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

Abstract

syndrome (WBS) is a multisystemic disorder caused by a hemizygous deletion of 1.5 Mb on chromosome 7q11.23 spanning 28 genes. A few patients with larger and smaller WBS deletion have been reported. They show clinical features that vary between isolated SVAS to the full spectrum of WBS phenotype, associated with epilepsy or autism spectrum behavior. Here we describe four patients with atypical WBS 7q11.23 deletions. Two carry B3.5 Mb larger deletion towards the telomere that includes Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxigenase activation protein gamma (YWHAG) genes. Other two carry a shorter deletion of B1.2 Mb at centromeric side that excludes the distal WBS genes BAZ1B and FZD9. Along with previously reported cases, genotype-phenotype correlation in the patients described here further suggests that haploinsufficiency of HIP1 and YWHAG might cause the severe neurological and neuropsychological deficits including epilepsy and autistic traits, and that the preservation of BAZ1B and FZD9 genes may be related to mild facial features and moderate neuropsychological deficits. This report highlights the importance to characterize additional patients with 7q11.23 atypical deletions comparing neuropsychological and clinical features between these individuals to shed light on the pathogenic role of genes within and flanking the WBS region.

WBSCR16 Is a Guanine Nucleotide Exchange Factor Important for Mitochondrial Fusion

“…In WBS itself, most contiguous gene deletions comprise ~1.5 megabase pairs (Mbp) that do not include WBSCR16 (Schubert, 2009). However, WBSCR16 , and a set of adjacent genes, are included in some larger and atypical deletions [(Fusco et al, 2014; Schubert, 2009) and unpublished data]. Efforts are underway to determine phenotypic differences in WBS patients in which WBSCR16 has or has not been deleted.…”

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.…”

Detecting Psychiatric Profile in Genetic Syndromes: A Comparison of Down Syndrome and Williams Syndrome

“…Also studies in WS have underlined the importance of genotype-phenotype correlation. For instance, Fusco and colleagues suggested that larger deletions extending distally in individuals with WS give more severe developmental delay and ID [76]. Moreover, hemizygosity of LIMK1, CLIP 2, GTF2IRD1 and GTF2I is generally associated with a better cognitive profile in WS [77,78].…”