Submission Details

The GAS2L2 gene was first reported in relation to primary ciliary dyskinesia in 2019 (Bustamante-Marin et al., PMID: 30665704). The specific disease entity, primary ciliary dyskinesia 41 (MONDO:0032757, OMIM #618449), is one of at least 45 different primary ciliary dyskinesias distinguished by a single monogenic cause. Affected patients can have childhood onset of symptoms or can be diagnosed as late as in the 6th decade of life (PMID: 36104176, PMID: 30665704). Consistent features among the limited number of well-characterized patients are sinusitis, otitis media, and bronchiectasis. Low nasal nitric oxide levels are observed in some patients, but not others. Adult patients can exhibit infertility. While neonatal respiratory distress and heterotaxy have not been found among the limited number of well-characterized patients, establishing the presence or absence of these symptoms in the patient population will require the emergence and characterization of additional affected individuals (PMID: 30665704). Biopsies of the airway epithelium show cilia with normal axonemal ultrastructure but hyperkinetic beat frequency with a normal waveform. Basal body orientation is disrupted, causing a lack of coordinated directionality of beating among the cilia of each cell. This curation has scored three suspected disease-causing GAS2L2 variants (two frameshift and one missense), which were reported in two homozygous probands and one compound heterozygous proband in two publications (PMID: 30665704, PMID: 36104176). One of the variants consists of an approximately 4-kilobase deletion affecting not only GAS2L2 but also a region within the adjacent RASL10B locus encoding part of the 3’UTR. The molecular mechanism appears to be biallelic loss of function with an autosomal recessive mode of inheritance, characterized in at least some cases by variants predicted to trigger the absence of a gene product. Please note that the limited number of patients and functional assays available has so far precluded a more thorough analysis of molecular mechanism, and an urgent need remains for additional published cases.

This gene-disease association is also supported by experimental evidence that human and mouse tissues exhibiting the highest levels of GAS2L2 expression include tissue types relevant to disease and known to have motile cilia, including the fallopian tube, lung, brain, and testis (PMID: 30665704, PMID: 23715323). Within the airway epithelium, the GAS2L2 protein exhibits strong subcellular localization to the base of the cilia and co-localizes with basal body markers (PMID: 30665704). Additional biochemical studies have demonstrated that GAS2L2 interacts through its C-terminal region with microtubule plus ends and with the microtubule plus end-associated protein EB1 (PMID: 24706950, PMID: 22885064, PMID: 12584248). When exogenously expressed, GAS2L2 stabilizes microtubule length (PMID: 24706950) and can promote microtubule bundling (PMID:12584248). The C-terminus of GAS2L2 also interacts with actin microfilaments (PMID: 12584248), including in ciliated cells (PMID: 30665704), consistent with a function in coordinating consistent ciliary basal body orientation relative to the actin cytoskeleton. While GAS2L2 can also interact with the G-protein-coupled A2A adenosine receptor and enhance its adenylate cyclase (cAMP-producing) activity (PMID: 23994616), it is not yet clear whether this function occurs in cell types with motile cilia or to what degree it impacts ciliary beat frequency. Phenotypes of affected human patients are recapitulated by various model organisms with GAS2L2 loss-of-function, including Xenopus laevis embryos and knockout mice. Silencing of two genes orthologous to GAS2L2 in Xenopus laevis embryos recapitulates the human patient phenotype of disoriented ciliary beat directionality and can be rescued by co-injection of human GAS2L2 mRNA (PMID: 30665704, PMID: 36878953). Respiratory epithelial cells from Gas2l2 knockout mice recapitulate the human patient features of hyperkinetic ciliary beat frequency, misalignment of basal feet, and disorientation of the ciliary beating pattern in each cell, while exhibiting the additional phenotypes of situs ambiguus and high neonatal mortality (PMID: 30665704). A conditional Gas2l2 knockout model further shows impaired mucociliary clearance (PMID: 30665704).

In summary, the evidence linking GAS2L2 with primary ciliary dyskinesia 41 has reached a score in the moderate range. This association has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Moderate classification. Additional genetic evidence will be required to reach a more definitive gene-disease association. This classification was approved by the ClinGen Motile Ciliopathy GCEP on September 14th, 2023 (SOP Version 9).