KDM6A

• Haploinsufficiency score: 3
• Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
• Haploinsufficiency Phenotype: KABUKI SYNDROME 2; KABUK2

Evidence for haploinsufficiency phenotype

PubMed ID	Description
22197486	Lederer et al. (2012) report de novo microdeletions in two females with Kabuki syndrome which include all or a portion of KDM6A. They also report a de novo deletion of exons 5-9 in a male patient with Kabuki syndrome. Authors discuss implications of KDM6A partially escaping X-inactivation and a possible partial compensation from the paralog on the Y chromosome. Both females had skewed X-inactivation with the deleted copy preferentially inactivated.
23076834	Miyake et al (2013) report mutations in three patients with Kabuki syndrome. Two male patients had nonsense mutations which would be predicted to cause nonsense-mediated decay based on location. Parental specimens were not available for testing but parents are reportedly healthy. One female patient had a de novo 3-bp deletion of a conserved amino residue in the Jumonji C domain.

Haploinsufficiency phenotype comments:

To date, six individuals (males and females) with Kabuki syndrome have been reported with mutations in KDM6A, including two nonsense mutations, one multiexonic intragenic deletion, two larger deletions containing KDM6A, and one 3-bp deletion. See GeneReviews.

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.