ClinGen Dosage Sensitivity Curation Page

NHS

  • Curation Status: Complete

Location Information

  • Xp22.2-p22.13
  • GRCh37/hg19 chrX: 17,393,543-17,754,114
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chrX: 17,375,200-17,735,994
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
14564667 Burdon et al. (2003) identify the gene responsible for Nance-Horan syndrome, which they name NHS. Loss of function variants of NHS were identified in five families with Nance-Horan syndrome, including four frameshift variants resulting in a premature stop codon and a nonsense variant. These variants segregated with the disease in all families and were not seen in 200 control chromosomes. One of the most relevant findings consists in a a six-generation family with a frameshift variant at exon 6 (2387insC:Ala796fs), 12 living affected individuals including two males with severe intellectual impairment.
15623749 Ramprasad et al. (2005) identified a nonsense variant (p.Q39*) in the NHS gene in a four generation Asian-Indian family with Nance-Horan syndrome. The variant was detected in all nine affected males and eleven carrier females, but not in unaffected family members. Carrier females had lens opacities, but none of them necessitated cataract surgery. None of affected members had brachymetacarpalia or intellectual disability.
16736028 Florijn et al. (2006) tested four families with Nance-Horan syndrome for variants in NHS. Two nonsense variants, one frameshift variant, and one splice-site variant were identified. The larger pedigree consists consists in a a five-generation family with two affected individuals (p.Arg373*) presenting congenital cataract, nystagmus, microphthalmia, dental abnormalities but no intellectual disability. Carrier females show only mild and variable symptoms of the disease.
22229851 Khan et al. (2012) described a three-generation family with eight individulas with Nance-Horan syndrome consisting in congenital or infantile cataract and facial dysmorphism as longface, bulbous nose and abnormal dentition. Three male patients also had developmental delay. A frameshift variant was identified in NHS gene (p.Lys744AsnfsX15 [c.2232delG]) which segregates in family and the majority of female carriers had at least Y-centered lens opacities.
28061824 Using whole exome sequencing, Tian et al. (2017) reported a four-generation family with four males with Nance-Horan syndrome including bilateral congenital cataract, microcornea, nystagmus and brachymetacarpia. Only one affected male had intellectual disability. A donor splicing site variant (c.1045+2T>A) was identified in NHS intron 4 causing a protein truncation. Carrier females manifest mild and variable phenotypes. Obligate female carriers received cataract surgery a long time before the study.

Haploinsufficiency phenotype comments:

Loss of function variants in males cause Nance-Horan syndrome, which is characterized by congenital cataracts and microcornea, dental anomalies, large anteverted pinnae, and mild to moderate intellectual disability. Carrier females may show mild ocular and dental anomalies. Variable expressivity has been reported amongst affected members of the same family. Knockdown of NHS gene in cellular assays demonstrated it is essential for coordinated actin regulatory protein dynamics. NHS gene knockout caused loss of cell shape with excessive cell spreading and lamellipod formation (PMID: 20332100).

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

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.