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Congenital fibrosis of the extraocular muscles v2.7 ZFHX4 Ida Ertmanska Tag Q3_26_expert_review was removed from gene: ZFHX4.
Tag Q3_26_NHS_review tag was added to gene: ZFHX4.
Congenital fibrosis of the extraocular muscles v2.7 ZFHX4 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: ZFHX4.
Tag Q3_26_promote_green tag was added to gene: ZFHX4.
Congenital fibrosis of the extraocular muscles v2.7 ZFHX4 Ida Ertmanska Phenotypes for gene: ZFHX4 were changed from Isolated congenital ptosis to congenital ptosis, MONDO:0008340
Congenital fibrosis of the extraocular muscles v2.6 ZFHX4 Ida Ertmanska Publications for gene: ZFHX4 were set to PMID: 41524020; 11935336; 32962661
Congenital fibrosis of the extraocular muscles v2.5 ZFHX4 Ida Ertmanska Classified gene: ZFHX4 as Amber List (moderate evidence)
Congenital fibrosis of the extraocular muscles v2.5 ZFHX4 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated patients reported in literature with heterozygous ZFHX4 variants and isolated congenital ptosis. Hence, this gene can be promoted to Green at the next update.
Congenital fibrosis of the extraocular muscles v2.5 ZFHX4 Ida Ertmanska Gene: zfhx4 has been classified as Amber List (Moderate Evidence).
Congenital fibrosis of the extraocular muscles v2.4 ZFHX4 Ida Ertmanska edited their review of gene: ZFHX4: Changed publications to: 41524020, 32962661, 17987257, 11935336
Congenital fibrosis of the extraocular muscles v2.4 ZFHX4 Ida Ertmanska changed review comment from: PMID: 41524020 Zhang et al., 2026
Cohort of patients with isolated congenital ptosis. Seq method: WES. Three novel heterozygous variants in ZFHX4, c.5145C>A (p.N1715K), c.10382C>T (p.A3461V), and c.10795G>A (p.A3599T), were identified in three patients of Han Chinese origin.

PMID: 32962661 Adhikari et al., 2020
Report of a Nepalese proband with congenital ptosis and a c.12411G>T, p.Leu4137Phe variant in exon 12 of ZFHX4.
Same variant reported in a Japanese kindred with hereditary congenital blepharoptosis (PMID: 17987257, Nakashima et al., 2008).

This gene is not yet associated with a disease entity in OMIM. ZFHX4 association with AD syndromic complex neurodevelopmental disorder was classified as Strong in ClinGen in December 2025 (Intellectual Disability and Autism GCEP).; to: PMID: 41524020 Zhang et al., 2026
Cohort of patients with isolated congenital ptosis. Seq method: WES. Three novel heterozygous variants in ZFHX4, c.5145C>A (p.N1715K), c.10382C>T (p.A3461V), and c.10795G>A (p.A3599T), were identified in three patients of Han Chinese origin.

PMID: 32962661 Adhikari et al., 2020
Report of a Nepalese proband with congenital ptosis and a c.12411G>T, p.Leu4137Phe variant in exon 12 of ZFHX4.
Same variant reported in a Japanese kindred with hereditary congenital blepharoptosis (PMID: 17987257, Nakashima et al., 2008).

PMID: 11935336 McMullan et al., 2002
Report of a patient with congenital bilateral isolated ptosis and a de novo balanced translocation 46,XY,t(1;8)(p34.3;q21.12). The 1p breakpoint does not disrupt a coding sequence, whereas the chromosome 8 breakpoint disrupts the ZFHX4 gene.

