [UM1 HG008900]; National Human Genome Research Institute [R01 HG009141]; EJP-RD; INB/ELIXIR-ES; Horizon 2020 research and innovation program [779257]; MRC [MR/S005021/1]; [305444]; MRC [MR/S01165X/1, MR/N025431/2, MR/V009346/1, MR/N010035/1, MR/S035699/1, MR/N025431/1] Funding Source: UKRI; Newton Fund [MR/N027302/2, MR/N027302/1] Funding Source: UKRIen_US
dc.description.sponsorshipThe project is supported by TUBITAK (The Scientific and Technological Research Council of Turkey) Project No. 216S771. Y.O. is supported by the Turkish Academy of Sciences' Young Investigator award, TUBA-GEB_IP (2017). P.F.C. is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Leverhulme Trust (RPG-2018-408), an MRC research grant (MR/S035699/1), an Alzheimer's Society Project Grant (AS-PG-18b-022). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. R.H. was supported by the European Research Council [309548], the Wellcome Investigator Award [109915/Z/15/Z]. the Medical Research Council (UK) [MR/N025431/1]; the Wellcome Trust Pathfinder Scheme [201064/Z/16/Z], the Newton Fund [UK/Turkey, MR/N027302/1], the Lily Foundation, the Stoneygate Trust, the Evelyn Trust and the Addenbrookes Charitable Trust (G100142). H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. Data were analysed using the RD-Connect Genome-Phenome Analysis platform developed under FP7/2007-2013 funded project (grant agreement n~ 305444) and funding from EJP-RD and INB/ELIXIR-ES. The study was further supported by the Horizon 2020 research and innovation program via grant 779257 'Solve-RD' (R.H., S.B., A.T. and H.L.). R.H. and H.L. are members of the European Reference Network for Rare Neuromuscular Diseases (EURO-NMD). R.H., P.F.C. and Y.O. were supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.en_US
dc.identifier.doi10.1093/brain/awab395
dc.identifier.endpage1518en_US
dc.identifier.issn0006-8950
dc.identifier.issn1460-2156
dc.identifier.issue4en_US
dc.identifier.pmid34791078en_US
dc.identifier.scopus2-s2.0-85132110761en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1507en_US
dc.identifier.urihttps://doi.org/10.1093/brain/awab395
dc.identifier.urihttps://hdl.handle.net/11616/100720
dc.identifier.volume145en_US
dc.identifier.wosWOS:000784790600001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherOxford Univ Pressen_US
dc.relation.ispartofBrainen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectconsanguineous familiesen_US
dc.subjectneurogenetic disease burdenen_US
dc.subjectwhole exome sequencingen_US
dc.subjectrate of consanguinityen_US
dc.titleHigh diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseasesen_US
dc.typeArticleen_US

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