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

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.

Figure 1. Facial, hand and foot phenotypes of patient P7.

(A) Age 1 month (trigonocephaly is appreciated); (B) 8 years (tooth malposition is appreciated). (C–H) Age 19 years.

Figure 2. Graphical representation of all the MAGEL2 pathological mutations reported so far.

WH-A and B: Winged-Helix A and B (residues 1013-1097 & 1098-1184); Ext: Winged-Helix B Extension (residues 1185-1227); USP7 BS (USP7 Binding Site, residues 949-1004). In italics, mutation p.Q638* found in the OTCS patient described here and in a SHFYNG patient. Bold and grey represent mutations found in severe arthrogryposis patients.