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Arthrogryposis v10.8 P4HA1 Ida Ertmanska gene: P4HA1 was added
gene: P4HA1 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: P4HA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: P4HA1 were set to 17135260; 28419360
Phenotypes for gene: P4HA1 were set to connective tissue disorder, MONDO:0003900
Review for gene: P4HA1 was set to RED
Added comment: PMID: 28419360 Zou et al., 2017
Report of 2 sibs with early-onset joint hypermobility, joint contractures, muscle weakness, mild bone dysplasia, as well as high myopia. Biallelic P4HA1 mutations detected: c.1543 + 2 T > G (predicted to cause exon 12 skipping: p.Ala418_Arg434del) and c.1323_1324insAG, p.Arg362Glyfs*9. Seq method: WES. Variants confirmed in trans.
Muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane.

PMID: 17135260 Holster et al., 2007
P4ha1-/- null mice are embryonically lethal with evidence of impaired assembly of collagen IV at the basement membrane, whereas P4ha1+/- mice have no abnormalities
Sources: Literature
Arthrogryposis v10.4 CLCF1 Ida Ertmanska changed review comment from: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling - multifocal neuronal hypoplasia phenotype.; to: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling - multifocal neuronal hypoplasia phenotype.

This gene is associated with AR Cold-induced sweating syndrome 2, OMIM:610313 in OMIM (accessed 11th May 2026). CLCF1 is not yet associated with a condition in G2P or ClinGen.
Arthrogryposis v10.4 CLCF1 Ida Ertmanska changed review comment from: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling.; to: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling - multifocal neuronal hypoplasia phenotype.
Arthrogryposis v10.4 CLCF1 Ida Ertmanska changed review comment from: PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).
; to: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling.
Arthrogryposis v10.1 CLCF1 Ida Ertmanska changed review comment from: PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal;
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 - 24yo American woman (non-consanguineous parents, German & Irish ancestry) - excessive sweating in cold temp from age 2 years, contractures, campodactyly, unable to suck or swallow until 5 months of age, erythematous rash until age 5 years; psychomotor development was normal. Compound het for CLCF1 variants c.31_53del and c.303delC.

PMID: 16782820 Rousseau et al., 2006; to: PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).
Arthrogryposis v9.30 DDR2 Ida Ertmanska gene: DDR2 was added
gene: DDR2 was added to Arthrogryposis. Sources: Literature
Q1_26_promote_green tags were added to gene: DDR2.
Mode of inheritance for gene: DDR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDR2 were set to 30449416
Review for gene: DDR2 was set to GREEN
Added comment: 30449416 Xu et al,, 2018
6 patients from 4 unrelated families, 2 previously reported. All patients were heterozygous for one of the recurring DDR2 variants: c.1829T>C (p.Leu610Pro) or c.2219A>G (p.Tyr740Cys).
Phenotypic spectrum: contractures (6/6, variable severity), corneal vascularization (5/6), skin with little subcutaneous tissue (4/6), keloid-like plaques (4/6), loss of toes/toenails (4/6), joint swellings (4/6), and other less penetrant features.

This gene is associated with AD Warburg-Cinotti syndrome 618175 and AR Spondylometaepiphyseal dysplasia, short limb-hand type 271665 (OMIM accessed 13th Mar 2026).
Sources: Literature
Arthrogryposis v5.10 FILIP1 Achchuthan Shanmugasundram changed review comment from: PMID:36344539 reported a single male with biallelic variant in FILIP1 (c.2665C > T/ p.Arg889Ter) gene and presenting with distal arthrogryposis with contractures of the knees and elbows, congenital clubfoot, muscular hypotonia, and mild learning disability.

PMID:36943452 reported five individuals from three unrelated families with three different biallelic variants in FILIP1 gene (including the variant reported in the patient from PMID:36344539) and presenting with an overlapping phenotype with congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly and facial dysmorphism.; to: PMID:36344539 reported a single male with biallelic variant in FILIP1 (c.2665C > T/ p.Arg889Ter) gene and presenting with distal arthrogryposis with contractures of the knees and elbows, congenital clubfoot, muscular hypotonia, and mild learning disability.

PMID:36943452 reported five individuals from three unrelated families with three different biallelic variants in FILIP1 gene (including the variant reported in the patient from PMID:36344539) and presenting with an overlapping phenotype with congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly and facial dysmorphism.

PMID:37163662 reported five individuals from four unrelated families with four different biallelic variants, out of which three individuals from two different families presented with congenital onset of contractures.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Arthrogryposis v3.102 EBP Arina Puzriakova Added comment: Comment on list classification: EBP will be flagged for GMS review to assess whether there is enough evidence and potential clinical value to rate as Green on this panel.

Flexion contractures may occur is a subset of patients with variants in this gene. However, as other manifestations such as skeletal malformations and skin abnormalities represent more prominent features of the disorder, it is less likely that cases would be tested under the Arthrogryposis panel. EBP is already Green on other relevant panels (Skeletal dysplasia v2.100, Palmoplantar keratodermas v1.7, etc).
Arthrogryposis SKI Alice Gardham marked SKI as ready
Arthrogryposis SKI Alice Gardham classified SKI as green
Arthrogryposis SKI Alice Gardham reviewed SKI