ZIC3

• Haploinsufficiency score: 3
• Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
• Haploinsufficiency Phenotype: HETEROTAXY, VISCERAL, 1, X-LINKED; HTX1

Evidence for haploinsufficiency phenotype

PubMed ID	Description
14681828	Ware (2004): Report of two families with X-linked classic heterotaxy due to nonsense mutations resulting in lack of protein. All affected individuals were male and female carriers were normal. Clinical features were variable and included cardiac-related heterotaxy and additional visceral anomalies.
9354794	Gebbia (1997): Report of two families with X-linked situs ambiguus (heterotaxy) with nonsense mutations. Males were affected and females were normal. Another family with a frameshift mutation had fully affected males and females had situs inversus.
21465648	Chung (2011): Report of a family with a 1.3 Mb focal deletion of ZIC3 where affected males have features consistent with classic heterotaxy as well as imperforate anus and other anomalies suggestive of VACTERL.

Haploinsufficiency phenotype comments:

In addition to the loss of function mutations described above, other reports of mutations include PMIDs: 17295247, 10980576, 21864452, and 20452998).

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.