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Skeletal dysplasia v10.17 POLR1D Ida Ertmanska changed review comment from: 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. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. 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 (P96) was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. HOWEVER Suppl Table S1 lists this proband as 'previously reported' - most likely overlapping a proband from PMID: 24603435.

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.; to: 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).
Skeletal dysplasia v10.17 POLR1D Ida Ertmanska changed review comment from: 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.; to: 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. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. 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 (P96) was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. HOWEVER Suppl Table S1 lists this proband as 'previously reported' - most likely overlapping a proband from PMID: 24603435.

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.
Skeletal dysplasia v10.17 POLR1D Ida Ertmanska changed review comment from: PMID: 24603435 Schaefer et al., 2014
Proband hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz.

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.; to: 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.
Skeletal dysplasia v7.25 ISCA-37447-Loss Arina Puzriakova Added comment: Comment on mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) has been agreed for the R104 Skeletal dysplasia panel as only Kagami-Ogata syndrome includes skeletal abnormalities.
Skeletal dysplasia v7.24 ISCA-37447-Loss Arina Puzriakova Region: ISCA-37447-Loss was added
Region: ISCA-37447-Loss was added to Skeletal dysplasia. Sources: ClinGen
Mode of inheritance for Region: ISCA-37447-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37447-Loss were set to 20585555; 24801763; 27406249; 33579810; 18176563; 28640239
Phenotypes for Region: ISCA-37447-Loss were set to Kagami-Ogata syndrome, OMIM:608149; Temple syndrome, OMIM:616222
Review for Region: ISCA-37447-Loss was set to GREEN
Added comment: Multiple unrelated cases curated in ClinGen - sufficient evidence to add this region (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37447)

DLK1-MEG3 Intergenic Region includes the paternally expressed DLK1 gene, the 2 differentially methylated regions (DMRs) DLK1/MEG3:IG-DMR and MEG3:TSS-DMR, and the 5' end of the maternally expressed gene MEG3 (4 exons).

The phenotype depends on the parental origin: Kagami Ogata syndrome/KOS (maternally derived imprinting) or Temple syndrome/TS (paternally derived imprinting)

Kagami-Ogata syndrome is characterized by typical facial features, skeletal abnormalities (including ""coat-hanger ribs"", and bell-shaped thorax), abdominal wall defects, and developmental delay.

Temple syndrome is a less specific phenotype including intrauterine and postnatal growth restriction, hypotonia, feeding difficulties in infancy, truncal obesity, and small feet and hands.
Sources: ClinGen
Skeletal dysplasia v1.176 FZD2 Eleanor Williams changed review comment from: Associated with Omodysplasia 2 (164745) in OMIM.

PMID: 25759469 - Saal et al 2015 - 1 family. proband with omodysplasia, her unaffected parents and her affected daughter. Identified a de novo mutation (c.1644G>A, p.Trp548*) in FZD2 in the proband and her daughter that was not found in unaffected family members. Show reduced ability of this mutant form of FZD2 to interact with its downstream target DISHEVELLED. Furthermore, expressing the mutant form of FZD2 in vitro is not able to facilitate the cellular response to canonical Wnt signaling like wild-type FZD2.

PMID: 29230162 - Türkmen et al 2017 - 1 patient. A heterozygous de novo mutation (G434V) in the frizzled class receptor 2 (FZD2) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs, first metacarpal bones, and middle phalanges of the 5th digits.

PMID: 29383830 - invalid pubmed id

PMID: 29383834 - Nagasaki et al 2018 - 1 patient. 16-year-old boy with OMOD2 or Robinow syndrome-like phenotype. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2.

PMID: 30455931 - Warren et al 2018 - 2 patients. Presented are two patients with autosomal dominant omodysplasia and mutations in the FZD2 gene. The mutations identified have been recently reported, suggesting the possibility of recurrent mutations. The phenotypes of these patients overlap with what has been previously reported, though intellectual disability as seen in our patient is not typical.

Total of 4 cases; to: Associated with Omodysplasia 2 (164745) in OMIM.

PMID: 25759469 - Saal et al 2015 - 1 family. proband with omodysplasia, her unaffected parents and her affected daughter. Identified a de novo mutation (c.1644G>A, p.Trp548*) in FZD2 in the proband and her daughter that was not found in unaffected family members. Show reduced ability of this mutant form of FZD2 to interact with its downstream target DISHEVELLED. Furthermore, expressing the mutant form of FZD2 in vitro is not able to facilitate the cellular response to canonical Wnt signaling like wild-type FZD2.

PMID: 29230162 - Türkmen et al 2017 - 1 patient. A heterozygous de novo mutation (G434V) in the frizzled class receptor 2 (FZD2) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs, first metacarpal bones, and middle phalanges of the 5th digits.

PMID: 29383830 - invalid pubmed id

PMID: 29383834 - Nagasaki et al 2018 - 1 patient. 16-year-old boy with OMOD2 or Robinow syndrome-like phenotype. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2.

PMID: 30455931 - Warren et al 2018 - 2 patients. Presented are two patients with autosomal dominant omodysplasia and mutations in the FZD2 gene. Patient 1 has a p.Trp548* alteration previously reported. Patient 2 has missense alteration p.Gly434Val also previously reported. The phenotypes of these patients overlap with what has been previously reported, though patient 2 also presented with intellectual disability which is not typical.

Total of 4 cases
Skeletal dysplasia v1.159 FZD2 Eleanor Williams commented on gene: FZD2: Associated with Omodysplasia 2 (164745) in OMIM.

PMID: 25759469 - Saal et al 2015 - 1 family. proband with omodysplasia, her unaffected parents and her affected daughter. Identified a de novo mutation (c.1644G>A, p.Trp548*) in FZD2 in the proband and her daughter that was not found in unaffected family members. Show reduced ability of this mutant form of FZD2 to interact with its downstream target DISHEVELLED. Furthermore, expressing the mutant form of FZD2 in vitro is not able to facilitate the cellular response to canonical Wnt signaling like wild-type FZD2.

PMID: 29230162 - Türkmen et al 2017 - 1 patient. A heterozygous de novo mutation (G434V) in the frizzled class receptor 2 (FZD2) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs, first metacarpal bones, and middle phalanges of the 5th digits.

PMID: 29383830 - invalid pubmed id

PMID: 29383834 - Nagasaki et al 2018 - 1 patient. 16-year-old boy with OMOD2 or Robinow syndrome-like phenotype. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2.

PMID: 30455931 - Warren et al 2018 - 2 patients. Presented are two patients with autosomal dominant omodysplasia and mutations in the FZD2 gene. The mutations identified have been recently reported, suggesting the possibility of recurrent mutations. The phenotypes of these patients overlap with what has been previously reported, though intellectual disability as seen in our patient is not typical.
Skeletal dysplasia v1.153 AGA Eleanor Williams Added phenotypes Aspartylglucosaminuria 208400 (Patients may be tall for their age, but lack of a growth spurt in puberty typically causes adults to be short) for gene: AGA
Skeletal dysplasia v1.147 AGA Tracy Lester reviewed gene: AGA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Aspartylglucosaminuria 208400 (Patients may be tall for their age, but lack of a growth spurt in puberty typically causes adults to be short); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v1.146 AGA Eleanor Williams reviewed gene: AGA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Skeletal dysplasia v1.145 AGA Eleanor Williams Source NHS GMS was added to AGA.
Rating Changed from Green List (high evidence) to Green List (high evidence)