Clefting

Gene: POLR1D

Green List (high evidence)

Comment on mode of inheritance: There are now 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). The majority of individuals with TCS2 have heterozygous POLR1D variants. Also, the biallelic individuals were noted to have craniofacial malformations but no clefting. Hence, the MOI should be updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.

Created: 12 Oct 2026, 2:02 p.m. | Last Modified: 12 Oct 2026, 2:03 p.m.

Panel Version: 7.11

PMID: 24603435 Schaefer et al., 2014
Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C.
F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant.
F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected.
Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation.

PMID: 25790162 Vincent et al., 2015
Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography.

PMID: 42706666 Nevondwe et al., 2026
Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes.

FUNCTIONAL: PMID: 27448281 - Watt et al., 2016 - zebrafish Polr1c-/- and polr1d-/- mutant embryos had smaller eyes than WT fish, disrupted midbrain-hindbrain boundary and necrotic cranial tissue at 24 hpf. At 3 dpf, polr1c-/- and polr1d-/- mutants showed smaller heads, microphthalmia, and hyploplastic jaws. Alcian blue staining revealed cartilage is hypoplastic in the knockout fish.

POLR1D is associated with AD, AR Treacher Collins syndrome 2, MIM:613717 (OMIM accessed 12th Oct 2026). The assocation between AD Treacher Collins syndrome 2 and POLR1D was classified as Definitive in ClinGen (12/15/2022, Craniofacial Malformations GCEP).

Created: 12 Oct 2026, 1:46 p.m. | Last Modified: 12 Oct 2026, 1:59 p.m.

Panel Version: 7.11

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Treacher Collins syndrome 2, OMIM:613717; Treacher Collins syndrome 2, MONDO:0013385

Publications

• 24603435
• 25790162
• 27448281
• 42706666

The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.

Created: 3 Aug 2022, 3:21 p.m. | Last Modified: 3 Aug 2022, 3:21 p.m.

Panel Version: 2.69

The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 5 Mar 2022, 5:14 p.m. | Last Modified: 5 Mar 2022, 5:14 p.m.

Panel Version: 2.65

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
TREACHER COLLINS SYNDROME 2; TCS2