PLCB4

Inheritance Pattern: AR

Disease ID:MONDO:0957544

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0013845

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013845

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013845

Submitter: ClinGen

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).

Inheritance Pattern: SD

Disease ID:MONDO:0013845

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0013845

Submitter: Illumina

The PLCB4 gene is located on chromosome 20 at 20p12.3-p12.2 and encodes the phospholipase C beta 4 protein. PLCB4 is one of four PLC beta isoforms in humans and functions in the DAG-IP3 cellular signalling pathway. PLCB4 also plays a specific role in craniofacial development through its role in the endothelin signaling pathway and development of the first and second pharyngeal arches. PLCB4 was first reported in relation to autosomal dominant auriculocondylar syndrome in 2012 (22560091: Rieder et al. 2012). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. This curation included eight unique variants reported in ten cases from two publications (22560091: Rieder et al. 2012; 23315542: Gordon et al. 2013), including at least 15 segregations in two large four-generation pedigrees. Variants in this gene also segregated in four more members of unrelated families. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reach. Missense variants located in the catalytic domain are the primary variant type recorded, with a hotspot at residue 621, and a dominant negative mechanism has been proposed. This gene-disease relationship is also supported by a shared function (endothelin signaling) with multiple other genes associated with auriculocondylar syndrome as well as evidence of reduced expression of DLX5 and DLX6, which are downstream targets of endothelin signaling and are involved in mandibular patterning, in patient mandibular osteoblasts (24123988: Clouthier et al. 2014; 22560091: Rieder et al. 2012). 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. Of note, rare cases of autosomal recessive inheritance associated with loss-of-function variants have been reported; heterozygous carriers of this variant type do not appear to show a phenotype (23315542: Gordon et al. 2013) . Differences between the phenotypes associated with autosomal recessive loss of function and autosomal dominant presumed dominant negative missense variants have been noted in both human and mouse models (19955421: Cheong et al. 2009; 8962098: Jiang et al. 1996; 9305844: Kim et al. 1997). The potential association of the PLCB4 gene with an autosomal recessive loss of function phenotype was not assessed as part of this curation.

Inheritance Pattern: AD

Disease ID:MONDO:0000107

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0013845

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013845

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0013845

Submitter: G2P