Exploring the Impact of Genetics in a Large Cohort of Moebius Patients by Trio Whole Exome Sequencing

Author:

Moresco Giada1,Bedeschi Maria Francesca2ORCID,Venturin Marco3ORCID,Villa Roberta4,Costanza Jole5,Mauri Alessia5ORCID,Santaniello Carlo5,Picciolini Odoardo6ORCID,Messina Laura6,Triulzi Fabio7,Miozzo Monica Rosa14,Rondinone Ornella1ORCID,Fontana Laura14ORCID

Affiliation:

1. Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy

2. Medical Genetics Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy

3. Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, 20054 Milan, Italy

4. Medical Genetics Unit, ASST Santi Paolo e Carlo, 20142 Milan, Italy

5. Research Laboratories Coordination Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy

6. Pediatric Physical Medicine & Rehabilitation Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy

7. Neuroradiology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy

Abstract

Moebius syndrome (MBS) is a rare congenital disorder characterized by non-progressive facial palsy and ocular abduction paralysis. Most cases are sporadic, but also rare familial cases with autosomal dominant transmission and incomplete penetrance/variable expressivity have been described. The genetic etiology of MBS is still unclear: de novo pathogenic variants in REV3L and PLXND1 are reported in only a minority of cases, suggesting the involvement of additional causative genes. With the aim to uncover the molecular causative defect and identify a potential genetic basis of this condition, we performed trio-WES on a cohort of 37 MBS and MBS-like patients. No de novo variants emerged in REV3L and PLXND1. We then proceeded with a cohort analysis to identify possible common causative genes among all patients and a trio-based analysis using an in silico panel of candidate genes. However, identified variants emerging from both approaches were considered unlikely to be causative of MBS, mainly due to the lack of clinical overlap. In conclusion, despite this large cohort, WES failed to identify mutations possibly associated with MBS, further supporting the heterogeneity of this syndrome, and suggesting the need for integrated omics approaches to identify the molecular causes underlying MBS development.

Funder

Fondazione IRCCS Ca′ Granda Ospedale Maggiore Policlinico di Milano

Publisher

MDPI AG

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