B9D2

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013609

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*B9D2* was first reported in relation to autosomal recessive ciliopathy-*B9D2* in 2011 (PMID: 21763481). This disease is associated with renal/biliary dysplasia, abnormal nervous system development, ciliation issues, and fetal death. This disorder is also 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). Nine variants (seven missense, one deletion, one splice-site) that have been reported in six probands in four publications (PMIDs: 21763481, 31411728, 26092869, 41165761) 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, 18287022, 19208769, 21422230, 41165761). 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). Adult B9D2 zebrafish mutants developed pronounced spinal curvature during later stages of development while the maternal-zygotic B9D2 zebrafish mutants (MZb9d2) exhibit severe dorsal curvature. These MZb9d2 mutants show reduced spinal canal cilia and decreased acetylation and polyglutamylation of axonemal microtubules, despite normal cilia length (PMID: 41165761). In summary, there is Moderate evidence overall supporting the relationship between *B9D2* and autosomal recessive Ciliopathy. This classification was originally approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on 06/12/2023 (SOP Version 9). It was re-evaluated on 3/25/2026 when new case reports and a novel zebrafish model were included (PMID: 41165761). As a result of this reevaluation, the classification did not change (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: PanelApp Australia