title: Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome.
abstract: 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), α 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 residues represent 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.
authors: INSERM U781, Tour Lavoisier 2ème étage, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, Paris 75015, France. chris.gordon@inserm.fr
authors: Christopher T
authors: CT
authors: Gordon
authors: Alice
authors: A
authors: Vuillot
authors: Sandrine
authors: S
authors: Marlin
authors: Erica
authors: E
authors: Gerkes
authors: Alex
authors: A
authors: Henderson
authors: Adila
authors: A
authors: AlKindy
authors: Muriel
authors: M
authors: Holder-Espinasse
authors: Sarah S
authors: SS
authors: Park
authors: Asma
authors: A
authors: Omarjee
authors: Mateo
authors: M
authors: Sanchis-Borja
authors: Eya Ben
authors: EB
authors: Bdira
authors: Myriam
authors: M
authors: Oufadem
authors: Birgit
authors: B
authors: Sikkema-Raddatz
authors: Alison
authors: A
authors: Stewart
authors: Rodger
authors: R
authors: Palmer
authors: Ruth
authors: R
authors: McGowan
authors: Florence
authors: F
authors: Petit
authors: Bruno
authors: B
authors: Delobel
authors: Michael R
authors: MR
authors: Speicher
authors: Paul
authors: P
authors: Aurora
authors: David
authors: D
authors: Kilner
authors: Philippe
authors: P
authors: Pellerin
authors: Marie
authors: M
authors: Simon
authors: Jean-Paul
authors: JP
authors: Bonnefont
authors: Edward S
authors: ES
authors: Tobias
authors: Sixto
authors: S
authors: García-Miñaúr
authors: Maria
authors: M
authors: Bitner-Glindzicz
authors: Pernille
authors: P
authors: Lindholm
authors: Brigitte A
authors: BA
authors: Meijer
authors: Véronique
authors: V
authors: Abadie
authors: Françoise
authors: F
authors: Denoyelle
authors: Marie-Paule
authors: MP
authors: Vazquez
authors: Christa
authors: C
authors: Rotky-Fast
authors: Vincent
authors: V
authors: Couloigner
authors: Sébastien
authors: S
authors: Pierrot
authors: Yves
authors: Y
authors: Manach
authors: Sylvain
authors: S
authors: Breton
authors: Yvonne M C
authors: YM
authors: Hendriks
authors: Arnold
authors: A
authors: Munnich
authors: Linda
authors: L
authors: Jakobsen
authors: Peter
authors: P
authors: Kroisel
authors: Angela
authors: A
authors: Lin
authors: Leonard B
authors: LB
authors: Kaban
authors: Lina
authors: L
authors: Basel-Vanagaite
authors: Louise
authors: L
authors: Wilson
authors: Michael L
authors: ML
authors: Cunningham
authors: Stanislas
authors: S
authors: Lyonnet
authors: Jeanne
authors: J
authors: Amiel
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004423:Ear / Q000002:abnormalities* / Q000473:pathology; D004427:Ear Diseases / Q000235:genetics* / Q000473:pathology; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D054799:Phospholipase C beta / Q000235:genetics; D016133:Polymerase Chain Reaction
chemical_list: C518042:PLCB4 protein, human; D054799:Phospholipase C beta; C498819:GNAI3 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go