This gene is not yet associated with a disease entity in OMIM. ZFHX4 association with AD syndromic complex neurodevelopmental disorder was classified as Strong in ClinGen in December 2025 (Intellectual Disability and Autism GCEP).
Congenital fibrosis of the extraocular muscles v2.4 ZFHX4 Ida Ertmanska reviewed gene: ZFHX4: Rating: GREEN; Mode of pathogenicity: None; Publications: 41524020, 32962661, 17987257; Phenotypes: congenital ptosis, MONDO:0008340; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital fibrosis of the extraocular muscles v2.4 ZFHX4 Nicky Cronbach gene: ZFHX4 was added
gene: ZFHX4 was added to Congenital fibrosis of the extraocular muscles. Sources: Literature
Mode of inheritance for gene: ZFHX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZFHX4 were set to PMID: 41524020; 11935336; 32962661
Phenotypes for gene: ZFHX4 were set to Isolated congenital ptosis
Penetrance for gene: ZFHX4 were set to unknown
Review for gene: ZFHX4 was set to GREEN
Added comment: Multiple unrelated cases of isolated congenital ptosis reported. Three unrelated Han-Chinese patients (PMID 41524020) and one Nepalese patient (32962661) with missense variants in ZFHX4, and one case (unspecified ethnicity) related to a translocation disrupting ZFHX4.
Sources: Literature
Congenital fibrosis of the extraocular muscles v2.4 Eleanor Williams List of related panels changed from R46 to R46; GT216; TP77
Congenital fibrosis of the extraocular muscles v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2025-04-30
Congenital fibrosis of the extraocular muscles v2.0 Arina Puzriakova promoted panel to version 2.0
Congenital fibrosis of the extraocular muscles v1.18 MYF5 Arina Puzriakova Tag Q4_23_promote_green was removed from gene: MYF5.
Tag Q4_23_NHS_review was removed from gene: MYF5.
Congenital fibrosis of the extraocular muscles v1.18 COL25A1 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: COL25A1.
Congenital fibrosis of the extraocular muscles v1.18 MYF5 Arina Puzriakova reviewed gene: MYF5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital fibrosis of the extraocular muscles v1.18 COL25A1 Arina Puzriakova reviewed gene: COL25A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital fibrosis of the extraocular muscles v1.17 MYF5 Arina Puzriakova Source NHS GMS was added to MYF5.
Source Expert Review Green was added to MYF5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital fibrosis of the extraocular muscles v1.17 COL25A1 Arina Puzriakova Source NHS GMS was added to COL25A1.
Source Expert Review Green was added to COL25A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital fibrosis of the extraocular muscles v1.16 MYF5 Ivone Leong Tag watchlist was removed from gene: MYF5.
Tag Q4_23_promote_green tag was added to gene: MYF5.
Tag Q4_23_NHS_review tag was added to gene: MYF5.
Congenital fibrosis of the extraocular muscles v1.16 MYF5 Ivone Leong commented on gene: MYF5: There is now enough evidence for this gene to be promoted to Green status. This gene should be promoted to Green at the next GMS review.
Congenital fibrosis of the extraocular muscles v1.16 MYF5 Ivone Leong Publications for gene: MYF5 were set to 29887215
Congenital fibrosis of the extraocular muscles v1.15 MYF5 Hannah Knight reviewed gene: MYF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 35186005; Phenotypes: Ophthalmoplegia, external, with rib and vertebral anomalies, 618155; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital fibrosis of the extraocular muscles v1.13 COL25A1 Achchuthan Shanmugasundram changed review comment from: PMID:35077597 reported five patients from three unrelated families identified with biallelic variants in COL25A1 gene. Of these four patients from three families had ocular congenital cranial dysinnervation disorder phenotype.

This gene has been associated with this phenotype in both OMIM and Gene2Phenotype (with 'strong' rating).; to: Comment on gene classification: There is sufficient evidence (five unrelated cases) for promoting this gene to GREEN at the next major review.

PMID:35077597 reported five patients from three unrelated families identified with biallelic variants in COL25A1 gene. Of these four patients from three families had ocular congenital cranial dysinnervation disorder phenotype.

This gene has been associated with this phenotype in both OMIM and Gene2Phenotype (with 'strong' rating).
Congenital fibrosis of the extraocular muscles v1.13 COL25A1 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: COL25A1.
Congenital fibrosis of the extraocular muscles v1.13 COL25A1 Achchuthan Shanmugasundram Publications for gene: COL25A1 were set to 25500261
Congenital fibrosis of the extraocular muscles v1.12 COL25A1 Achchuthan Shanmugasundram reviewed gene: COL25A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35077597; Phenotypes: Fibrosis of extraocular muscles, congenital, 5, OMIM:616219; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital fibrosis of the extraocular muscles v1.12 MYF5 Ivone Leong Tag watchlist tag was added to gene: MYF5.
Congenital fibrosis of the extraocular muscles v1.12 MYF5 Ivone Leong changed review comment from: PMID:29887215. 3 families and 5 patients. All patients have external ophthalmoplegia, 3/5 torticollis, 4/5 scoliosis, 0/5 hypotonia/weakness.

