A De Novo Nonsense Mutation in MAGEL2 in a Patient Initially Diagnosed as Opitz-C: Similarities Between Schaaf-Yang and Opitz-C Syndromes

Roser Urreizti,Daniel Grinberg,Julia Ponomarenko,Bru Cormand,Jochen Hecht,Neus Roca-Ayats,Lluïsa Vilageliu,Anna Maria Cueto-Gonzalez,Eduardo F Tizzano,Carlos Company,Héctor Franco-Valls,Susana Balcells,Sílvia Mort-Farre,Magda Montfort,Giovanni Neri,John M Opitz,Stephan Ossowski,Mattia Bosio,Luca Cozzuto

doi:10.1038/srep44138

Abstract

Opitz trigonocephaly C syndrome (OTCS) is a rare genetic disorder characterized by craniofacial anomalies, variable intellectual and psychomotor disability, and variable cardiac defects with a high mortality rate. Different patterns of inheritance and genetic heterogeneity are known in this syndrome. Whole exome and genome sequencing of a 19-year-old girl (P7), initially diagnosed with OTCS, revealed a de novo nonsense mutation, p.Q638*, in the MAGEL2 gene. MAGEL2 is an imprinted, maternally silenced, gene located at 15q11-13, within the Prader-Willi region. Patient P7 carried the mutation in the paternal chromosome. Recently, mutations in MAGEL2 have been described in Schaaf-Yang syndrome (SHFYNG) and in severe arthrogryposis. Patient P7 bears resemblances with SHFYNG cases but has other findings not described in this syndrome and common in OTCS. We sequenced MAGEL2 in nine additional OTCS patients and no mutations were found. This study provides the first clear molecular genetic basis for an OTCS case, indicates that there is overlap between OTCS and SHFYNG syndromes, and confirms that OTCS is genetically heterogeneous. Genes encoding MAGEL2 partners, either in the retrograde transport or in the ubiquitination-deubiquitination complexes, are promising candidates as OTCS disease-causing genes.

Highlights

Some cases that point to autosomal recessive inheritance because of affected sibs or parental consanguinity
By means of whole-exome and genome sequencing, we have found a de novo truncating mutation in the maternally-silenced MAGEL2 gene in a patient clinically diagnosed as Opitz C
Given the uncertain role of CD96 in Opitz trigonocephaly C syndrome (OTCS), as mentioned above, MAGEL2 might be the first gene clearly associated with Opitz C syndrome

Summary

Introduction

Some cases that point to autosomal recessive inheritance because of affected sibs or parental consanguinity. We previously performed whole exome sequencing (WES) in 5 OTCS patients with normal CD96 and ASXL1 genes[5]. We present the results of one of them, a 19 year-old Spanish woman, in whom we found a de novo nonsense mutation in MAGEL2. Several de novo truncating mutations, similar to the one described here, have been reported previously in patients with Schaaf-Yang syndrome (SHFYNG, MIM #615547)[6,7], a condition with some resemblances to Prader-Willi syndrome, and in two patients with a distinct severe arthrogryposis phenotype[8]. Fountain et al.[9] described 18 additional SHFYNG patients with similar mutations. We present a detailed phenotypic description of this female patient, originally diagnosed as OTCS, and we describe her phenotype in light of the main features of SHFYNG

Methods

Results

Conclusion