Targeted molecular investigation in patients within the clinical spectrum of Auriculocondylar syndrome.
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.
Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, São Paulo, Brazil.
Vanessa L
VL
Romanelli Tavares
Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), Bauru, São Paulo, Brazil.
Roseli M
RM
Zechi-Ceide
Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, São Paulo, Brazil.|Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da USP, São Paulo, São Paulo, Brazil.
Debora R
DR
Bertola
Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U11163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
Christopher T
CT
Gordon
Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, São Paulo, Brazil.
Simone G
SG
Ferreira
Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, São Paulo, Brazil.
Gabriella S P
GS
Hsia
Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, São Paulo, Brazil.|Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da USP, São Paulo, São Paulo, Brazil.
Guilherme L
GL
Yamamoto
Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, São Paulo, Brazil.
Suzana A M
SA
Ezquina
Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), Bauru, São Paulo, Brazil.
Nancy M
NM
Kokitsu-Nakata
Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), Bauru, São Paulo, Brazil.
Siulan
S
Vendramini-Pittoli
Centro de Atendimento Integral ao Fissurado Lábio Palatal (CAIF), Curitiba, Paraná, Brazil.
Renato S
RS
Freitas
Centro de Atendimento Integral ao Fissurado Lábio Palatal (CAIF), Curitiba, Paraná, Brazil.
Josiane
J
Souza
Hospital de Crânio e Face, Sociedade Brasileira de Pesquisa e Assistência para Reabilitação Craniofacial (SOBRAPAR), Campinas, São Paulo, Brazil.
Cesar A
CA
Raposo-Amaral
Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, São Paulo, Brazil.
Mayana
M
Zatz
Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U11163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.|Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
Jeanne
J
Amiel
Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), Bauru, São Paulo, Brazil.
Maria L
ML
Guion-Almeida
Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, São Paulo, Brazil.
Maria Rita
MR
Passos-Bueno
D000328:Adult; D002648:Child; D004423:Ear / Q000002:abnormalities* / Q000473:pathology; D004427:Ear Diseases / Q000145:classification / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D019332:Endothelin-1 / Q000235:genetics; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics; D015870:Gene Expression; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008844:Micrognathism / Q000145:classification / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D054799:Phospholipase C beta / Q000235:genetics*; D010855:Pierre Robin Syndrome / Q000145:classification / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D009626:Terminology as Topic
D019332:Endothelin-1; C518042:PLCB4 protein, human; D054799:Phospholipase C beta; C498819:GNAI3 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
Auriculocondylar syndrome; PLCB4; Pierre Robin sequence; clinical heterogeneity; ear dysplasia; micrognathia; pharyngeal arch; question mark ear