EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder.

Ephrin receptor and their ligands, the ephrins, are widely expressed in the developing brain. They are implicated in several developmental processes that are crucial for brain development. Deletions in genes encoding for members of the Eph/ephrin receptor family were reported in several neurodevelopmental disorders. The ephrin receptor A7 gene (EPHA7) encodes a member of ephrin receptor subfamily of the protein-tyrosine kinase family. EPHA7 plays a role in corticogenesis processes, determines brain size and shape, and is involved in development of the central nervous system. One patient only was reported so far with a de novo deletion encompassing EPHA7 in 6q16.1. We report 12 additional patients from nine unrelated pedigrees with similar deletions. The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance. Four patients had tiny deletions involving only EPHA7, suggesting a critical role of EPHA7 in a neurodevelopmental disability phenotype. We provide further evidence for EPHA7 deletion as a risk factor for neurodevelopmental disorder and delineate its clinical phenotype.

The GRIA3 c.2477G > A Variant Causes an Exaggerated Startle Reflex, Chorea, and Multifocal Myoclonus.

BACKGROUND: Hemizygous mutations in GRIA3 encoding the GluA3 subunit of the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor are known to be associated with neurodevelopmental disorders, including intellectual disability, hypotonia, an autism spectrum disorder, sleep disturbances, and epilepsy in males. OBJECTIVE: To describe a new and consistent phenotype in 4 affected male patients associated with an undescribed deleterious variant in GRIA3. METHODS: We evaluated a large French family in which segregate a singular phenotype according to an apparent X-linked mode of inheritance. Molecular analyses using next generation sequencing and in vitro functional studies using 2-electrode voltage clamp recordings on Xenopus laevis oocytes and a ß-lactamase reporter assay in transfected human embryonic kidney (HEK293) cells were performed. RESULTS: In addition to mild intellectual disability and dysarthria, affected patients presented a tightly consistent early-onset movement disorder combining an exaggerated startle reflex with generalized chorea and multifocal myoclonus. The unreported GRIA3 missense variant c.2477G > A; p.(Gly826Asp) affecting the fourth transmembrane domain of the protein was identified in index patients and their unaffected mothers. Functional studies revealed that variant receptors show decreased current response evoked by agonist (ie, kainic acid and glutamate) and reduced expression on the cell surface in favor of pathogenicity by a loss-of-function mechanism. CONCLUSIONS: Taken together, our results suggest that apart from known GRIA3-related disorders, an undescribed mutation-specific singular movement disorder does exist. We thus advocate considering GRIA3 mutations in the differential diagnosis of hyperekplexia and generalized chorea with myoclonus. © 2020 International Parkinson and Movement Disorder Society.

TCF12 microdeletion in a 72-year-old woman with intellectual disability.

Heterozygous mutations in TCF12 were recently identified as an important cause of craniosynostosis. In the original series, 14% of patients with a mutation in TCF12 had significant developmental delay or learning disability. We report on the first case of TCF12 microdeletion, detected by array-comparative genomic hybridization, in a 72-year-old patient presenting with intellectual deficiency and dysmorphism. Multiplex ligation-dependent probe amplification analysis indicated that exon 19, encoding the functionally important basic helix-loop-helix domain, was included in the deleted segment in addition to exon 20. We postulate that the TCF12 microdeletion is responsible for this patient's intellectual deficiency and facial phenotype.

Spatiotemporal expression in mouse brain of Kiaa2022, a gene disrupted in two patients with severe mental retardation.

We previously identified an inactivating disruption of the X-linked KIAA2022 gene by a chromosomal rearrangement in two male patients with severe mental retardation. In order to determine if KIAA2022 has a role during the development of the central nervous system, we have cloned its murine ortholog, Kiaa2022, determined its genomic structure and studied its expression during mouse development. We show that Kiaa2022 is preferentially expressed in the central nervous system and that the transcript is highly expressed in postmitotic neurons. The expression of Kiaa2022 is first detectable at E10.5 to reach a maximum at P3 where it is notably expressed in the hippocampus, the entorhinal cortex and strongly in the ventral premammillary nucleus. After P3, the expression of Kiaa2022 decreases and maintains very low levels thereafter. Our results show that Kiaa2022 is expressed in the developing brain and that it may play a role in postmitotic, maturing neurons.