Long-read sequencing reveals a hidden Alu-mediated splice defect in CPLANE1, causing orofaciodigital syndrome type VI.

Jelena Pozojevic, Henrike Lisa Sczakiel, Saranya Balachandran, Nathalie Kruse, Martin Atta Mensah, Wiebke Hülsemann, Kristian Händler, Malte Spielmann

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Article in European journal of human genetics : EJHG, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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8 authors.

Jelena PozojevicInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Germany.

Henrike Lisa SczakielInstitute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.

Saranya BalachandranInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Germany.

Nathalie KruseInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Germany.

Martin Atta MensahInstitute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.

Wiebke HülsemannHandchirurgie, Katholisches Kinderkrankenhaus Wilhelmstift, Hamburg, Germany.

Kristian HändlerInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Germany.

Malte SpielmannInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Germany. spielmann@molgen.mpg.de.ORCID http://orcid.org/0000-0002-0583-4683

Funding

Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation) 2022_EKEA.55

6 · The paper itself

Abstract

Orofaciodigital syndrome type VI (OFD VI) is a recessive ciliopathy characterized by excessive polydactyly, molar tooth sign, cleft lip, and developmental delay, caused by pathogenic variants in CPLANE1. Here, we present a patient with OFD VI that remained genetically unexplained after routine genetic testing, including short-read whole genome sequencing (WGS). Using long-read sequencing, we found two biallelic splice-site variants in CPLANE1, c.8633-4_8633-3del, and an Alu element insertion close to an exon-intron boundary. Transcript analysis showed that each variant independently resulted in exon skipping, and quantitative expression studies revealed reduced total CPLANE1 mRNA levels in patient-derived fibroblasts. Based on these findings, we were able to re-classify the c.8633-4_8633-3del variant from a variant of uncertain significance (VUS) to likely pathogenic. The identification of an Alu element insertion missed by short-read WGS highlights the added diagnostic value of long-read sequencing in uncovering cryptic, transposable element-associated pathogenic variants.

Identifiers

PMID42732008

DOI10.1038/s41576-025-00862-x

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.