Submission Details

MKKS was first reported in relation to autosomal recessive Bardet-Biedl syndrome (BBS) in 2000 by two groups, Slavotinek et al. (PMID: 10973238) and Katsanis et al. (PMID: 10973251). BBS is a rare genetically heterogeneous ciliopathy, characterized by rod-cone dystrophy, polydactyly, obesity, genital anomalies, renal anomalies, and intellectual disabilities. MKKS variants have also been reported in relation to cases diagnosed as McKusick-Kaufman syndrome (PMID: 10802661). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic MKKS loss of function) have been found to be consistent among patients diagnosed with either Bardet-Biedl syndrome 6 (MIM# 605231) or McKusick-Kaufman syndrome (MIM# 236700), while the phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic MKKS variants have been lumped into a single disease entity, referred to as MKKS-related ciliopathy.

This curation includes twelve variants (five missense, three nonsense and four frameshift) that have been reported in thirteen probands in eight publications (PMIDs: 10973238, 10973251, 12107442, 20472660, 15770229, 20177705, 28761321 and 30718709). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

This gene-disease association is also supported by experimental data showing that MKKS is expressed in tissues affected by BBS (PMID: 10973238 ). This gene-disease association is also supported by biochemical evidence that the MKKS protein shares a function with the products of the BBS10 and BBS12 genes to mediate the assembly of the BBSome, a complex that performs vesicle transport to primary cilia and contributes to adipocyte differentiation. Through yeast two hybrid and coimmunoprecipitatin assays, Rachel et al. 2012 show that MKKS physically interacts with CEP290, a critical protein in ciliary biogenises and function, and that MKKS variants found in human BBS patients disrupt this protein-protein interaction (PMID: 22446187). Finally, multiple Mkks-knockout mouse models show that mice without a functional copy of Mkks display severe retinal degeneration compared to wild-type mice (PMIDs: 30901771 and 15772095).

In summary, MKKS is definitively associated with autosomal recessive MKKS-related 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 Retina GCEP on May 2nd, 2024 (SOP Version 10).