Submission Details

ANOS1 was first reported in relation to X-linked recessive hypogonadotropic hypogonadism 1 with or without anosmia in 1991 (Legouis et al., PMID: 1913827). Hypogonadotropic hypogonadism with or without anosmia (formerly referred to as Kallman syndrome if anosmia is present) is characterized by absent or incomplete sexual maturation due to defects in gonadotropin release or action. Anosmia, or impaired sense of smell, can also be present along with variable features such as cleft palate, sensorineural hearing loss, and unilateral renal agenesis. Nine variants (missense, splicing, nonsense, frameshift) that have been reported in 9 probands in 3 publications (Hardelin et al., 1992, PMID:1518845; Jiang et al., 2020, PMID: 31669640; Nie et al., 2017, PMID: 28780519) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by a C. elegans model, expression studies, in vitro functional assays, and biochemical function studies (Cariboni et al., 2014, PMID:15471890; Hardelin et al., 1999, PMID: 10340754; Rugarli et al., 1993, PMID: 8513320; Rugarli et al., 2002, PMID: 11874923). In summary, ANOS1 is definitively associated with X-linked recessive hypogonadotropic hypogonadism 1 with or without anosmia. 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 Syndromic Disorders GCEP on 03.28.2022 (SOP Version 8).