Novel compound heterozygous CPLANE1 variants identified in a Chinese family with Joubert syndrome.

Joubert syndrome (JS) and JS-related disorders (JSRD) are a group of neurodevelopmental diseases that share the "molar tooth sign" on axial brain magnetic resonance imaging (MRI), accompanied by cerebellar vermis hypoplasia, ataxia, hypotonia, and developmental delay. To identify variants responsible for the clinical symptoms of a Chinese family with JS and to explore the genotype-phenotype associations, we conducted a series of clinical examinations, including blood tests, brain MRI scans, ultrasound imaging, and ophthalmologic examination. Genomic DNA was extracted from the peripheral blood of the six-person family, and the pathogenic variants were detected by whole-exome sequencing (WES) and verified by Sanger sequencing. WES revealed two novel compound heterozygous variants in CPLANE1: c.1270C>T (p.Arg424*) in exon 10 and c.8901C>A (p.Tyr2967*) in exon 48 of one child, inherited from each parent. Both variants were absent in ethnically matched Chinese control individuals and were either absent or present at very low frequencies in public databases, suggesting that these variants could be the pathogenic triggers of the JS phenotype. Notably, these CPLANE1 sequence variants were related to the pathogenesis of autosomal recessive JS in this study. The newly discovered variants expand the mutation spectrum of CPLANE1, which assists in understanding the molecular mechanism underlying JS and improving the recognition of genetic counseling, particularly for families with a history of autosomal recessive JS.