Novel ANO5 mutation c.1067G>T (p.C356F) identified by whole genome sequencing in a big family with atypical gnathodiaphyseal dysplasia

Abstract

Background: Gnathodiaphyseal dysplasia (GDD) is a rare skeletal disorder that has not been well studied. Methods: Sanger sequencing, whole-genome sequencing (WGS), and bioinformatics and structural modeling analyses were performed. Results: A family with patients with fibro-osseous lesions of the jawbones were initially diagnosed with cherubism. Sequencing of SH3BP2, which is the causal gene of cherubism, revealed no pathogenic mutation. Through WGS, we identified a novel mutation c.1067G>T (p.C356F) in ANO5, and bioinformatics analyses and structural modeling showed that the mutation was deleterious. Because ANO5 is the gene responsible for GDD, we reappraised the clinical data of the patients, and the diagnosis was corrected to atypical GDD. A review of the literature showed that 67% of GDD cases confirmed by molecular testing were initially misdiagnosed.Conclusions: The novel mutation c.1067G>T (p.C356F) in ANO5 is responsible for the atypical GDD observed in our patients. GDD should be included in the differential diagnosis for patients with fibro-osseous lesions. † These authors contributed equally to this work.

Introduction of a Cys360Tyr Mutation in ANO5 Creates a Mouse Model for Gnathodiaphyseal Dysplasia

“…(8)(9)(10)(11) Heretofore, 11 missense mutations in the ANO5 gene have been identified to be associated with GDD from various races and ethnicities. (7,(12)(13)(14)(15)(16)(17)(18) Two of them, C356R and C356G, were first reported in a large Japanese family and resulted in reduced cell adhesion and more rounded cell morphology owing to the regulation of intracellular calcium homeostasis. (7) The T513I mutation in ANO5 protein caused a gain of function enabling CaCCs and phospholipid scrambling at low cytosolic Ca 2+ levels.…”

Familial gigantiform cementoma with recurrent ANO5 p.Cys356Tyr mutations: Clinicopathological and genetic study with literature review

“…Owing to the similarities in the clinicopathological features and genetic alterations between GDD and FGC, we suggest that FGC may be an atypical subtype of GDD, which may have no systemic symptoms, classic long bone curvature, and cortical thickening, with fibro-osseous lesions of the jawbone as the only obvious symptoms. Other studies have also reported atypical cases of GDD where the patient's age of onset, the extent of expansion, and pathological and imaging manifestations also overlap with those of FGC (Andreeva et al, 2016;Zeng et al, 2019).…”

“…However, whether FGC and GDD are genetically related remains unclear. Recently, a missense mutation in ANO5 (also known as TMEM16E) was identified in GDD and was considered a suspected causative mutation for GDD (Duong et al, 2016;Jin et al, 2017;Marconi et al, 2013;Mizuta et al, 2007;Otaify et al, 2018;Tsutsumi et al, 2004;Zeng et al, 2019).…”

Gnathodiaphyseal dysplasia with a novel genetic variant in a large family from Iran

“…Moreover, numerous types of identified variants in ANO5 are available at HGMD®. Zeng et al ( 2019 ) have reported a novel mutation c.1067G>T (p.C356F) in ANO5 which is the causes of GDD. This mutation has been specified as a deleterious variant by bioinformatics analyses and structural modeling.…”