Biallelic intragenic tandem duplication of CPLANE1 in Joubert syndrome: A case report

• Published in: Clinical genetics Vol. 103; no. 4; pp. 448 - 452
• Main Authors: Martínez‐Granero, Francisco, Martínez‐Cayuelas, Elena, Rodilla, Cristina, Núñez‐Moreno, Gonzalo, Rodríguez de Alba, Marta, Blanco‐Kelly, Fiona, Romero, Raquel, Minguez, Pablo, Ayuso, Carmen, Lorda‐Sanchez, Isabel, Corton, Marta, Almoguera, Berta
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2023
• Subjects: Abnormalities, Multiple - genetics; Brain; Breakpoints; Case reports; Cerebellum; Congenital defects; Copy number; CPLANE1; developmental delay; Exons; Eye Abnormalities - genetics; Genetic disorders; Humans; intragenic duplication; Joubert syndrome; Kidney Diseases, Cystic - diagnosis; long‐read sequencing; Neurodevelopmental disorders; Retina - pathology; developmental delay; CPLANE1; long-read sequencing; Joubert syndrome; intragenic duplication
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.14306

Joubert syndrome (JS) is a clinically and genetically heterogeneous genetic disorder. To date, 40 JS‐causing genes have been reported and CPLANE1 is one of the most frequently mutated, with biallelic pathogenic missense and truncating variants explaining up to 14% of JS cases. We present a case of JS diagnosed after the identification of a novel biallelic intragenic duplication of exons 20–46 of CPLANE1. The quadruplication was identified by short‐read sequencing and copy number variant analysis and confirmed in tandem by long PCR with the breakpoints defined by a nanopore‐based long‐read sequencing approach. Based on the genetic findings and the clinical presentation of the patient, a brain MRI was ordered, evidencing the molar tooth sign, which confirmed the diagnosis of JS in the patient. This is, to the best of our knowledge, the first report of an intragenic duplication in this gene as the potential molecular mechanism of JS.