Monogenic hearing loss

Gene: POLR1D

Green List (high evidence)

Comment on list classification: There are 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). All 3 biallelic individuals were noted to have hearing loss. Numerous other individuals with TCS2 have heterozygous POLR1D variants. As per GeneReviews entry for TCS, conductive hearing loss is one of the main features of this syndrome, present in >75% of individuals (https://www.ncbi.nlm.nih.gov/sites/books/NBK1532/)
Hence, this gene should be rated Green on Monogenic hearing loss, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 12 Oct 2026, 2:55 p.m. | Last Modified: 12 Oct 2026, 2:56 p.m.

Panel Version: 6.47

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: 36158048 Yang, Zhen, & Li., 2022
Case report - Chinese fetus with micrognathia and a het POLR1D NM_015972:c.91del, p.Q31Rfs*10 variant, inherited from a healthy mother. Method: Trio WES. After abortion at 20 weeks, fetus showed "characteristic facial dysmorphism with retrognathia, downward-slanting palpebral fissures, lower eyelid colobomas between the external and middle thirds, low-set microtic ears, and cleft palate without cleft lip."

PMID: 39289962 Sun et al. ,2024
Report of a Chinese female, 8 years old, with Treacher Collins Syndrome 2 (conductive hearing loss, smaller jaw, bilateral preauricular fistulas and cup-shaped ear deformities). She was het for POLR1D NM_015972.4:c.38_47del variant, inherited from the mother (mildly affected, small jaw noted).

PMID: 41752027 Camarillo-Benitez et al., 2026
Report of 11 patients from 3 Mexican families. Seq method: WES + Sanger.
F1 and F2 probands harboured TCOF1 variants. In Family 3, a heterozygous pathogenic POLR1D variant, c.290_291delAG (p.G99fs), was identified among multiple affected relatives (5 females). 3/5 affected individuals had severe hearing loss.

PMID: 42706666 Nevondwe et al., 2026
Report of 10 South African probands with Treacher Collins Syndrome, including individual FRASC28 (7yo male) with 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, 2:10 p.m. | Last Modified: 12 Oct 2026, 3:04 p.m.

Panel Version: 6.50

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
• 36158048
• 39289962
• 41752027
• 42706666

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

Phenotypes
#613717:Treacher Collins syndrome 2[Zygomatic complex hypoplasiaMandibular hypoplasia; Microtia Hearing loss, conductive; Downslanting palpebral fissuresColoboma, lower eyelid; Choanal stenosisChoanal atresia; Cleft palate; Motor development delayed (in some patients)Speech development delayed (in some patients); Caused by mutation in the polymerase I, RNA, subunit D gene (POLR1D,)]

Publications

• PMID:21131976
• 24603435
• 8955128