ClinGen Dosage Sensitivity Curation Page

NSDHL

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
please see GeneReviews link for a review of literature supporting clinical consequence of loss of function mutations

Haploinsufficiency phenotype comments:

The NSDHL-related disorders include: CHILD (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects) syndrome, an X-linked dominant condition that is usually male lethal during gestation and thus predominantly affects females; and CK syndrome, an X-linked recessive disorder that affects males. Complete loss of function mutations are generally associated with CHILD syndrome whereas CK syndrome is generally associated with hypomorphic (partial loss of function) mutations. Female carriers of mutations associated with CK syndrome (hypomorphic alleles) generally have have normal physical features, intellect and brain imaging but may display behavioral problems such as irritability and aggression. Some examples of the documented loss of function variants include: Bornholdt (2015), 3 cases, +0.3 c.208C>T p.Q70* c.894G>A p.W298* c.906C>A p.Y302* Konig (2000), 2 cases, +0.2 c.262C>T p.R88* c.628C>T p.Q210* Hummel (2003), +0.1 c.451G>T p.E151* Danarti (2010), +0.1 c.766C>T p.R256* Estap? (2015), +0.1 c.357_358delAG p.Arg119Serfs*1d Yu (2018), +0.1 ex. 3-4 del Yang (2015), 2 cases, +0.1 ex. 4-7 del

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

Triplosensitivity phenotype comment:

At this time, there are no reported focal whole gene duplications of NSDHL.

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.