ARMC2

Inheritance Pattern: AR

Disease ID:MONDO:0017173

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0032748

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0032748

Submitter: ClinGen

Spermatogenic failure 38 (SPGF38) is one of many types of spermatogenic failure characterized by asthenozoospermia and associated with variants in a single gene. SPGF38 phenotypes include male infertility due to morphologic abnormalities of the flagella (MMAF) such as shortness, irregular shape, coiling of the tail, and reduced sperm count. Structural analysis of affected flagella have revealed absent central pair complexes, loss of the circular formation of the microtubules (9+2 arrangement), and other structural abnormalities (PMID:30686508). *ARMC2* was first reported in relation to autosomal recessive spermatogenic failure 38 in 2019 (Coutton et al., PMID: 30686508). After a thorough literature search, no patients were found to be published in association with PCD, so *ARMC2* was only curated in association with SPGF38. In this curation, 7 variants (1 missense, 3 nonsense, 2 frameshift, 1 splice site) that have been reported in 7 probands in 3 publications (PMIDs: 30686508, 35543806) are included. All reported probands were homozygous, with 3 families reported as consanguineous. There was one missense variant reported (c.2279T>A, p.Ile760Asn). Immunostaining or RNA analysis could not be performed on the patient’s sperm to verify the impact of the missense change due to lack of a biological sample (PMID:30686508). There is also a splice site variant included in this curation, which the authors confirmed to skip exon 8 and result in an early termination codon in exon 9 (18 exons total) at the RNA level (PMID:30686508). The other 5 variants were predicted null variants which formed a stop codon upstream of the last 50 base pairs of the penultimate exon, and are therefore expected to undergo nonsense-mediated decay. The mechanism of pathogenicity appears to be LOF. This gene-disease relationship is also supported by expression studies, biochemical evidence, functional assays, and animal models (PMIDs: 30686508, 34982025, 23715323). GTEx expression data revealed increased expression in the testis compared to other tissues in unaffected individuals, which is consistent with the SPGF38 phenotype (PMID:23715323). Tagged *ARMC2* protein was found to be upregulated in regenerating chlamydomonas flagella compared to fully grown flagella, which supports the biochemical role of *ARMC2* in axonemal assembly (PMID: 34982025). Functional alteration of patient sperm cells was observed through the absence of SPAG6, a known marker of the central pair complex. This supports the suspected role of *ARMC2* mutations in contributing to the absent central pair complex flagellar phenotype (PMID:30686508). A chlamydomonas model demonstrates flagellar immotiltiy (0% velocity) similar to human patients with SPGF38. Additionally, the *armc2/pf27* mutants also had radial spokes limited to the proximal region of the flagella, which is consistent with the structural defects seen in flagellar cross-sections of patients (PMID:34982025). The immotility and mislocalized radial spoke phenotypes seen in the *armc2/pf27* null chlamydomonas model were rescued using a wild-type copy of chlamydomonas *ARMC2* (PMID:34982025). Finally, a mouse model generated using the CRISPR-Cas9 system recapitulated the male infertility, MMAF (short, coiled, or thick), and reduced sperm count phenotypes seen in SPGF38 patients (PMID:30686508). In summary, *ARMC2* is definitively associated with autosomal recessive spermatogenic failure 38. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Motile Ciliopathy GCEP on the meeting date 5/10/2023 (SOP Version [9]).