ORIGINAL ARTICLE Targeted Molecular Investigation in Patients within the Clinical Spectrum of Auriculocondylar Syndrome Vanessa L. Romanelli Tavares, 1 Roseli M. Zechi-Ceide, 2 Debora R. Bertola, 1,3 Christopher T. Gordon, 4,5 Simone G. Ferreira, 1 Gabriella S. P. Hsia, 1 Guilherme L. Yamamoto, 1,3 Suzana A. M. Ezquina, 1 Nancy M. Kokitsu-Nakata, 2 Siulan Vendramini-Pittoli, 2 Renato S. Freitas, 6 Josiane Souza, 6 Cesar A. Raposo-Amaral, 7 Mayana Zatz, 1 Jeanne Amiel, 4,5,8 Maria L. Guion-Almeida, 2 and Maria Rita Passos-Bueno 1 * 1 Centro de Pesquisas Sobre o Genoma Humano e C elulas-Tronco, Departamento de Gen etica e Biologia Evolutiva, Instituto de Bioci^ encias, Universidade de S~ ao Paulo, S~ ao Paulo, S~ ao Paulo, Brazil 2 Departamento de Gen etica Clı ´nica, Hospital de ReabilitaS c~ ao de Anomalias Craniofaciais, Universidade de S~ ao Paulo (HRAC-USP), Bauru, S~ ao Paulo, Brazil 3 Instituto da CrianS ca do Hospital das Clı ´nicas da Faculdade de Medicina da USP, S~ ao Paulo, S~ ao Paulo, Brazil 4 Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Sant e et de la Recherche M edicale (INSERM) U11163, Institut Imagine, Paris, France 5 Paris Descartes-Sorbonne Paris Cit e University, Institut Imagine, Paris, France 6 Centro de Atendimento Integral ao Fissurado L abio Palatal (CAIF), Curitiba, Paran a, Brazil 7 Hospital de Cr^ anio e Face, Sociedade Brasileira de Pesquisa e Assist^ encia para ReabilitaS c~ ao Craniofacial (SOBRAPAR), Campinas, S~ ao Paulo, Brazil 8 D epartement de G en etique, H^ opital Necker-Enfants Malades, Assistance Publique—H^ opitaux de Paris, Paris, France Manuscript Received: 8 July 2016; Manuscript Accepted: 5 December 2016 Auriculocondylar syndrome, mainly characterized by micro- gnathia, 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 syn- drome. 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 ¼ 3), Pierre Robin sequence-plus (n ¼ 3), micro- gnathia with additional craniofacial malformations (n ¼ 4), or non-specific auricular dysplasia (n ¼ 1), which could rep- resent 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 pub- lished, which showed that the pattern of auricular abnor- mality and full cheeks were associated with molecularly Conflict of interest: The authors declare no conflict of interest. Grant sponsor: CEPID/FAPESP; Grant number: 2013/08028-1; Grant sponsor: CNPq; Grant number: Process PQ10/2011.  Correspondence to: Dr. Maria Rita Passos-Bueno, Departamento de Gen etica e Biologia Evolutiva, Instituto de Bioci ^ encias, Universidade de S~ ao Paulo, Rua do Mat~ ao, 277, Sala 200, S~ ao Paulo, SP 05508-090, Brazil. E-mail: passos@ib.usp.br Article first published online in Wiley Online Library (wileyonlinelibrary.com) DOI 10.1002/ajmg.a.38101 How to Cite this Article: Romanelli Tavares VL, Zechi-Ceide RM, Bertola DR, Gordon CT, Ferreira SG, Hsia GSP, Yamamoto GL, Ezquina SAM, Kokitsu-Nakata NM, Vendramini-Pittoli S, Freitas RS, Souza J, Raposo-Amaral CA, Zatz M, Amiel J, Guion-Almeida ML, Passos-Bueno MR. 2017. Targeted molecular investigation in patients within the clinical spectrum of Auriculocondylar syndrome. Am J Med Genet Part A 173A:938–945. Ó 2017 Wiley Periodicals, Inc. 938