ZDHHC15

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*ZDHHC15* was first reported in relation to complex neurodevelopmental disorder in 2005, when Mansouri et al. described a female with severe intellectual disability, seizures, and a *de novo* balanced translocation (46,XX,t(X;15)(q13.3;cen)) (PMID: 15915161). The breakpoint on 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. Moysés-Oliveira et al. (2015, PMID: 26290131) reported a 42-year-old female with amenorrhea and a balanced translocation (46,X,t(X;9)(q13;p11.1), with no documented neurodevelopmental phenotypes. The X chromosome breakpoint disrupted *ZDHHC15* at intron 10, and ZDHHC15 was demonstrated to be absent in the patient’s peripheral blood. Due to the absence of neurodevelopmental phenotypes, 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 shown as “non-scoreable evidence” in the evidence summary. The last case available in the literature was reported by Sifrim et al. (2016, PMID: 27479907). 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 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). *Zdhhc15*-KO male mice did not show deficits in the number and morphology of dopaminergic neurons, anxiety levels, social interactions, or learning and memory when compared to wild-type (WT) mice (PMID: 33462194). KO mice exhibited a significant increase in locomotion induced by novelty or amphetamine, and had reduced levels of dopamine and its metabolites in the striatum. 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 primary rat hippocampal cultures, shRNA-mediated knock-down of *Zdhhc15* resulted in reduced dendritic outgrowth, arborization, spine maturation and palmitoylation of PSD-95, a substrate of Zdhhc15 (PMID: 31189538). The defects were rescued by a WT 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 a Disputed classification. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 30, 2021 (SOP Version 8).

Inheritance Pattern: Unknown

Disease ID:MONDO:0010363

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0010363

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0010363

Submitter: PanelApp Australia