ClinGen Dosage Sensitivity Curation Page

ANOS1

  • Curation Status: Complete

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Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
28122887 Goncalves et al. (2017) The ANOS1 gene (also known as Kallmann syndrome 1 gene, or KAL1), is the most commonly involved gene in congenital hypogonadotropic hypogonadism (CHH) and responsible for X-linked Kallmann syndrome. Authors performed sequencing on 42 unrelated males with CHH (20 with KS and 22 with normosmic CHH) in order to determine prevalence of ANOS1 variants . Three different ANOS1 variants were identified: Family 1: Splice acceptor site variant (c.542-IG>C)-exon skipping, production of abnormal mRNA. This variant was shown to lead to skipping of exon 5 in the ANOS1 transcript in a patient with self-reported normosmia (but hyposmic upon testing). Absent in 85 normal controls. Family 2: Nonsense variant (c.571C>T; p.Arg191*) Family 3: 4.8 Mb contiguous gene deletion Xp22.31-p22.32 region including ANOS1 (deleted genes ANOS1, VCX3B, VCX2, PNPLA4, VCX, STS, HDHD1, VCX3A and NLGN4X).
12050219 Soderlund et al. (2002) sequenced the entire ANOS1 gene in 12 males with Kallmann syndrome. Three variants were identified: Patient 5: nucleotides 158-168 were duplicated in exon 1. The 11 bp insertion causes a termination codon within the same exon (19 codons after the insertion). Patient 6: Deletion of exon 5 Patient 12: C->T change codon 262 from CGA (arginine) to TGA (premature termination signal)
24232061 Marlin et al. (2013) described two brothers with variable severity of sensorineural hearing loss (severe unilateral for one and profound bilateral for the other), cryptorchidism, hyposmia, and mirror movements of the upper limbs. One of them also presented with unilateral renal agenesis and metatarsus of one foot. Array analysis showed 570 kb deletion containing the entire VCS3B and ANOS1 gene. The deletion arr Xp22.31 (8,112,876-8,665,494)x0 was found to be inherited from a mother with a mosaic deletion.
21717404 Kryminska et al (2011) described a family in which the male proband and his maternal uncle with Kallmann syndrome were found to have an intragenic deletion of the ANOS1 (KAL1) gene from exons 4-14 (c.469-?_6314+?del) identified by MLPA. Three carrier females were also identified in this family.
25328414 Husny et al. (2014) identified a c.612G>A ( p.Trp204*) in a family of 4 brothers with a diagnosis of Kallmann syndrome and five heterozygous female family members.
18463157

Haploinsufficiency phenotype comments:

Loss of function variants in the ANOS1 gene, including whole or partial gene deletions, pathogenic missense variants, pathogenic nonsense variants and pathogenic splice site variants, cause Kallmann syndrome in males. Female carriers are typically unaffected, although some females have been described as having variable presentation of GnRH deficiency (PMID: 21209029)

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
18657637 Mencarelli et al. performed oligo arrays on 84 patients with mild to severe intellectual disability and multiple congenital anomalies. They described a 0.8 MB duplication at Xp22.31 including the ANOS1 (KAL1), FAM8A, and FAM9B genes in a female with autism, skeletal defects, short stature, facial asymmetry, and heart defect in inherited from a clinically normal father.

Triplosensitivity phenotype comment:

There have been no focal duplications of ANOS1 gene reported.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.