Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures

Abstract

Patients with a submicroscopic deletion at 1q43q44 present with intellectual disability (ID), microcephaly, craniofacial anomalies, seizures, limb anomalies, and corpus callosum abnormalities. However, the precise relationship between most of deleted genes and the clinical features in these patients still remains unclear. We studied 11 unrelated patients with 1q44 microdeletion. We showed that the deletions occurred de novo in all patients for whom both parents' DNA was available (10/11). All patients presented with moderate to severe ID, seizures and non-specific craniofacial anomalies. By oligoarray-based comparative genomic hybridization (aCGH) covering the 1q44 region at a high resolution, we obtained a critical deleted region containing two coding genes-HNRNPU and FAM36A-and one non-coding gene-NCRNA00201. All three genes were expressed in different normal human tissues, including in human brain, with highest expression levels in the cerebellum. Mutational screening of the HNRNPU and FAM36A genes in 191 patients with unexplained isolated ID did not reveal any deleterious mutations while the NCRNA00201 non-coding gene was not analyzed. Nine of the 11 patients did not present with microcephaly or corpus callosum abnormalities and carried a small deletion containing HNRNPU, FAM36A, and NCRNA00201 but not AKT3 and ZNF238, two centromeric genes. These results suggest that HNRNPU, FAM36A, and NCRNA00201 are not major genes for microcephaly and corpus callosum abnormalities but are good candidates for ID and seizures.

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.…”

“…16 However, other studies suggest critical regions that do not include ZBTB18. 8,10,12 To our knowledge, no point mutations in ZBTB18 have been described so far. Here, we describe a patient with a de novo non-sense mutation in ZBTB18 and phenotypic features of the 1q43q44 microdeletion syndrome.…”

“…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.…”

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

“…By taking a converse approach, an individual gene or part of a gene can be linked to specific phenotypes in a series of patients with different, but overlapping losses and diverging combinations of phenotypes [Poot and Kas, 2013]. This approach has allowed to successively pinpoint HNRNPU and HNRPU-AS1 , also known as C1orf199 or NCRN00201, as a candidate gene for seizures within region 1q44 [Ballif et al, 2012;Thierry et al, 2012].…”