After consulting the Genomics England Clinical Team it was decided to leave this gene as Amber on this panel.; to: PMID:29887215. 3 families and 5 patients. 2 families from the same village Turkey with the same variant (c.23_32delAGTTCTCACC) and 1 family from Yemen (c.283C>T). All patients have external ophthalmoplegia, 3/5 torticollis, 4/5 scoliosis, 0/5 hypotonia/weakness.

After consulting the Genomics England Clinical Team it was decided that this gene is appropriate for the Congenital fibrosis of the extraocular muscles panel. This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). As 2 of the cases could be due to founder effect (Turkish families) and only 1 other case, there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating until more evidence is available.
Congenital fibrosis of the extraocular muscles v1.12 MYF5 Ivone Leong Entity copied from Congenital myopathy v2.56
Congenital fibrosis of the extraocular muscles v1.12 MYF5 Ivone Leong gene: MYF5 was added
gene: MYF5 was added to Congenital fibrosis of the extraocular muscles. Sources: Expert Review Amber,Expert list,Literature
Mode of inheritance for gene: MYF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYF5 were set to 29887215
Phenotypes for gene: MYF5 were set to Ophthalmoplegia, external, with rib and vertebral anomalies, OMIM:618155
Mode of pathogenicity for gene: MYF5 was set to Other
Congenital fibrosis of the extraocular muscles v1.11 TUBB2B Ivone Leong Publications for gene: TUBB2B were set to 23001566
Congenital fibrosis of the extraocular muscles v1.10 TUBB2B Ivone Leong Added comment: Comment on phenotypes: This gene is also associated with ortical dysplasia, complex, with other brain malformations 7
Congenital fibrosis of the extraocular muscles v1.10 TUBB2B Ivone Leong Phenotypes for gene: TUBB2B were changed from Cortical dysplasia, complex, with other brain malformations 7; Fibrosis of extraocular muscles, congenital to congenital fibrosis of extraocular muscles, MONDO:0007614
Congenital fibrosis of the extraocular muscles v1.9 GRHL2 Ivone Leong Phenotypes for gene: GRHL2 were changed from Fibrosis of extraocular muscles, congenital to congenital fibrosis of extraocular muscles, MONDO:0007614
Congenital fibrosis of the extraocular muscles v1.8 COL25A1 Ivone Leong Phenotypes for gene: COL25A1 were changed from Fibrosis of extraocular muscles, congenital, 5 616219; Fibrosis of extraocular muscles, congenital, 5 to Fibrosis of extraocular muscles, congenital, 5, OMIM:616219
Congenital fibrosis of the extraocular muscles v1.7 TUBB3 Ivone Leong Phenotypes for gene: TUBB3 were changed from CFEOM3A; Fibrosis of extraocular muscles, congenital, 3A 600638 to Fibrosis of extraocular muscles, congenital, 3A, OMIM:600638
Congenital fibrosis of the extraocular muscles v1.6 PHOX2A Ivone Leong Phenotypes for gene: PHOX2A were changed from Fibrosis of extraocular muscles, congenital, 2 602078; Fibrosis of extraocular muscles, congenital, 2 to Fibrosis of extraocular muscles, congenital, 2, OMIM:602078
Congenital fibrosis of the extraocular muscles v1.5 KIF21A Ivone Leong Phenotypes for gene: KIF21A were changed from Congenital fibrosis of the extraocular muscles; Fibrosis of extraocular muscles, congenital, 1 135700; Fibrosis of extraocular muscles, congenital, 3B 135700 to Fibrosis of extraocular muscles, congenital, 1, OMIM:135700; Fibrosis of extraocular muscles, congenital, 3B, OMIM:135700
Congenital fibrosis of the extraocular muscles v1.3 Catherine Snow Panel version has been signed off
Congenital fibrosis of the extraocular muscles v1.2 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Congenital fibrosis of the extraocular muscles v1.0 Ivone Leong promoted panel to version 1.0
Congenital fibrosis of the extraocular muscles v0.10 Ivone Leong List of related panels changed from to R46
