Submission Details

Autosomal dominant

12/19/2019

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.

22560091 23315542 24123988 22560091