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.

Cellular and disease functions of the Prader–Willi Syndrome geneMAGEL2

“…Furthermore, patients with truncating mutations in MAGEL2 have a higher prevalence of autism spectrum disorder (ASD) compared to classical PWS (94-96, 100). Recently, a new case of de novo nonsense mutation in MAGEL2 was reported in an infant diagnosed with Opitz trigonocephaly C syndrome characterized by craniofacial anomalies, intellectual and psychomotor disability, and cardiac defects with a high mortality rate (101). …”

MAGEL2‐related disorders: A study and case series

“…The gene MAGEL2 , which resides in the PWS locus, is a single‐exon gene encoding the melanoma‐antigen‐subfamily‐like‐2 protein and is part of a large ubiquitination complex that regulates endocytosis, receptor recycling and cell‐surface localization. In mouse models, Magel2 regulates the cell cycle, neuronal signal transduction, neurite growth, and muscle function . Because the maternal genetic region is silenced through methylation, all classes of mutations in the maternal MAGEL2 allele are clinically insignificant .…”

“…For example, some patients with arthrogryposis multiplex congenita (AMC, OMIM #208100), which is characterized by limb deformities, craniofacial anomalies, genital abnormalities, growth delay, and respiratory issues, have been shown to harbor truncating MAGEL2 mutations . Furthermore, a patient previously thought to have Opitz trigonocephaly C syndrome (OMIM #211750), a rare, high‐mortality genetic syndrome characterized by facial dysmorphism, intellectual and developmental delay, hypotonia, and distal arthrogryposis, was also found to carry a truncating mutation in MAGEL2 …”

Exome sequencing in Crisponi/cold‐induced sweating syndrome–like individuals reveals unpredicted alternative diagnoses

“…A de novo nonsense mutation in MAGEL2 was identified in one individual presenting with severe congenital contractures initially diagnosed as having Opitz‐C syndrome (OTCS; MIM#211750), indicating that there is an overlap between OTCS and SHFYNG syndromes. In addition, MAGEL2 mutations were reported in individuals initially diagnosed as having Chitayat‐Hall syndrome (MIM#208080) leading to the conclusion that Chitayat‐Hall and SHFYNG syndromes are likely the same disorder .…”