Skeletal dysplasia

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. The 3 biallelic individuals were noted to have craniofacial malformations including mandibular hypoplasia and micro/retrognathia. This gene-phenotype assocation is supported by a knockout zebrafish model. Hence, the MOI should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 12 Oct 2026, 2:04 p.m. | Last Modified: 12 Oct 2026, 2:04 p.m.

Panel Version: 10.17

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, 1:31 p.m. | Last Modified: 12 Oct 2026, 1:59 p.m.

Panel Version: 10.17

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

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

Publications

• 24603435
• 25790162
• 27448281
• 42706666

Green List (high evidence)

Dysostoses with predominant craniofacial involvement gp of SD >3 cases. Do you report variants in this gene as part of your current diagnostic practice? - YES for TCS; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Treacher Collins syndrome 2 613717

Variants in this GENE are reported as part of current diagnostic practice

I don't know

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: POLR1D; Initial rating suggestion: green

Created: 6 Mar 2019, 11:36 a.m.

Comment when marking as ready: Associated with phenotype in OMIM and G2P. Numerous variants reported

Created: 29 Jul 2016, 12:54 p.m.

Green List (high evidence)

Tier 3

Created: 17 Jun 2016, 8:07 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Treacher Collins syndrome 2 613717

Variants in this GENE are reported as part of current diagnostic practice