Submission Details

MKS1 was first reported in relation to autosomal recessive Meckel Syndrome (MKS) in 2006 (Kyttala et al., PMID: 16415886). Additionally, MKS1 was initially associated with Bardet-Biedl Syndrome (BBS) in 2008 (Leitch et al., PMID: 18327255) and with Joubert Syndrome (JS) in 2014 (Romani et al., PMID: 24886560). Typical features of MKS include cystic kidneys, occipital encephalocele, and polydactyly. BBS patients also commonly present with polydactyly, while also showing obesity and retinitis pigmentosa. Finally, JS is characterized by cerebellar vermis hypoplasia, cystic kidney disease, liver fibrosis, polydactyly, and/or retinal dystrophy. Each of these diseases is considered a ciliopathy, as pathogenic mutations in MKS1 cause primary cilia dysfunction in affected individuals. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found no difference in inheritance pattern between these three disorders, and phenotypic variability between them was considered within the spectrum of a single disease. Therefore, Meckel syndrome 1 (MIM#: 249000), Bardet-Biedl syndrome 13 (MIM#: 615990) and Joubert syndrome 28 (MIM#: 617121) have been lumped into a single curation under the name ciliopathy-MKS1.

Fifteen variants (four splicing, three nonsense, five missense, two in-frame deletions, and one frameshift deletion) that have been reported in ten probands in seven publications (PMIDs: 24886560, 33193692, 34359301, 26490104, 18327255, 24608809, 17397051) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached. Although unclear, the mechanism of pathogenicity may be a spectrum, with biallelic truncating mutations in MKS1 leading to MKS and less damaging mutations causing BBS or JS. Of note, a recurrent splice-altering pathogenic variant NM_017777.4(MKS1): c.1408-34_1408-6del (ClinVar ID: 188400) was initially described as a founder mutation causing MKS in the Finnish population and is prevalent in many other mostly European populations (PMID: 16415886, 17377820).

This gene-disease association is also supported by expression studies in mouse embryos showing that MKS1 expression is prominent in tissues showing MKS-characteristic malformations: brain, liver, kidney and digits of the upper limbs, with intense proximal tubule staining in the human fetus (PMID: 16415886, 17185389). The MKS1 protein localizes to the cilia transition zone, supporting the role of MKS1 in ciliary function and co-immunoprecipitation experiments showed that the MKS1 protein interacts with TMEM67, a protein also associated with MKS. Finally, using RNAi to silence MKS1 expression, it has been shown that ciliary formation and cilia length were significantly decreased in targeted cells when compared to control cells (PMID: 17185389). Confirming these results, Weatherbee et. al. showed that primary cilia formation is reduced in mesenchymal and epithelial tissues of Mks1-knockout mice. This publication goes on to provide evidence that mutant mice recapitulate the main features seen in human MKS patients, including polydactyly, cystic kidneys, and occipital encephalocele (PMID: 19776033). A second Mks1-null mouse model similarly recapitulates these primary human MKS features (PMID: 23454480).

In summary, MKS1 is definitively associated with autosomal recessive ciliopathy- MKS1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina GCEP on September 5, 2024 (SOP Version 10).

MKS1 was first reported in relation to autosomal recessive Meckel Syndrome (MS) in 2006 (Kyttala et al., PMID: 16415886). Additionally, MKS1 was initially associated with Bardet-Biedl Syndrome (BBS) in 2008 (Leitch et al., PMID: 18327255) and with Joubert Syndrome (JS) in 2014 (Romani et al., PMID: 24886560). Typical features of MS include cystic kidneys, occipital encephalocele, and polydactyly. BBS patients also commonly present with polydactyly, while also showing obesity and retinitis pigmentosa. Finally, JS is characterized by cerebellar vermis hypoplasia, cystic kidney disease, liver fibrosis, polydactyly, and/or retinal dystrophy. Each of these diseases is considered a ciliopathy, as pathogenic mutations in MKS1 cause primary cilia dysfunction in affected individuals. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found no difference in inheritance pattern between these three disorders, and phenotypic variability between them was considered to be consistent with a single spectrum of disease. Therefore, Meckel syndrome 1 (MIM#: 249000), Bardet-Biedl syndrome 13 (MIM#: 615990) and Joubert syndrome 28 (MIM#: 617121) have been lumped into a single curation under the name MKS1-related ciliopathy.

Fifteen variants (four splicing, three nonsense, five missense, two in-frame deletions, and one frameshift deletion) that have been reported in ten probands in seven publications (PMIDs: 24886560, 33193692, 34359301, 26490104, 18327255, 24608809, 17397051) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Although unclear, the mechanism of pathogenicity may be a spectrum, with biallelic truncating mutations in MKS1 leading to MS and less damaging mutations causing BBS or JS.

This gene-disease association is also supported by an expression study showing that MKS1 protein localizes to the basal body of cilia, supporting the role of MKS1 in ciliary function. These authors also conducted co-immunoprecipitation experiments showing that the MKS1 protein interacts with TMEM67, a protein previously associated with Meckel Syndrome. Finally, using RNAi to silence MKS1 expression, this group shows that ciliary formation and cilia length were significantly decreased in targeted cells when compared to control cells (PMID: 17185389). Confirming these results, Weatherbee et. al. show that primary cilia formation is reduced in mesenchymal and epithelial tissues of MKS1-knockout mice. This publication goes on to provide evidence that mutant mice recapitulate the main features seen in human Meckel Syndrome patients, including polydactyly, cystic kidneys, and occipital encephalocele (PMID: 19776033). A second MKS1-null mouse model similarly recapitulates these primary human MKS features (PMID: 23454480).

In summary, MKS1 is definitively associated with autosomal recessive MKS1-related ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina GCEP on September 5, 2024 (SOP Version 10).