Long-read DNA and RNA sequencing reveal an intronic retrotransposon insertion in TCOF1 causing Treacher Collins syndrome
Ferraro, F.; Kuehn, N.; Rots, D.; van der Linde, H. C.; Mohseni, B.; van Unen, L.; Drost, M.; Nellist, M.; Koekkoek, M.; Schot, R.; de Gier, H. W.; Pleumeekers, M.; Barakat, T. S.; Kleefstra, T.; Weerts, M.; van Dooren, M. F.; van Ham, T. J.
Show abstract
Treacher Collins syndrome (TCS) is a craniofacial genetic disorder caused by loss of function variants in TCOF1, POLR1B, POLR1C or POLR1D. Here we describe two previously undiagnosed half-siblings affected with clinical TCS, and their apparently unaffected parent. Diagnostic short-read RNA-Sequencing identified aberrant expression of TCOF1 and optical genome mapping detected a large genomic insertion therein. Long-read genome sequencing (LR-GS) resolved a deep intronic 3.5 kb SINE-VNTR-Alu (SVA) retrotransposon insertion in intron 17 of TCOF1. Long read RNA-Seq demonstrated that the insertion was partially exonized inducing isoform switch to the shorter non-canonical TCOF1 isoform c. SVA-insertion was confirmed in both half-siblings and we detected mosaicism one paarent. This is the first description of a retrotransposon causing TCS, and the first intronic SVA causing isoform switch as a disease mechanism. This work demonstrates the potential of LR-RNA-Seq and LR-GS, to identify pathogenic variants in unexplained genetic disorders.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting 94%
- Inherited variants in CHD3 demonstrate variable expressivity in Snijders Blok-Campeau syndrome 93%
- Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome 93%
Similar papers in this journal
- Genome Sequencing and Comprehensive Rare Variant Analysis of 465 Families with Neurodevelopmental Disorders 94%
- Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy 93%
- Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease 93%
Similar papers in this journal
- Evaluating Genome Sequencing Strategies: Trio, Singleton, and Standard Testing in Rare Disease Diagnosis 93%
- The Genomic Landscape of Rare Disorders in the Middle East 93%
- Multi-modal investigation of the schizophrenia-associated 3q29 genomic interval reveals global genetic diversity with unique haplotypes and segments that increase the risk for non-allelic homologous recombination 92%
Similar papers in this journal
- BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations 93%
- Re-evaluation and Re-analysis of 152 research exomes five years after the initial report reveals clinically relevant changes in 20% 93%
- Axenfeld-Rieger syndrome associated with a megabase-scale inversion separating PITX2 from a conserved enhancer locus 92%
Similar papers in this journal
- A comparative medical genomics approach may facilitate the interpretation of rare missense variation 92%
- Exome sequencing as a first-tier test for copy number variant detection : retrospective evaluation and prospective screening in 2418 cases 92%
- Advancing Genotype-Phenotype Analysis through 3D Facial Morphometry: Insights from Cri-du-Chat Syndrome 91%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.