ZNF41

• Haploinsufficiency score: 1
• Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity

Evidence for haploinsufficiency phenotype

PubMed ID	Description
14628291	Shoichet et al., 2003 report a female patient with severe nonsyndromic mental retardation (MR) and a de novo balanced translocation t(X;7)(p11.3;q11.21) with sequenced breakpoints that localize within ZNF41 gene on Chr. X and a non-coding region on Chr. 7. Functional studies showed skewed X-inactivation and absent mRNA expression of ZNF41 in patient cell lines, suggesting the translocation leads to a loss-of-function for ZNF41. Two additional suspected pathogenic sequence-level ZNF41 alterations, a missense and splice-site change, were identified from a cohort of 210 patients with X-linked MR that were not present in >400 control X chromosomes. The missense variant results in a proline to leucine substitution while the splice-site variant was shown to result in absent ZNF41 isoform expression, suggesting a loss-of-function. However, since sufficient data was not provided to demonstrate loss of function for the missense and splice site changes, we did not count these changes as evidence. Additional male and female affected family members of these two index patients (both males) were identified as carriers of the respective mutations.

Haploinsufficiency phenotype comments:

While a translocation and two sequence-level alterations predicted to disrupt normal ZNF41 function have been identified in patients with nonsyndromic MR, deletions involving ZNF41 have not been reported in the literature.

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.