Genetic Epilepsy

Gene: ZDHHC15

Red List (low evidence)

1 reported case of an 18 yo M with hypotonic cerebral palsy, focal-onset epilepsy, cortical visual impairment, intellectual disability, autism spectrum disorder, anxiety, and aggressive behaviors with hemizygous p.H158R variant shown to affect protein function in yeast complementation assay (Lewis et al Neurology Genetics 2021 PMID 34345675).

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Other background info:

Protein function of x4 ZDHHC15 variants assessed by Lewis et al. x2 variants identified through Jin et al Nat Genet 2020 (PMID 32989326) - maternally inherited p.H158R and p.L13P. x1 identified through Gene Matcher p.S330P and x1 through GeneDx maternally inherited p.K115R. Only p.H158R variant shown to affect protein function. In Drosophilia model LoF variants caused flight and co-ordinated movement defects supporting role in motor dysfunction.

Conflicting evidence for ID phenotype

1 case with intellectual disability and balanced translocation with breakpoints near the ZDHHC15 gene - functional studies showing absence of ZDHHC15 transcript variants. This patient showed skewed lyonization, with 100% inactivation of the normal X chromosome. PMID: 15915161

1 case with NO intellectual disability and balanced translocation with breakpoints in the ZDHHC15 gene - functional studies showing no gene expression in the patient's peripheral blood (PMID 26290131)
Sources: Expert list, Literature

Created: 5 Oct 2021, 4:47 a.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Mental retardation X-linked 91, 300577; cerebral palsy; intellectual disability; autism spectrum disorder; epilepsy

Publications

• 34345675
• 15915161
• 26290131
• 32989326

Red List (low evidence)

Hemizygous missense (p.H158R) identified in a patient with a mixed neurodevelopmental phenotype that included cerebral palsy, intellectual disability, autism spectrum disorder, and epilepsy. In yeast, vacuolar fragmentation phenotype was not rescued by yeast expressing the variant. In Drosophila, mutant flies had increased average time to execute a coordinated axial twisting task and were less likely to initiate flights.
No PubMed ID available, Mutation in ZDHHC15 Leads to Hypotonic Cerebral Palsy, Autism, Epilepsy, and Intellectual Disability. https://ng.neurology.org/content/7/4/e602

Created: 2 Aug 2021, 7:11 a.m. | Last Modified: 2 Aug 2021, 7:11 a.m.

Panel Version: 0.8602

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
cerebral palsy; intellectual disability; autism spectrum disorder; epilepsy

Red List (low evidence)

no OMIM phenotype number.
Conflicting evidence:
1 case with intellectual disability and balanced translocation with breakpoints near the ZDHHC15 gene - functional studies showing absence of ZDHHC15 transcript variants.
1 case with NO intellectual disability and balanced translocation with breakpoints in the ZDHHC15 gene - functional studies showing no gene expression in the patient's peripheral blood.

Created: 4 Mar 2020, 1:30 a.m. | Last Modified: 4 Mar 2020, 1:30 a.m.

Panel Version: 0.1621

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Intellectual disability, X-linked 91, 300577