Submission Details

Variants in ZDHHC15 were first implicated in complex neurodevelopmental disorders (MONDO: 0100038) in 2005 when Mansouri et al. described a 29 year old female with severe intellectual disability, seizures, and a de novo balanced translocation (46,XX,t(X;15)(q13.3;cen)) (PMID:15915161). The breakpoint at the X chromosome was 3.9 kb upstream of the first exon of ZDHHC15. Though the authors demonstrated that ZDHHC15 expression was absent in primary lymphocytes from the patient, expression status in other tissues of interest is not known. The patient was initially clinically suspected to have Prader Willi syndrome (PWS); methylation status of the Prader Willi/Angelman region was said to be normal, but the PWS phenocopy genes were not assessed. For these reasons and the fact that the reported variant was not actually within the ZDHHC15 gene, the group decided not to score this case.

Since the initial report, only two other females with variants in ZDHHC15 have been reported in the literature (PMIDs: 15915161, 26290131, 27479907). In 2015, Moyses-Oliveira et al. reported a 42 year old female with amenorrhea. No phenotypes associated with a neurodevelopmental disorder were reported. This individual was also found to have a balanced translocation (46,X,t(X;9)(q13;p11.1). The X chromosome breakpoint was reported to disrupt ZDHHC15 at intron 10, and ZDHHC15 was demonstrated to be absent in the patient’s peripheral blood. Due to this as well as the absence of the neurodevelopmental disorder phenotype, this variant was also not scored. Please note that due to the limitations of the GCI, translocations are not able to be formally entered as evidence; these cases are represented as “non-scoreable evidence” in the evidence summary. The last case available in the literature was reported by Sifrim et al. in 2016. A female patient with a de novo missense variant in ZDHHC15 was diagnosed with non-syndromic congenital heart defects. It was unclear if this patient had a neurodevelopmental disorder phenotype. Given the seemingly disparate presentations among the three reported females with variants involving this gene, this variant was also not scored. No affected males with variants in ZDHHC15 have been reported.

The experimental evidence for ZDHHC15 includes a mouse model (PMID:33462194) and a cell culture model (PMID:31189538). Mejias et al. created a mouse model using zdhhc15-KO adult male mice, which did not show deficits in number and morphology of dopaminergic neurons, anxiety levels, social interactions, learning and memory functions when compared to WT mice. They did show a significant increase in novelty-induced locomotion; a similar effect was also seen in response to amphetamine. The zdhhc15-KO mice had reduced levels of dopamine and its metabolites in striatum in comparison to the wild type mice. However, there was no significant difference in the palmitoylation levels of known ZDHHC15 substrates in striatal tissues when comparing the zdhhc15-KO and WT mice. In the cell culture model study performed by Shah et al, ShRNA mediated knock down of zDHHC15 in primary rat hippocampal cultures reduced dendritic outgrowth, arborization, spine maturation and palmitoylation of PSD-95 a substrate of zDHHC15. The defects were rescued by cells expressing a wild type zDHHC15 construct but not by a palmitoylation defective ZDHHC15 construct. Though there is some data that might suggest a possible role of ZDHHC15 in cognitive and social phenotypes, since genetic evidence had a total of score 0, the experimental evidence was also not scored.

Overall, there is a lack of sufficient genetic evidence to support this gene-disease relationship and weak experimental evidence available in the literature for ZDHHC15, resulting in Disputed classification. The ClinGen Intellectual Disability and Autism Gene Curation Expert Panel approved this classification on 07/30/2021 (SOP Version 8).