Submission Details

B9D1 was first reported in relation to autosomal recessive ciliopathy in 2011 (PMID: 21493627). This disorder is characterized by abnormal development/structure of cilia and renal malformations/cysts. The B9D1 gene encodes one of three B9D-containing proteins, which all interact with basal bodies and primary cilia in mammalian cells and have a role in ciliogenesis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity (autosomal recessive Ciliopathy): autosomal recessive Meckel Syndrome 9 (OMIM: 614209) and autosomal recessive Joubert Syndrome 27 (OMIM: 617120).

Twelve variants (missense, nonsense, splicing, large deletion) that have been reported in 9 probands in 7 publications (PMIDs: 24886560, 21493627, 32622957, 25920555, 27894351, 34338422, 26092869) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. There were four missense variants downgraded for homozygosity/consanguinity. One proband had a deletion impacting several genes (only one of which was implicated in ciliopathy) in trans with a splicing variant, and both variants were scored as loss of function variants due to severely decreasing ciliogenesis evident in cell analysis. In another patient, a missense variant compound heterozygous to another missense variant was scored as loss of function due to RNA analysis demonstrating an impact on splicing.

This gene-disease association is also supported by experimental evidence (animal models, cell culture models, expression studies, biochemical functional evidence, and evidence of interactions with other proteins (PMIDs: 21763481, 22179047, 20150540). Two mouse models were available (PMIDs: 21763481, 22179047), one where a homozygous whole exon deletion led to cysts and other kidney anomalies in mice, and the other showing significantly decreased ciliation in homozygous knockout mice compared to the wild type. Evidence in IMCD3 cells further shows the influence on ciliation which B9D1 has, in its localization to the transition zone, and shows that it interacts with other proteins definitively associated with ciliogenesis/Joubert Syndrome, including CC2D2A, AHI1, and CC2D2A (PMID: 22179047). The protein is also known to be essential to ciliation, indicated in a C. elegan model, when inhibiting it as well as the NPHP pathway led to defective ciliary function, while no such effect was seen when only the NPHP pathway was inhibited alone.

The protein is an essential part of the B9D1 complex, which interacts with several other proteins associated with autosomal recessive Ciliopathy manifesting as Joubert/Meckel Syndrome. In summary, B9D1 is “Definitively” associated with autosomal recessive Ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on 05/08/2023 (SOP Version 9).