Submission Details

B9D2 was first reported in relation to autosomal recessive ciliopathy in 2011 (PMID: 21763481). This disease is associated with renal/biliary dysplasia, abnormal nervous system development, ciliation issues, and fetal death. This disorder is characterized by abnormal development/structure of cilia and renal malformations/cysts. The B9D2 gene encodes one of the three B9D-containing proteins, which all interact with the basal body and primary cilia in mammalian cells. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity (autosomal recessive Ciliopathy): Meckel Syndrome 10 (OMIM: # 614175) and Joubert Syndrome 34 (OMIM # 614175).

Five variants (all missense) that have been reported in 4 probands in 3 publications (PMIDs: 21763481, 31411728, 26092869) are included in this curation. The mechanism of pathogenicity appears to be loss of function. Three of the variants were homozygous, and one of them had functional evidence in the form of mass spectrometry showing impaired interaction with MSK1. The fourth proband was a compound heterozygous case where both variants were shown to impact transition zone targeting and localization. All variants that exhibited functional evidence were upgraded. This gene-disease relationship is also supported by experimental evidence (a mouse model, expression studies, interaction evidence, functional alteration evidence; PMIDs: 17127412, 21422230, 18287022, 19208769). The mouse model showed that mice with homozygous deletions in B9D2 had defective ciliation in their kidneys (PMID: 18287022). Expression level evidence in C. elegans and human nasal polyps or turbinates showed expression in the ciliary transition zone, and that levels of ciliation are positively correlated with B9D2 expression (PMIDs: 17127412, 21422230). The C. elegans study also demonstrated colocalization of B9D1, B9D2, NPHP1, and NPHP4. B9D1 is definitive for autosomal recessive ciliopathy and NPHP1 and NPHP4 are definitive for autosomal recessive nephronophthisis 1 and autosomal recessive nephronophthisis 4, respectively. Functional alteration evidence in the form of RNAi inhibition in P. Tetraulia and IMCD3 cells shows that insufficient B9D2 leads to defective ciliogenesis (PMIDs: 17127412, 19208769).

While there is limited genetic evidence, a good deal of experimental evidence is available. In summary, there is “Moderate” evidence overall supporting the relationship between B9D2 and autosomal recessive Ciliopathy. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on 06/12/2023 (SOP Version 9).