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 recessive auriculocondylar syndrome (ACS) (MIM 620458) in 2013 (Gordon et al., PMID: 23315542). PLCB4 has also been associated with an autosomal dominant form of ACS (MIM 614669). 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 recessive ACS shares the same craniofacial malformations (distinctive question mark outer ear deformity, temporomandibular joint ankylosis, full cheeks, micrognathia, and microstomia) as the dominant form, with additional extra-cranial features that commonly include swallowing problems, GERD, laryngomalacia, central sleep apnea, and genital hypertrophy. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unrelated patients from five publications (PMID: 23315542; Kido et al., 2013, PMID: 23913798; Leoni et al., 2016, PMID: 27007857; Vegas et al., 2022, PMID: 35170830; Gülsüm Kayhan et al., 2022, DOI:10.5336/caserep.2022-89352). The variants reported in these individuals included a homozygous multi-exon deletion, compound heterozygous splice variants, and three unique homozygous frameshift variants, suggesting biallelic loss of function as the mechanism of disease. Heterozygous carriers of these variants were unaffected. 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). In addition, while craniofacial malformation has not been reported in knock-out mouse models, the knock-out mice do recapitulate other features that have been described in association with autosomal recessive ACS, including impaired visual processing, movement disorders, and sleep disruption (Jiang et al., 1996, PMID: 8962098; Kim et al., 1997, PMID: 9305844; Cheong et al., 2009, PMID: 19955421; Ikeda et al., 2009, PMID: 19898623).

This gene-disease pair was originally evaluated by the ClinGen Syndromic Disorders GCEP on 06/07/2023. It was re-evaluated on 06/30/2025 (SOP version 11). As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of a case report (DOI:10.5336/caserep.2022-89352).