Evaluating Face2Gene as a Tool to Identify Cornelia de Lange Syndrome by Facial Phenotypes.

Ana Latorre-Pellicer,Laura Trujillano,Beatriz Puisac,Ilaria Parenti,Marta Gil-Salvador,Rebeca Antoñanzas-Pérez,Ángela Ascaso,Feliciano J Ramos,Cristina Lucia-Campos,Iñigo Marcos-Alcalde,Antonio Musio,Juan Pié,Maria Arnedo,Gloria Bueno-Lozano,Frank J Kaiser,Paulino Gómez-Puertas

doi:10.3390/ijms21031042

Abstract

Characteristic or classic phenotype of Cornelia de Lange syndrome (CdLS) is associated with a recognisable facial pattern. However, the heterogeneity in causal genes and the presence of overlapping syndromes have made it increasingly difficult to diagnose only by clinical features. DeepGestalt technology, and its app Face2Gene, is having a growing impact on the diagnosis and management of genetic diseases by analysing the features of affected individuals. Here, we performed a phenotypic study on a cohort of 49 individuals harbouring causative variants in known CdLS genes in order to evaluate Face2Gene utility and sensitivity in the clinical diagnosis of CdLS. Based on the profile images of patients, a diagnosis of CdLS was within the top five predicted syndromes for 97.9% of our cases and even listed as first prediction for 83.7%. The age of patients did not seem to affect the prediction accuracy, whereas our results indicate a correlation between the clinical score and affected genes. Furthermore, each gene presents a different pattern recognition that may be used to develop new neural networks with the goal of separating different genetic subtypes in CdLS. Overall, we conclude that computer-assisted image analysis based on deep learning could support the clinical diagnosis of CdLS.

Highlights

Cornelia de Lange syndrome (CdLS, OMIM #122470, #300590, #610759, #614701, #300882) is a rare congenital condition characterized by a wide spectrum of symptoms and physical features, with a characteristic facial gestalt, intellectual disability, limb reduction and growth retardation as the main phenotypic manifestations [1]
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Summary

Introduction

Cornelia de Lange syndrome (CdLS, OMIM #122470, #300590, #610759, #614701, #300882) is a rare congenital condition characterized by a wide spectrum of symptoms and physical features, with a characteristic facial gestalt, intellectual disability, limb reduction and growth retardation as the main phenotypic manifestations [1]. CdLS has mainly been associated with genetic variants in genes encoding different structural and regulatory elements of the cohesin complex. Approximately 80% of CdLS patients show pathogenic variants in one of these cohesin complex associated genes. Even in the presence of variants affecting the same causative gene, a wide clinical spectrum, from classical to mildly affected patients, is known [6]. The cohesin complex is involved in sister chromatids cohesion, but it exhibits novel biological functions, such as the regulation of gene transcription [7,8,9], extending the range of pathomechanisms relevant for cohesinopathies and potentially explaining the variability in the clinical manifestations of CdLS [10,11,12,13]. Other chromatin dysregulation disorders [14], cohesinopathies [15] and/or transcriptomopathies [16] present overlapping phenotypes with CdLS, such as CHOPS syndrome (OMIM #616368), KBG syndrome (OMIM #148050), Rubinstein–Taybi syndrome (RSTS, OMIM #180849, #613684), Wiedemann–Steiner syndrome (WDSTS, OMIM #605130), Coffin-Siris syndrome (CSS, OMIM #135900) and Nicolaides–Baraitser syndrome (NCBRS, OMIM #601358)

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Methods

Conclusion