Recurrent Distal 7q11.23 Deletion Including HIP1 and YWHAG Identified in Patients with Intellectual Disabilities, Epilepsy, and Neurobehavioral Problems

Abstract

We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ∼1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (∼180-500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1⁻(/)⁻) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function.

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

“…In particular, larger WBS deletions extending distally show a more severe developmental delay (DD) or ID phenotype with serious impairments in cognitive function sometimes accompanied by infantile spasms and epilepsy, infrequently diagnosed in WBS patients with common deletion. 10 In this study, we identified two WBS patients with larger deletions towards the telomere. Both patients presented severe DD, ID, and neuropsychological deficits.…”

“…Among the genes deleted distally to the WBS common deletion interval, HIP1 and YWHAG have been proposed as the most compelling candidate genes for susceptibility to autistic traits, epilepsy, and ID. 10 In a loss-of-function model, mice with targeted mutation in the Hip1 gene developed a neurological phenotype, characterized by failure to thrive, tremor, gait ataxia, and epilepsy. 11 Moreover, Hip1 is crucial for a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor trafficking in primary hippocampal neurons whose defects are associated with major progressive neurological deficits.…”

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

“…Three genes-MAGI2 (MIM: 606382), HIP1 (MIM: 601767), and YWHAGhave been suggested as possible candidates for these atypical features. [46][47][48][49][50][51][52][53] Ramocki et al 51 suggested that haploinsufficiency of HIP1 is sufficient to alter neuronal homeostasis and cause focal and generalized epilepsies and cognitive dysfunction. However, their findings do not exclude the possibility that YWHAG loss of function is sufficient to cause neurological phenotypes alone, as proven by our results.…”

Distal 7q11.23 Duplication, an Emerging Microduplication Syndrome: A Case Report and Further Characterisation

“…Subsequently, in 2010, the deletion of the distal portion (between LCR-C and LCR-D) was identified as a different entity, named distal chromosome 7q11.23 deletion (MIM 613729). The haploinsufficiency of the genes HIP and YWHAG was suggested to be critical for the manifestations of that microdeletion syndrome [Ramocki et al, 2010]. Although 4 patients with a duplication of HIP or HIP / YWHAG were also described by Ramocki et al [2010], which did not comprise the genes between LCR-P and LCR-C, there was no evidence of the relevance of the overexpression of these genes.…”

“…The haploinsufficiency of the genes HIP and YWHAG was suggested to be critical for the manifestations of that microdeletion syndrome [Ramocki et al, 2010]. Although 4 patients with a duplication of HIP or HIP / YWHAG were also described by Ramocki et al [2010], which did not comprise the genes between LCR-P and LCR-C, there was no evidence of the relevance of the overexpression of these genes. However, Cornell et al [2016] recently provided strong evidence that the duplication of YWHAG causes neuronal migration delay in the developing cerebral cortex of mice, in a similar manner as YWHAG knockdown does.…”