A de novo nonsense mutation in ZBTB18 plus a de novo 15q13.3 microdeletion in a 6-year-old female

Am J Med Genet A. 2017 May;173(5):1251-1256. doi: 10.1002/ajmg.a.38145. Epub 2017 Mar 27.


ZBTB18 has been proposed as candidate gene for microcephaly and abnormalities of the corpus callosum based on overlapping microdeletions of 1q43q44. More recently, de novo mutations of ZBTB18 have been identified in patients with syndromic and non-syndromic intellectual disability. Heterozygous microdeletions of 15q13.3 encompassing the candidate gene CHRNA7 are associated with developmental delay or intellectual disability with speech problems, hypotonia, and seizures. They are characterized by significant variability and reduced penetrance. We report on a patient with a de novo ZBTB18 nonsense mutation and a de novo 15q13.3 microdeletion, both in a heterozygous state, identified by next generation sequencing and array-CGH. The 6-year-old girl showed global developmental delay, absent speech, therapy-refractory seizures, ataxia, muscular hypotonia, and discrete facial dysmorphisms. Almost all of these features have been reported for both genetic aberrations, but the severity could hardly been explained by the microdeletion 15q13.3 alone. We assume an additive effect of haploinsufficiency of ZBTB18 and CHRNA7 in our patient. Assembling the features of our patient and the published patients, we noted that only one of them showed mild anomalies of the corpus callosum. Moreover, we hypothesize that nonsense mutations of ZBTB18 are associated with a more severe phenotype than missense mutations. This report indicates that haploinsufficiency of additional genes beside ZBTB18 causes the high frequency of corpus callosum anomalies in patients with microdeletions of 1q43q44 and underlines the importance of an NGS-based molecular diagnostic in complex phenotypes.

Keywords: 15q13.3 microdeletion syndrome; 1q43q44 microdeletion; NGS panel diagnostic; ZBTB18; agenesis of corpus callosum; array CGH.

Publication types

  • Case Reports

MeSH terms

  • Agenesis of Corpus Callosum / genetics*
  • Agenesis of Corpus Callosum / physiopathology
  • Chromosome Deletion
  • Chromosome Disorders / genetics*
  • Chromosome Disorders / pathology
  • Chromosomes, Human, Pair 15 / genetics
  • Codon, Nonsense
  • Corpus Callosum / physiopathology
  • Female
  • Haploinsufficiency / genetics
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Intellectual Disability / physiopathology
  • Repressor Proteins / genetics*
  • Seizures / genetics*
  • Seizures / pathology
  • alpha7 Nicotinic Acetylcholine Receptor / genetics*


  • Chrna7 protein, human
  • Codon, Nonsense
  • Repressor Proteins
  • ZBTB18 protein, human
  • alpha7 Nicotinic Acetylcholine Receptor

Supplementary concepts

  • Chromosome 15q13.3 Microdeletion Syndrome