Cargando…

Mutation in ZDHHC15 Leads to Hypotonic Cerebral Palsy, Autism, Epilepsy, and Intellectual Disability

OBJECTIVE: To determine whether mutations reported for ZDHHC15 can cause mixed neurodevelopmental disorders, we performed both functional studies on variant pathogenicity and ZDHHC15 function in animal models. METHODS: We examined protein function of 4 identified variants in ZDHHC15 in a yeast compl...

Descripción completa

Detalles Bibliográficos
Autores principales: Lewis, Sara A., Bakhtiari, Somayeh, Heim, Jennifer, Cornejo, Patricia, Liu, James, Huang, Aris, Musmacker, Andrew, Jin, Sheng Chih, Bilguvar, Kaya, Padilla-Lopez, Sergio R., Kruer, Michael C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323736/
https://www.ncbi.nlm.nih.gov/pubmed/34345675
http://dx.doi.org/10.1212/NXG.0000000000000602
Descripción
Sumario:OBJECTIVE: To determine whether mutations reported for ZDHHC15 can cause mixed neurodevelopmental disorders, we performed both functional studies on variant pathogenicity and ZDHHC15 function in animal models. METHODS: We examined protein function of 4 identified variants in ZDHHC15 in a yeast complementation assay and locomotor defects of loss-of-function genotypes in a Drosophila model. RESULTS: Although we assessed multiple patient variants, only 1 (p.H158R) affected protein function. We report a patient with a diagnosis of hypotonic cerebral palsy, autism, epilepsy, and intellectual disability associated with this bona fide damaging X-linked variant. Features include tall forehead with mild brachycephaly, down-slanting palpebral fissures, large ears, long face, facial muscle hypotonia, high-arched palate with dental crowding, and arachnodactyly. The patient had mild diminished cerebral volume, with left-sided T2/FLAIR hyperintense periatrial ovoid lesion. We found that loss-of-function mutations in orthologs of this gene cause flight and coordinated movement defects in Drosophila. CONCLUSIONS: Our findings support a functional expansion of this gene to a role in motor dysfunction. Although ZDHHC15 mutations represent a rare cause of neurodevelopmental disability, candidate variants need to be carefully assessed before pathogenicity can be determined.