Expanding the clinical phenotype of patients with a ZDHHC9 mutation

Abstract

In 2007, 250 families with X-linked intellectual disability (XLID) were screened for mutations in genes on the X-chromosome, and in 4 of these families, mutations in the ZDHHC9 gene were identified. The ID was either isolated or associated with a marfanoid habitus. ZDHHC9 encodes a palmitoyl transferase that catalyzes the posttranslational modification of NRAS and HRAS. Since this first description, no additional patient with a ZDHHC9 mutation has been reported in the literature. Here, we describe a large family in which we identified a novel pathogenic ZDHHC9 nonsense mutation (p.Arg298*) by parallel sequencing of all X-chromosome exons. The mutation cosegregated with the clinical phenotype in this family. An 18-year-old patient and his 40-year-old maternal uncle were evaluated. Clinical examination showed normal growth parameters, lingual fasciculation, limited extension of the elbows and metacarpophalangeal joints, and acrocyanosis. There was neither facial dysmorphism nor marfanoid habitus. Brain MRI detected a dysplastic corpus callosum. Neuropsychological testing showed mild intellectual disability. They both displayed generalized anxiety disorder, and the younger patient also suffered from significant behavior impairment that required attention or treatment. Speech evaluation detected satisfactory spoken language since both were able to provide information and to understand conversations of everyday life. Occupational therapy examination showed impaired visual-spatial and visual-motor performance with poor drawing/graphic skills. These manifestations are not specific enough to guide ZDHHC9 screening in patients with ID, and emphasize the value of next generation sequencing for making a molecular diagnosis and genetic counseling in families with XLID.

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

“…In these genes, we identified likely pathogenic variants in 39 of the 248 families (16%) and in 16 of the 157 families (10%), which together with the 24 families from these two cohorts that were resolved through this screen and were published earlier, 7, 20, 21, 23, 45, 46, 47, 48, 49, 50 account for 21 and 18% of the cohorts (for details, see Supplementary Tables 5 and 6). The variants include co-segregating protein truncating variants, in-frame deletions or missense changes and none of them were reported in 61 486 unrelated individuals (ExAC Browser).…”

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

“…This altered autopalmitoylation level of DHHC9 is predicted to affect the palmitoylation of target proteins that might be involved in intellectual development [252]. By combining the value of next generation sequencing, it would be important to identify novel target proteins of DHHC9 associated with ID for providing molecular diagnosis and therapeutic treatment [249,253].…”

Functional network dynamics in a neurodevelopmental disorder of known genetic origin

“…This is because, unlike neurodevelopmental disorders defined by behavioural impairments, they have a highly specific and known aetiology, common across all cases. Here, we studied a group of individuals with mutations in ZDHHC9, a rare recurrent cause of X-linked intellectual disability (XLID; Han et al, 2017;Raymond et al, 2007;Schirwani, Wakeling, Smith, Study, & Balasubramanian, 2018;Masurel-Paulet et al 2014). We previously found that individuals with ZDHHC9 mutations are susceptible to a combined phenotype of speech and language impairments, cognitive difficulties and Rolandic Epilepsy (RE; Baker et al, 2015).…”