Panel types changed to GMS Rare Disease; GMS signed-off
Congenital fibrosis of the extraocular muscles v0.8 GRHL2 Morag Shanks reviewed gene: GRHL2: Rating: RED; Mode of pathogenicity: ; Publications: 29110737; Phenotypes: Fibrosis of extraocular muscles, congenital; Mode of inheritance: Unknown
Congenital fibrosis of the extraocular muscles v0.8 COL25A1 Morag Shanks reviewed gene: COL25A1: Rating: AMBER; Mode of pathogenicity: ; Publications: 25500261; Phenotypes: Fibrosis of extraocular muscles, congenital, 5 616219; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital fibrosis of the extraocular muscles v0.8 TUBB2B Morag Shanks reviewed gene: TUBB2B: Rating: RED; Mode of pathogenicity: ; Publications: 23001566; Phenotypes: Fibrosis of extraocular muscles, congenital; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital fibrosis of the extraocular muscles v0.8 TUBB3 Morag Shanks reviewed gene: TUBB3: Rating: GREEN; Mode of pathogenicity: ; Publications: 20074521, 27428177; Phenotypes: Fibrosis of extraocular muscles, congenital, 3A 600638; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital fibrosis of the extraocular muscles v0.8 PHOX2A Morag Shanks reviewed gene: PHOX2A: Rating: GREEN; Mode of pathogenicity: ; Publications: 11600883, 22311481, 14597037; Phenotypes: Fibrosis of extraocular muscles, congenital, 2 602078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital fibrosis of the extraocular muscles v0.8 KIF21A Morag Shanks reviewed gene: KIF21A: Rating: GREEN; Mode of pathogenicity: ; Publications: 15223798, 15621876, 15621877, 18332320; Phenotypes: Fibrosis of extraocular muscles, congenital, 1 135700, Fibrosis of extraocular muscles, congenital, 3B 135700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital fibrosis of the extraocular muscles v0.7 GRHL2 Ivone Leong gene: GRHL2 was added
gene: GRHL2 was added to Congenital fibrosis of the extraocular muscles. Sources: Wessex and West Midlands GLH,Expert Review Red
Mode of inheritance for gene: GRHL2 was set to Unknown
Publications for gene: GRHL2 were set to 29110737
Phenotypes for gene: GRHL2 were set to Fibrosis of extraocular muscles, congenital
Congenital fibrosis of the extraocular muscles v0.7 COL25A1 Ivone Leong Source Wessex and West Midlands GLH was added to COL25A1.
Source Expert Review Amber was added to COL25A1.
Added phenotypes Fibrosis of extraocular muscles, congenital, 5 616219 for gene: COL25A1
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Congenital fibrosis of the extraocular muscles v0.7 TUBB2B Ivone Leong Source Wessex and West Midlands GLH was added to TUBB2B.
Source Expert Review Red was added to TUBB2B.
Added phenotypes Fibrosis of extraocular muscles, congenital for gene: TUBB2B
Publications for gene TUBB2B were changed from 11425694; 23001566 to 23001566
Congenital fibrosis of the extraocular muscles v0.7 TUBB3 Ivone Leong Source Wessex and West Midlands GLH was added to TUBB3.
Source Expert Review Green was added to TUBB3.
Added phenotypes Fibrosis of extraocular muscles, congenital, 3A 600638 for gene: TUBB3
Publications for gene TUBB3 were changed from to 20074521; 27428177
Rating Changed from Red List (low evidence) to Green List (high evidence)
Congenital fibrosis of the extraocular muscles v0.7 PHOX2A Ivone Leong Source Wessex and West Midlands GLH was added to PHOX2A.
Source Expert Review Green was added to PHOX2A.
Mode of inheritance for gene PHOX2A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Fibrosis of extraocular muscles, congenital, 2 602078 for gene: PHOX2A
Publications for gene PHOX2A were changed from 11600883 to 11600883; 14597037; 22311481
Rating Changed from Red List (low evidence) to Green List (high evidence)
Congenital fibrosis of the extraocular muscles v0.7 KIF21A Ivone Leong Source Wessex and West Midlands GLH was added to KIF21A.
