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
27821535	Cowan (2016) reviewed CNVs in 225 pts with heterotaxy and heterotaxy-spectrum congenital heart defects. Reported male patient with heterotaxy with an assumed de novo 2.9-3.33 kb deletion including the third exon of ZIC3.
24123890	Cowan 2014 report ZIC3 sequencing variants from 440 unrelated pts with heterotaxy and congenital heart disease. 11 variants found among 15 patients, 8 of which were novel. 4 inherited, 10 assumed de novo, 1 unknown inheritance. Two of the variants were nonsense, one an assumed de novo in a male with heterotaxy. The other nonsense variant was found inherited from an unaffected carrier mother in a female with congenital heart anomalies who was sequenced rather than her affected son with heterotaxy. Functional studies demonstrated decreased gene transactivation and abnormal subcellular localization and supported loss of function mechanism of disease.
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.

Haploinsufficiency phenotype comments:

Several additional publications report nonsense and other disruptive variants associated with heterotaxy and congenital heart defects: 9354794, 21465648, 30622330, 30120289, 22171628, 27406248, 23427188.

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.