The MNS1 gene was first reported in relation to spermiogenesis and motile ciliary function in 2012 (PMID:22396656). Primary Ciliary Dyskinesia (PCD) is a condition of impaired ciliary function characterized by neonates with respiratory distress, recurrent chest infections and cough (PMID: 31534215). Heterotaxy is present with approximately 50% penetrance, most often in the form of situs inversus totalis. Immotile sperm and female infertility are also reported for some affected patients. Given the overlap with MNS1 function as a microtubule inner protein (PMID:31668805) and PCD, this gene was evaluated for gene-disease association with PCD.
At the time of this review at least one individual with a phenotype possibly consistent with PCD and a homozygous loss of function variant in MNS1 has been identified in the literature. However, other individuals in the family who were homozygous for this variant only presented with laterality defects or potential infertility (PMID:31534215). Other potential individuals with variants in MNS1 are present in the literature; however in these reports, conflicting or confounding data was also identified. For example, in one family, the proband presented with situs inversus totalis and features of PCD; however, this individual was also homozygous for a frameshift variant in another PCD gene. Other individuals in the family were also affected by PCD but did not carry the MNS1 variant. (PMID:30148830).
Experimental evidence supporting this gene-disease relationship includes studies demonstrating that MNS1 localizes to tissue types relevant to disease and known to have motile cilia, evidence suggesting interaction between MNS1 and another known PCD gene (CCDC114), as well as a knockout mouse model that expresses laterality defects and sperm abnormalities (PMID:22396656, 30148830).
Of note, there are other individuals who are published in the literature with variants in this gene, but with phenotypes that are not specific or detailed enough to support a relationship between MNS1 and PCD. In summary, MNS1 has a Disputed association to Primary Ciliary Dyskinesia based on a small number of experimental evidence data points. This classification was approved by the ClinGen Motile Ciliopathy GCEP on August 11th, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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