Source Expert Review Green was added to KIF21A.
Added phenotypes Fibrosis of extraocular muscles, congenital, 1 135700; Fibrosis of extraocular muscles, congenital, 3B 135700 for gene: KIF21A
Publications for gene KIF21A were changed from 15621876 to 15621876; 15621877; 15223798; 18332320
Rating Changed from Red List (low evidence) to Green List (high evidence)
Congenital fibrosis of the extraocular muscles v0.6 COL25A1 Anna de Burca gene: COL25A1 was added
gene: COL25A1 was added to Congenital fibrosis of the extraocular muscles. Sources: Literature
Mode of inheritance for gene: COL25A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COL25A1 were set to 25500261
Phenotypes for gene: COL25A1 were set to Fibrosis of extraocular muscles, congenital, 5
Review for gene: COL25A1 was set to AMBER
Added comment: PMID:25500261 reports a consanguineous family with a homozygous missense variant in COL25A1 and a second simplex compound heterozygote for a nonsense mutation and a 12.4 kb deletion spanning exons 4–10 of COL25A1. All affected individuals had features of congenital cranial dysinnervation disorder.
Sources: Literature
Congenital fibrosis of the extraocular muscles v0.5 PHOX2A Anna de Burca gene: PHOX2A was added
gene: PHOX2A was added to Congenital fibrosis of the extraocular muscles. Sources: Literature
Mode of inheritance for gene: PHOX2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PHOX2A were set to 11600883
Phenotypes for gene: PHOX2A were set to Fibrosis of extraocular muscles, congenital, 2
Review for gene: PHOX2A was set to AMBER
Added comment: Gene also known as ARIX.
Sources: Literature
Congenital fibrosis of the extraocular muscles v0.4 KIF21A Anna de Burca gene: KIF21A was added
gene: KIF21A was added to Congenital fibrosis of the extraocular muscles. Sources: Literature
Mode of inheritance for gene: KIF21A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF21A were set to 15621876
Phenotypes for gene: KIF21A were set to Congenital fibrosis of the extraocular muscles
Review for gene: KIF21A was set to GREEN
Added comment: Heterozygous missense variants identified in multiple unrelated families of different ethnicities. Arginine 954 appears to represent a mutational hotspot, although other missense variants have also been reported.
Sources: Literature
Congenital fibrosis of the extraocular muscles v0.3 TUBB2B Anna de Burca gene: TUBB2B was added
gene: TUBB2B was added to Congenital fibrosis of the extraocular muscles. Sources: Literature
Mode of inheritance for gene: TUBB2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBB2B were set to 11425694; 23001566
Phenotypes for gene: TUBB2B were set to Cortical dysplasia, complex, with other brain malformations 7
Review for gene: TUBB2B was set to AMBER
Added comment: The association between TUBB2B and polymicrogyria is well documented but in addition PIMD:11425694 and 23001566 report the same two generation family where the mother and two daughters have polymicrogyria, intellectual disability and CFEOM. A missense variant in TUBB2B was present in the mother and two affected daughters and absent in the father and two unaffected siblings. In vitro functional studies showed altered microtubule dynamics.
Sources: Literature
Congenital fibrosis of the extraocular muscles v0.2 TUBB3 Anna de Burca gene: TUBB3 was added
gene: TUBB3 was added to Congenital fibrosis of the extraocular muscles. Sources: Literature
Mode of inheritance for gene: TUBB3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TUBB3 were set to CFEOM3A
Review for gene: TUBB3 was set to AMBER
Added comment: Sources: Literature
Congenital fibrosis of the extraocular muscles v0.0 Ellen McDonagh Added Panel Congenital fibrosis of the extraocular muscles
Set panel types to: GMS Rare Disease