ClinGen Dosage Sensitivity Curation Page

NHS

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
14564667 Burdon et al. (2003) identify the gene responsible for Nance-Horan Sydnrome, which they name NHS. Loss of function mutations of NHS were identified in five families with Nance-Horan Syndrome, including four frameshift mutations resulting in a premature stop codon and a nonsense mutation. These mutations segregated with the disease in all families and were not seen in 200 control chromosomes.
15623749 Ramprasad et al. (2005) identified a nonsense mutation in the NHS gene in a four generation Asian-Indian family. The mutation was detected in all affected males and carrier females, but not in unaffected family members.
16736028 Florijn et al. (2006) test four families with Nance-horan syndrome for mutations in NHS. Two nonsense mutations, one frameshift mutation, and one splice-site mutation were identified.

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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.