Targeted molecular investigation in patients within the clinical spectrum of Auriculocondylar syndrome

Abstract

Auriculocondylar syndrome, mainly characterized by micrognathia, small mandibular condyle, and question mark ears, is a rare disease segregating in an autosomal dominant pattern in the majority of the families reported in the literature. So far, pathogenic variants in PLCB4, GNAI3, and EDN1 have been associated with this syndrome. It is caused by a developmental abnormality of the first and second pharyngeal arches and it is associated with great inter- and intra-familial clinical variability, with some patients not presenting the typical phenotype of the syndrome. Moreover, only a few patients of each molecular subtype of Auriculocondylar syndrome have been reported and sequenced. Therefore, the spectrum of clinical and genetic variability is still not defined. In order to address these questions, we searched for alterations in PLCB4, GNAI3, and EDN1 in patients with typical Auriculocondylar syndrome (n = 3), Pierre Robin sequence-plus (n = 3), micrognathia with additional craniofacial malformations (n = 4), or non-specific auricular dysplasia (n = 1), which could represent subtypes of Auriculocondylar syndrome. We found novel pathogenic variants in PLCB4 only in two of three index patients with typical Auriculocondylar syndrome. We also performed a detailed comparative analysis of the patients presented in this study with those previously published, which showed that the pattern of auricular abnormality and full cheeks were associated with molecularly characterized individuals with Auriculocondylar syndrome. Finally, our data contribute to a better definition of a set of parameters for clinical classification that may be used as a guidance for geneticists ordering molecular testing for Auriculocondylar syndrome. © 2017 Wiley Periodicals, Inc.

ITPR1 Mutation Contributes to Hemifacial Microsomia Spectrum

“…Each targeted mutation of Edn1, Ednra, and G protein alpha subunits (Gα q ) in mice led to a reduction in jaw size (Ivey et al, 2003;Yanagisawa et al, 2003;Ozeki et al, 2004;Vieux-Rochas et al, 2010). Notably, EDN1 and PLCB4 mutations are linked to human ACS (Rieder et al, 2012;Gordon et al, 2013;Romanelli Tavares et al, 2017), which exhibits a typical phenotype including micrognathia, small mandibular condyle, and auricular malformation with a question mark earlobe (Gordon et al, 2013;Kido et al, 2013). The phenotypes of ACS are commonly observed in HM patients, suggesting the defects in EDN-PLC-DLX5/6 signaling may underlie the craniofacial defects in HM.…”

“…The deletion of Edn1 or Ednra1 in mice can result in severe mandibular deformity, as mandibular arch-derived structures transform into maxillary-like structures (Sato et al, 2008;Tavares et al, 2012). PLCB4, EDN, and EDNRA are closely related to human auriculocondylar syndrome (ACS, MIM #614669, #602483, #615706), which shares similar phenotypes with OAVS like ear and mandibular deformities (Rieder et al, 2012;Romanelli Tavares et al, 2017), suggesting a functional link with ITPR1.…”

Further phenotypic delineation of the auriculocondylar syndrome type 2 with literature review

“…All those point variants occur within highly conserved catalytical X and Y domains of phospholipase C beta 4 protein (Fig. 3a) (Leoni et al 2016;Rieder et al 2012;Gordon et al 2013a, b;Romanelli Tavares et al 2017;Kido et al 2013). However, three exceptional recessively inherited cases (two sporadic and one familial), presenting with a more severe phenotype and additional atypical symptoms, have been reported in the medical literature.…”

“…However, the core features include the variable degree of micrognathia, often associated by temporomandibular joint ankylosis, cleft palate, and distinctive ear malformations in the form of cleft or notch within the helix, giving the appearance of a question mark. Other frequently noted features comprise facial asymmetry, hearing impairment, prominent cheeks, preauricular tags, and microstomia (Gordon et al 2015;Romanelli Tavares et al 2017).…”

Investigação funcional do novo locus candidato, HDAC9, causativo da síndrome aurículo-condilar

“…In the second arch, the NCC differentiate into parts of the outer ear, the stapes, the temporal styloid process, the upper part of the hyoid bone and the lesser cornu of the hyoid bone (Johnson, 2010;Minoux & Rijli, 2010). Santagati &Rijli, 2003 andGammill &Bronner-Fraser, 2003) The structures affected in ACS -mandible, mandibular condyle, external ear -originate from the neural crest cells in the first and second pharyngeal arches, and for that reason ACS is classified as a "first and second arch syndrome", along with other conditions such as Oculo- Although ACS, PRS, OAVS and TCS all have overlapping features -highlighting the importance of meticulous clinical evaluation -the etiological mechanism and genes affected differ from one syndrome to another (Passos-Bueno et al, 2009;Romanelli-Tavares, 2017).…”