ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.