POLR1B – Treacher Collins Syndrome Type 4

Treacher Collins syndrome (MONDO:0002457) is a rare autosomal dominant mandibulofacial dysostosis characterized by malar and mandibular hypoplasia due to defective neural crest cell development. While TCOF1, POLR1C, and POLR1D are established TCS genes, recent evidence implicates POLR1B as a fourth causative locus.

Exome sequencing in four unrelated individuals with TCS negative for known genes identified three heterozygous missense variants in POLR1B: c.3007C>A (p.Arg1003Ser), c.3007C>T (p.Arg1003Cys), and c.2046T>A (p.Ser682Arg) (PMID:31649276). A subsequent report described a recurrent c.3007C>T (p.Arg1003Cys) variant in an additional patient, bringing the total to four cases with the same substitution (PMID:34012383).

All reported POLR1B variants arose de novo in an autosomal dominant pattern, with no extended familial segregation data available. No additional affected relatives were documented.

Affected individuals uniformly exhibit malar flattening (HP:0000272), atresia of the external auditory canal (HP:0000413), downslanted palpebral fissures (HP:0000494), conductive hearing impairment (HP:0000405), micrognathia (HP:0000347), and microtia (HP:0008551) (PMID:34012383).

The variant spectrum clusters at two critical residues in exon 15 (Arg1003) and exon 9 (Ser682), with a recurrent p.Arg1003Cys substitution found in four of four unrelated probands, suggesting a mutational hotspot (PMID:34012383).

Functional modeling via zebrafish knockdown of polr1b recapitulated TCS craniofacial anomalies, demonstrating altered ribosomal gene expression, massive p53-dependent apoptosis in the neuroepithelium, and reduced neural crest derivatives, supporting a loss-of-function mechanism (PMID:31649276).

Integrating genetic and in vivo functional data supports a Moderate level of clinical validity for POLR1B in Treacher Collins syndrome type 4. Key take-home: POLR1B should be included in diagnostic panels for autosomal dominant TCS to improve molecular diagnosis and inform genetic counseling.

References

• Genetics in medicine • 2020 • POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4. PMID:31649276
• Molecular syndromology • 2021 • A Recurrent Variant in POLR1B, c.3007C>T; p.Arg1003Cys, Associated with Atresia of the External Canal and Microtia in Treacher Collins Syndrome Type 4. PMID:34012383

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