ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
24193349 Authors report a "de novo" non-sense mutation in ZBTB18 (c.397G4T - p.Glu133*) in a patient (female 34 months old) with global developmental delay, prominent speech delay, microcephaly, short stature, and discrete facial dysmorphisms. Patient with normal corpus callosum. They mention that such clinical features are consistent with the phenotype of patients with 1q43q44 microdeletions. They also compare 1q43q44 microdeletions comprising or not ZBTB18 gene: "Out of 27 patients with deletions distal or proximal (including the AKT3 gene) to ZBTB18, only 5 (19%) showed corpus callosum abnormalities and 10 (37%) had microcephaly, compared with 82 and 97%, respectively, of patients with deletions including ZBTB18."
28283832 Authors report a female patient (12 years old) with a "de novo" non-sense mutation in ZBTB18 (c.599del - p.Ser200*) and first seizure at 8 months old (rapidly responded to valproate therapy), global developmental delay, speech delay, behavioral problems, moderate intellectual disability and abnormal corpus callosum. They also suggest according to their data and other studies that corpus callosum abnormalities related to ZBTB18 is not a fully penetrant trait.
27598823 Authors describe three patient with ZBTB18 loss of function mutations: A patient with a frameshift alteration (c.943_944delAG - p.R315Gfs*4), a second one with a nonsense alteration (c.1183C>T - p.Q395*) and a third one with another nonsense alteration (c.133C>T - p.R45*). All these patients had corpus callosum abnormalities, global developmental delay and intellectual disability.

Haploinsufficiency phenotype comments:

MRD22 is characterized by impaired intellectual development with frequent cooccurrence of corpus callosum anomalies, hypotonia, microcephaly, growth problems, and variable facial dysmorphism; 2 additional de novo LOF variants are described in van der Schoot et al., 2018 (PMID: 29573576). This brings the total to at least 7 reported de novo LOF variants. According to van der Schoot and collaborators, they made "... a complete overview of pathogenic variants in ZBTB18 detected to date".

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Could not find any evidence associating ZBTB18 to triplosensitivity.