ZDHHC9

Gene Facts

• HGNC Symbol: ZDHHC9 (HGNC:18475)
• HGNC Name: zinc finger DHHC-type palmitoyltransferase 9
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: ZDHHC10, CXorf11
• Alias symbols: ZNF379, CGI-89, ZNF380, DHHC9
• %HI: 13.32
• pLI: 0.74
• LOEUF: 0.48
• Cytoband: Xq26.1
• Genomic Coordinates:

  GRCh37/hg19:	chrX:128937264-128977862
  GRCh38/hg38:	chrX:129803288-129843886

• MANE Select Transcript: NM_016032.4 ENST00000357166.11
• Function: Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as ADRB2, HRAS, NRAS and CGAS (PubMed:16000296, PubMed:27481942, PubMed:37802025). The ZDHHC9-GOLGA7 complex is a palmitoyltransferase specific for HRAS and NRAS (PubMed:16000296). May have a palmitoyltransferase activity toward the beta-2 adrenergic receptor/ADRB2 and therefore regulate G protein- coupled receptor signaling (PubMed:27481942). Acts as a regulator of innate immunity by catalyzing p... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-11289
• ClinGen Curation ID: CCID:008130
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 10/12/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• syndromic X-linked intellectual disability Raymond type

HI Evidence

• PUBMED: 17436253
  Raymond et al. (2007) identified 4 ZDHHC9 variants in 4 families with X-linked intellectual disability, three of which also had Marfanoid habitus (also reported in Tarpey et al, PMID: 19377476), including a 4-bp dup (frameshift), a splicing variant (IVS3+5 G>C) which resulted in a truncated protein confirmed by RNA studies, and two missense. Female carriers were unaffected.
• PUBMED: 20848651
  Boone et al. (2010) identified a deletion of exons 10-11 in ZDHHC9 in a 4-year-old male with developmental delay, significant behavioral problems and significant speech delay, but no autistic features or dysmorphic features at the time of clinical evaluation. The same genomic deletion was identified in the patient’s brother, who has a milder developmental delay, as well as in their unaffected mother.
• PUBMED: 24357419
  Masurel et al. (2014) identified a nonsense variant (p.R298*) in a 18-year-old patient and his 40-year-old maternal uncle, who had 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.
• PUBMED: 26350204
  Gnozeva et al. (2015) screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID‐associated genes using targeted next‐generation sequencing. Two patients with ID were found to have a frame shift (c.878_879insT) or a nonsense variant (p.R298*) in ZDHHC9 gene. The nonsense variant was the same with that reported by Masurel 2014.
• PUBMED: 26633542
  Retterer et al. (2016) did a study of the diagnostic yield of whole-exome sequencing (WES) in 3,040 consecutive cases at a single clinical laboratory. One individual, described as having an "abnormality of the nervous system" was found to have a splicing variant in ZDHHC9.
• PUBMED: 29681091
  Shirwani et al. (2018) reported 2-kb exons 6-7 deletion (by microarray) in a family where two siblings and their maternal uncle presented with XLID. Both had some distinctive facial features in common, including elongated and down-slanting palpebral fissures and high hairline, however no marfanoid habitus and seizures. The mother and grandmother were unaffected carriers.

• HI Evidence Comments: Additional publications: 1. Kosaki et al. 2020 did WES on a cohort of 360 patients who visited a hospital in Japan for genetic evaluation and reported a frame shift variant (c.451delC) in an affected male. 2. Anazi et al. 2017 reported a non-coding variant (c.487+5_487+19delGTAAAACTACAGGGA) in a 10 yo boy, born to parents who were 1st-degree cousins. He had global developmental delay, subtle dysmorphic features in the form of an elongated face, large prominent ears and high-arched palate without neurocutaneous marks. He had hypertonia and hyperreflexia in all extremities and abnormal brain MRI. No functional study was performed. The ClinGen ID/Autism GCEP evaluated the relationship between this gene and X-linked intellectual disability in 2020. They concluded that this relationship was Definitive; in addition to the case-level evidence cited above, they also noted gene-level experimental evidence, including the following: "The relationship between ZDHHC9 and syndromic X-linked ID is supported by animal models and in vitro functional assays. Kouskou et al. 2018 (PMID: 29944857) showed that Zdhhc9 knockout mice exhibit altered behavior that is consistent with reduced anxiety levels. Knockout mice also scored lower on the Morris water maze test indicating deficits in hippocampal-dependent spatial learning and memory. MRI analyses revealed a 36% reduction in corpus callosum volume. Shimell et al. 2019 (PMID: 31747610) investigated Zdhcc9 function in hippocampal cultures. Loss of Zdhhc9 function resulted in shorter dendritic arbors and fewer inhibitory synapses, suggesting an important role for Zdhhc9 in neuronal development."

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: So far, no focal duplication of only this gene reported.

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.