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Background Joubert syndrome (JBTS) is a rare genetic disorder that is characterized by midbrain‐hindbrain malformations. Multiple variants in genes that affect ciliary function contribute to the genetic and clinical heterogeneity of JBTS and its subtypes. However, the correlation between genotype and phenotype has not been elucidated due to the limited number of patients available. Methods In this study, we observed different clinical features in two siblings from the same family. The older sibling was classified as a pure JBTS patient, whereas her younger sibling displayed oral‐facial‐digital defects and was therefore classified as an oral‐facial‐digital syndrome type VI (OFD VI) patient. Next, we performed human genetic tests to identify the potential pathogenic variants in the two siblings. Results Genetic sequencing indicated that both siblings harbored compound heterozygous variants of a missense variant (c.1067C>T, p.S356F) and a frameshift variant (c.8377_8378del, p.E2793Lfs*24) in CPLANE1 (NM_023073.3). Conclusion This study reports that two novel CPLANE1 variants are associated with the occurrence of JBTS and OFD VI. These results help elucidate the intrafamilial phenotypic variability associated with CPLANE1 variants., In this study, we observed different clinical features in two siblings from the same family. The older sibling was classified as a pure JBTS patient, whereas her younger sibling displayed oral‐facial‐digital defects and was therefore classified as an oral‐facial‐digital syndrome type VI (OFD VI) patient.

Background Joubert syndrome (JS, OMIM: 213300) is a recessive developmental disorder characterized by cerebellar vermis hypoplasia and a distinctive mid‐hindbrain malformation called the “molar tooth sign” on axial magnetic resonance imaging. To date, more than 35 ciliary genes have been identified as the causative genes of JS. Methods Whole exome sequencing was performed to detect the causative gene mutations in a Chinese patient with JS followed by Sanger sequencing. RT‐PCR and Sanger sequencing were used to confirm the abnormal transcript of centrosomal protein 104 (CEP104, OMIM: 616690). Results We identified two novel heterozygous mutations of CEP104 in the proband, which were c.2364+1G>A and c.414delC (p.Asn138Lysfs*11) (GenBank: NM_014704.3) and consistent with the autosomal recessive inheritance mode. Conclusion Our study reported the fourth case of JS patients with CEP104 mutations, which expands the mutation spectrum of CEP104 and elucidates the clinical heterogeneity of JS., (a) We report on a Chinese patient diagnosed with Joubert syndrome (JS), presenting developmental delay, hypotonia, oculomotor apraxia, and molar tooth sign. (b) Whole exome sequencing identified two novel heterozygous mutations of CEP104 in the proband, which were c.2364+1G>A and c.414delC (p.Asn138LysfsTer11). (c) This is the fourth case of JS patients with CEP104 mutations, which expands the mutation spectrum of CEP104 and elucidates the clinical heterogeneity of JS.

Background: The relationships among phenotypes, genes, and variants play a key role for monogenic disorders in the era of precision medicine. Information about this is erupting with the current rapid development of genomic technology. However, it is time-consuming and error-prone to manually capture the information from the literature. Thus, how to capture this information rapidly and accurately is a bottleneck to be solved. Results: Here, we present VarfromPDB, an automated and integrated method to mine the genes and variants related to a Mendelian disorder from multiple public curated databases and literature. To demonstrate the procedure, feasibility and application, we used a monogenic disorder, Joubert syndrome, as an example to capture the related genes from multiple sources including HPO, OrphaNet, ClinVar, UniProt and PubMed abstracts. The captured gene list is more comprehensive than that from DisGeNET and DISEASES databases. Conclusion: VarfromPDB is a an automated and integrated tool to compile the up-to-date disease-genevariant database with comprehensive. It is valuable for genetic researchers and has great potential in facilitating the application of genetic testing for precision medicine. The source code for VarfromPDB is freely available at https://CRAN.R-project.org/package=VarfromPDB.