POLR1D – Treacher Collins Syndrome

Treacher Collins syndrome (TCS) is a craniofacial ribosomopathy caused by haploinsufficiency of RNA polymerase I subunits. In 2011, a heterozygous deletion of POLR1D and 20 additional heterozygous mutations were identified in 252 unrelated individuals with TCS, establishing POLR1D as a novel causal gene (PMID:21131976). These mutations included frameshift, nonsense, and missense variants distributed across the coding sequence, consistent with loss‐of‐function.

Subsequent familial studies confirmed autosomal dominant inheritance: whole exome sequencing in a father and two daughters with craniofacial features overlapping TCS and Klippel–Feil syndrome revealed a segregating exon 2 missense variant c.T332C (p.Leu111Pro) in POLR1D, present in all three affected members (PMID:25348728). These data reinforce segregation in multi‐generation pedigrees.

An autosomal recessive mechanism has also been described: direct sequencing in two consanguineous families identified four affected children homozygous for c.163C>G (p.Leu55Val) in POLR1D, with carriers unaffected, demonstrating that biallelic loss can underlie TCS in rare cases (PMID:24603435).

Clinical features of POLR1D‐related TCS include bilateral mandibulofacial dysostosis (HP:0005321), micrognathia (HP:0000347), downward‐slanting palpebral fissures, external ear anomalies, and conductive hearing impairment (HP:0000405). Penetrance is high in heterozygotes but variable expressivity is observed, necessitating detailed phenotypic assessment.

Functional studies in Drosophila and in vitro assays have shown that TCS‐associated POLR1D missense mutations (e.g., G52E orthologous to human p.Gly52Glu) impair heterodimerization with POLR1C, reduce rRNA levels, and arrest neural crest cell development, recapitulating the human phenotype (PMID:35656583). In autosomal recessive families, quantitative RT‐PCR demonstrated a 50% reduction in mature ribosome biogenesis associated with p.Leu55Val (PMID:24603435).

No conflicting evidence has been reported. Collectively, genetic and experimental data meet criteria for a definitive gene–disease association. Testing for POLR1D variants informs molecular diagnosis, genetic counseling, and potential therapeutic targeting of ribosome biosynthesis pathways in TCS.

Key Take-home: POLR1D haploinsufficiency is a well‐established cause of Treacher Collins syndrome, with both autosomal dominant and rare autosomal recessive mechanisms, supported by robust segregation and functional data.

References

• Nature Genetics • 2011 • Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. PMID:21131976
• American Journal of Medical Genetics Part A • 2015 • Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes. PMID:25348728
• Genetics in Medicine • 2014 • Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome. PMID:24603435
• Developmental Dynamics • 2022 • A clinically-relevant residue of POLR1D is required for Drosophila development. PMID:35656583

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