Prenatal diagnosis of auriculocondylar syndrome with a novel missense variant of GNAI3: a case report

Abstract

Background: Auriculocondylar syndrome (ACS) is a rare disorder characterized by micrognathia, mandibular condyle hypoplasia, and auricular abnormalities. Only 6 pathogenic variants of GNAI3 have been identified associated with ACS so far. Here, we report a case of prenatal genetic diagnosis of ACS carrying a novel GNAI3 variant.

Case presentation: A woman with 30 weeks of gestation was referred to genetic counseling for polyhydramnios and fetal craniofacial anomaly. Severe micrognathia and mandibular hypoplasia were identified on ultrasonography. The mandibular length was 2.4 cm, which was markedly smaller than the 95th percentile. The ears were low-set with no cleft or notching between the lobe and helix. The face was round with prominent cheeks. Whole-exome sequencing identified a novel de novo missense variant of c.140G > A in the GNAI3 gene. This mutation caused an amino acid substitution of p.Ser47Asn in the highly conserved G1 motif, which was predicted to impair the guanine nucleotide-binding function. All ACS cases with GNAI3 mutations were literature reviewed, revealing female-dominated severe cases and right-side-prone deformities.

Conclusion: Severe micrognathia and mandibular hypoplasia accompanied by polyhydramnios are prenatal indicators of ACS. We expanded the mutation spectrum of GNAI3 and summarized clinical features to promote awareness of ACS.

Keywords: Auriculocondylar syndrome; Case report; Craniofacial deformity; GNAI3; Prenatal diagnosis.

Fig. 1

A Pedigree of a Chinese prenatal case with auriculocondylar syndrome (ACS). The proband, an affected fetus, is depicted as a filled diamond and indicated by a black arrow. B Recording of the amniotic fluid indexes (AFIs) measured by ultrasonography. The median, upper 95th, and upper 99th percentiles of AFI in normal singleton pregnancy are plotted as solid, dashed, and dotted lines, respectively (data from Moore & Cayle, [9]). The AFIs of this case are indicated by red crosses and the single deepest pockets (SDPs) are also presented accordingly. C Craniofacial features of the affected fetus visualized by ultrasonography at 29 weeks of gestation. D Craniofacial features of the affected fetus visualized by ultrasonography at 29 weeks and 6 days of gestation. The mandibular hypoplasia (severe micrognathia, retrognathia, short and vertical mandibular ramus, linear configuration of the mandibular body, and loss of mandibular angle) is indicated by white arrows; the low-set ears are indicated by white arrows; the round face is indicated by blue arrows

Fig. 2

A Whole exome sequencing of the GNAI3 heterozygous c.140G > A variant (indicated in a red box). B Sanger sequencing of the GNAI3 heterozygous c.140G > A variant (indicated by a red arrow). C Evaluation of the amino acid conservation by Ugene. Each residue in alignment is assigned a color according to the ClustalX color scheme. The Ser47 of Gαi3 (indicated in a red box) is highly conserved accross various species. D In silico prediction of the GNAI3 c.140G > A variant by PolyPhen, MutationTaster, PROVEAN, and SIFT. E The three dimensional molecular structure of Gαi3 and the guanosine diphosphate (GDP) ligand by SWISS-MODEL and Swiss-PdbViewer. The overview (left panel) and magnified views of the wild-type Ser47 (middle panel) and mutant Asn47 (right panel) are shown accordingly. The H-bonds to GDP are shown as green dashed lines, with H-bond distances (Å) shown in green numbers. F Schematic representation of all the identified mutations in the GNAI3 gene (NM_0064). Five guanine nucleotide-binding sites (G1–G5) are indicated by gray boxes. The novel missense mutation in the present report is shown in red