Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome

Christopher T. Gordon*, Alice Vuillot, Sandrine Marlin, Erica Gerkes, Alex Henderson, Adila AlKindy, Muriel Holder-Espinasse, Sarah S. Park, Asma Omarjee, Mateo Sanchis-Borja, Eya Ben Bdira, Myriam Oufadem, Birgit Sikkema-Raddatz, Alison Stewart, Rodger Palmer, Ruth McGowan, Florence Petit, Bruno Delobel, Michael R. Speicher, Paul AuroraDavid Kilner, Philippe Pellerin, Marie Simon, Jean Paul Bonnefont, Edward S. Tobias, Sixto García-Miñaúr, Maria Bitner-Glindzicz, Pernille Lindholm, Brigitte A. Meijer, Véronique Abadie, Françoise Denoyelle, Marie Paule Vazquez, Christa Rotky-Fast, Vincent Couloigner, Sébastien Pierrot, Yves Manach, Sylvain Breton, Yvonne M.C. Hendriks, Arnold Munnich, Linda Jakobsen, Peter Kroisel, Angela Lin, Leonard B. Kaban, Lina Basel-Vanagaite, Louise Wilson, Michael L. Cunningham, Stanislas Lyonnet, Jeanne Amiel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Background Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, β 4 (PLCB4) and guanine nucleotide binding protein (G protein), a inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. Results We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residuesrepresent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. Conclusions These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.

Original languageEnglish
Pages (from-to)174-186
Number of pages13
JournalJournal of Medical Genetics
Issue number3
StatePublished - 2013


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