PLCB4 – Auriculocondylar Syndrome

Auriculocondylar syndrome (ACS) is a rare craniofacial malformation characterized by question-mark ears, micrognathia, and mandibular condyle hypoplasia. Heterozygous missense mutations in PLCB4 were first described in multiple autosomal-dominant pedigrees, disrupting the catalytic domain and acting via a dominant-negative mechanism ([PMID:22560091]). Complete loss-of-function alleles, including homozygous splice site and deletion variants, have been reported in recessive cases with additional features such as central apnea and macropenis ([PMID:23913798]).

The genetic spectrum now includes at least 36 unrelated probands with PLCB4 variants, comprising missense, splice site, frameshift, and structural deletion mutations ([PMID:38618928]). Variants cluster in functional motifs, notably hotspots at Arg621 and Asp360, and extend the phenotype to gastrointestinal dysmotility and hearing impairment. One representative variant selected for discussion is c.986A>C (p.Asn329Thr). Multiple de novo and familial events underscore allelic heterogeneity.

Segregation analysis in multigenerational families demonstrates co-segregation of PLCB4 variants with ACS, with at least seven additional affected relatives reported across three pedigrees ([PMID:22560091]). In autosomal-dominant cases, incomplete penetrance and variable expressivity are observed within sibships. Compound heterozygous splice-site mutations in unrelated parents confirm autosomal recessive inheritance for complete loss-of-function alleles.

Functional assays in patient-derived osteoblasts reveal significant reduction of DLX5/6 expression downstream of EDNRA signaling, consistent with disruption of the endothelin-1-DLX5/6 pathway. CRISPR/Cas9 F0 mouse models of PLCB4 missense variants recapitulate craniofacial defects and reveal an atavistic palatal bone, corroborating a dominant-negative mechanism in vivo ([PMID:35284927]).

No studies have refuted the role of PLCB4 in ACS, and all reported variants are absent from large population databases. The convergence of human genetic, segregation, and robust functional data supports a definitive gene–disease relationship. Ongoing reports continue to expand the variant and phenotypic spectrum but do not alter the core mechanism.

Integration of genetic and experimental findings confirms that PLCB4 dysfunction—via dominant-negative missense alleles or recessive loss-of-function alleles—disrupts neural crest cell specification in the first and second pharyngeal arches. Additional atypical features, such as apnea and intestinal dysmotility, should be recognized in clinical evaluation. Key take-home: PLCB4 variant testing is essential for molecular diagnosis and management of ACS, guiding surveillance for both craniofacial and extra-craniofacial manifestations.

References

• American journal of human genetics • 2012 • A human homeotic transformation resulting from mutations in PLCB4 and GNAI3 causes auriculocondylar syndrome. PMID:22560091
• American journal of medical genetics. Part A • 2013 • Further characterization of atypical features in auriculocondylar syndrome caused by recessive PLCB4 mutations. PMID:23913798
• Molecular Genetics & Genomic Medicine • 2024 • Auriculocondylar syndrome 2 caused by a novel PLCB4 variant in a male Chinese neonate: A case report and review of the literature. PMID:38618928
• Disease models & mechanisms • 2022 • Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants. PMID:35284927

Evidence Based Scoring (AI generated)