Submission Details

The PLCB4 gene is located on chromosome 20 at 20p12.3-p12.2 and encodes phospholipase C beta 4, which catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate and functions as the direct signaling effector of the endothelin receptor type A (EDNRA)-Gq/11 pathway. EDNRA signaling plays a critical role in establishing the identity of neural crest cells that form the lower jaw and middle ear structures.

The PLCB4 gene was first reported in relation to autosomal dominant auriculocondylar syndrome (ACS) (MIM 614669) in 2012 (Rieder et al., PMID: 22560091). PLCB4 has also been associated with an autosomal recessive form of ACS (MIM 620458). Per criteria outlined by the ClinGen Lumping and Splitting Working group, we found differences in inheritance pattern, phenotype, and molecular mechanism. Therefore, the relationships between PLCB4 and autosomal dominant and autosomal recessive ACS were curated separately.

Autosomal dominant ACS is a craniofacial malformation syndrome primarily characterized by a distinctive question mark outer ear deformity, temporomandibular joint ankylosis, full cheeks, micrognathia, microstomia, and obstructive sleep apnea, with variable expressivity. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. To date, all variants associated with autosomal dominant ACS have been missense variants that cluster at hotspots within the X and Y subdomains of phosphatidylinositol-specific phospholipase C catalytic domain; some of these variants have been shown to have a dominant-negative effect on EDNRA signaling (Kanai et al., 2022, PMID: 35284927). This curation included 14 heterozygous missense variants reported in 20 unrelated patients from six publications and are included in this curation (PMID: 22560091; Romanelli Talvares et al., 2017, PMID: 28328130; Nabil et al., 2020, PMID: 32201334; Vegas et al., 2022, PMID: 35170830; Peart et al., 2022, PMID: 34995019). In addition, 1.8 pts were awarded for segregation in three families. This gene-disease relationship is also supported by the gene’s biochemical function in EDNRA signaling that is shared with two other genes also associated with ACS (GNAI3 and EDN1) (Clouthier et al., 2014, PMID: 24123988), altered expression of genes downstream of EDNRA signaling in patient cells (PMID: 22560091), and recapitulation of the skeletal and mandibular phenotype observed in human patients in a knock-in mouse model (PMID: 35284927). In summary, PLCB4 is definitively associated with autosomal dominant auriculocondylar syndrome. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on 06.07.2023 (SOP Version 9.0).