Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Abstract

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-017-1772-0) contains supplementary material, which is available to authorized users.

Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene

“…Some of the features seen, such as CC anomalies have been linked to haploinsufficiency of the ZBTB18 gene (Ballif et al., ). Seizures seen in some cases with a 1q43q44 deletion are explained by loss of the HNRNPU (OMIM# 602869) gene (Depienne et al., ; Hamdan et al., ; Hemming et al., ; de Kovel et al., ). Dysmorphic facial features (e.g., hypertelorism, strabismus, prominent nasal tip, bulbous nose, abnormal philtrum or lips, micro‐ or retrognathia, abnormal ears) and other clinical features, such as growth problems are inconsistently described in these patients and have not been linked to a specific gene in the 1q43q44 region yet.…”

“…In approximately half of the described cases, CC anomalies, hypotonia, microcephaly, growth problems and variable facial dysmorphologies were reported as well (Cohen et al., ). Presumably, pathogenic variants in ZBTB18 cause variable CC anomalies with a reduced penetrance (Depienne et al., ).…”

Syndromes Hidden within the 16p11.2 Deletion Region

“…Such dissection of CNVs into regions with shared phenotypes has allowed pinpointing HNRNPU as a gene for epilepsy within the 1q44 region [Caliebe et al, 2010;Ballif et al, 2012;Depienne et al, 2017]. In a cohort of 300 patients with severe early-onset obesity, of whom 143 also had developmental delay, 5 patients with overlapping deletions at chromosome 16p11.2 were found, and 2 in 7,366 controls [Bochukova et al, 2010].…”

HNRNPU: Key to Neurodevelopmental Disorders such as Intellectual Delay, Epilepsy, and Autism

“…Studying 17 patients with 1q43q44 microdeletions, 4 with ZBTB18 mutations and 7 with HNRNPU mutations, Depienne et al [2017] concluded that AKT3 haploinsufficiency is the main driver for microcephaly. HNRNPU alterations mostly lead to epilepsy, and to some degree of intellectual disability, and ZBTB18 deletions or mutations were associated with variable corpus callosum anomalies, albeit with incomplete penetrance.…”