Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43–q44

Abstract

Submicroscopic deletions involving chromosome 1q43-q44 result in cognitive impairment, microcephaly, growth restriction, dysmorphic features, and variable involvement of other organ systems. A consistently observed feature in patients with this deletion are the corpus callosal abnormalities (CCAs), ranging from thinning and hypoplasia to complete agenesis. Previous studies attempting to delineate the critical region for CCAs have yielded inconsistent results. We conducted a detailed clinical and molecular characterization of seven patients with deletions of chromosome 1q43-q44. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. Four patients had CCAs, and shared the smallest region of overlap that contains only three protein coding genes, CEP170, SDCCAG8, and ZNF238. One patient with a small deletion involving SDCCAG8 and AKT3, and another patient with an intragenic deletion of AKT3 did not have any CCA, implying that the loss of these two genes is unlikely to be the cause of CCA. CEP170 is expressed extensively in the brain, and encodes for a protein that is a component of the centrosomal complex. ZNF238 is involved in control of neuronal progenitor cells and survival of cortical neurons. Our results rule out the involvement of AKT3, and implicate CEP170 and/or ZNF238 as novel genes causative for CCA in patients with a terminal 1q deletion.

A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome

“…The majority (66%) developed seizures. 1, [8][9][10][11][12]15 Incomplete penetrance is a possible explanation for the absence of ACC in this girl, given that the corpus callosum was apparently normal in at least five patients with 1q43q44 microdeletions that included ZBTB18 as described previously. 1,9,12 We note that brainspecific loss of ZBTB18 in mice leads to a small brain phenotype with ACC and cerebellar hypoplasia.…”

“…1, [8][9][10][11][12] 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. 1, [8][9][10][11][12] Furthermore, IUGR was seen in 3 out of 14 of these patients (21%) and postnatal growth retardation was seen in 7 out of 23 patients (30%). Collectively, these results support a crucial role for ZBTB18, but with contributions to the phenotype of other genes in patients with larger deletions.…”

“…These include AKT3, ADSS, CEP170, Clorf100, Clorf101, Clorf121, Clorf199, EFCAB2, FAM36A, HNRNPU, HNRNPU-AS1, PLD5, PNAS-4, and SDCCA8. 1, 3,[8][9][10][11][12][13][14] Specifically, ZBTB18 has repeatedly been identified as a strong candidate gene for microcephaly and/or ACC. 7,9,11,14,15 ZBTB18 is particularly compelling since a brain-specific knock-out of this gene in mice causes microcephaly and callosal anomalies.…”

Subtelomeric deletions of 1q43q44 and severe brain impairment associated with delayed myelination

“…8,10,12,14,15 Now, precise genotype-phenotype correlation has been evaluated through the accumulation of patients with variable deletion sizes, and a minimal essential region has been proposed for expressing the main characteristics of 1q44 deletion syndrome. 7,8,[14][15][16] Ballif et al 17 evaluated 22 patients with small interstitial deletions of 1q44 and demonstrated critical regions for microcephaly, ACC and seizures. Consequently, AKT3 was reported to be the gene responsible for microcephaly; zinc finger protein 238 gene (ZNF238) for ACC; and heterogeneous nuclear ribonucleoprotein U gene (HNRNPU) for seizures 17 ( Figure 5).…”

“…3 Several studies have investigated the critical region for 1q44 subtelomeric deletion syndrome and found that the core phenotypic features of 1q44 subtelomeric deletion syndrome are microcephaly, abnormalities of the corpus callosum (ACC) and seizures. [4][5][6][7][8][9][10][11][12][13][14][15][16] Recently, Ballif et al 17 analyzed patients with microdeletions of 1q44 and proposed certain genes that may be responsible for individual features.…”