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Auriculocondylar syndrome 2 (Auriculocondylar syndrome 2) is a rare autosomal dominant craniofacial malformation disorder hallmarked by micrognathia (HP:0000347), temporomandibular joint ankylosis (HP:0002660), cleft palate (HP:0000175) and question-mark ear malformation (HP:0008559). Affected individuals present with lower jaw hypoplasia and characteristic ear dysmorphology due to defects in first and second pharyngeal arch patterning.
Genetic studies have identified heterozygous missense variants in PLCB4, encoding phospholipase C β4, as causative for ARCND2. In an exome sequencing screen of five independent probands, two novel PLCB4 missense changes were discovered (PMID:22560091). Follow-up multigenerational pedigrees revealed three additional families segregating distinct PLCB4 substitutions, confirming autosomal dominant inheritance and showing at least six affected relatives with co-segregation of PLCB4 alleles.
The variant spectrum in ARCND2 is dominated by missense changes disrupting highly conserved catalytic domains. A representative allele, c.986A>C (p.Asn329Thr), has been reported in an affected individual and lies within the active site of the enzyme.
Functional assays demonstrate a dominant-negative mechanism: known PLCB4 missense variants significantly inhibit EDNRA-Gq/11 signaling in cellular reporter systems (PMID:35284927). CRISPR/Cas9 engineering of an orthologous PLCB4 variant in F0 mouse embryos recapitulates human mandibular and palatal bone anomalies, including an atavistic posterior palate ossification.
Integration of genetic and experimental data supports a strong gene–disease relationship: multiple unrelated probands, segregation in three families, and concordant functional and animal model evidence. No conflicting reports have been described.
Key Take-home: PLCB4 variant testing reliably informs diagnosis of ARCND2 and guides genetic counseling in affected families.
Gene–Disease AssociationStrongEight unrelated probands with PLCB4 variants, segregation in three pedigrees and concordant functional data Genetic EvidenceStrongEight unrelated probands with missense PLCB4 variants across multiple families reached ClinGen genetic cap Functional EvidenceModerateDominant-negative reporter assays and CRISPR/Cas9 mouse model recapitulate ARCND2 phenotype |