8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature.

Ilaria Catusi,Monica Saccani,Lidia Larizza,Chiara Baldo,Rachele Cantone,Ornella Galesi,Maria Garzo,Angela Peron,Francesca Forzano,Anna Paola Capra,Flaviana Elia,Enrico Grosso,Maria Paola Canevini,Silvana Briuglia,Michela Malacarne,Corrado Romano,Maria Paola Recalcati

doi:10.3390/genes12050652

Abstract

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.

Highlights

Deletions of the distal region of the short arm of chromosome 8 have been frequently reported in the literature as either isolated terminal/interstitial deletions or terminal deletions associated with more proximal duplications [1]
To date only five patients carrying 8p23.2-pter microdeletions have been characterized by chromosomal microarray (CMA) analysis in the literature and other cases have been reported in the DECIPHER database [7,9,10,11]
The critical region (CR) comprises several genes out of which the OMIM genes FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2, most of which share a role in neural differentiation and function [12,13,14,15,16,17], are main candidates for developmental delay (DD)/intellectual disability (ID), microcephaly and neurobehavioral disorders

Summary

Introduction

Deletions of the distal region of the short arm of chromosome 8 have been frequently reported in the literature as either isolated terminal/interstitial deletions or terminal deletions associated with more proximal duplications [1]. Large deletions including the 8p23.1 region and isolated microdeletions of the more distal 8p23.2-pter region have rarely been reported in patients displaying various clinical features, including developmental delay (DD)/intellectual disability (ID), microcephaly, mildly dysmorphic features, language delay and/or behavioral problems [7]. Microdeletions of this region are hardly ever recorded in the database of genomic variants (DGV) which collects copy number variants (CNVs) in healthy control samples [8]. The CR comprises several genes out of which the OMIM genes FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2, most of which share a role in neural differentiation and function [12,13,14,15,16,17], are main candidates for DD/ID, microcephaly and neurobehavioral disorders

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