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28 Aug 2026	Arthrogryposis v10.21	SMARCAD1	Ida Ertmanska gene: SMARCAD1 was added gene: SMARCAD1 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: SMARCAD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMARCAD1 were set to 21820097; 24909267; 26932190; 29409814; 30289605; 33400266; 34909722; 35212137 Phenotypes for gene: SMARCAD1 were set to Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600 Review for gene: SMARCAD1 was set to AMBER Added comment: HURIEZ SYNDROME PMID: 35212137 Loh et al., 2022 Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age. Family 1 - proband had mild hyperkeratosis of soles, thin palmar skin, and weak, pointed nails. Sanger seq revealed a heterozygous 11-bp deletion in SMARCAD1: g.94253671_94253682del. Family 2 - male proband presented with scleroatrophy of hands, contracture of the little finger, sclerodactyly of distal extremities, hypoplastic nails, hypohidrosis. Proband and his affected mother were both het for a deletion affecting the SMARCAD1 donor splice site: g.94253673del Family 3 - case previously described in PMID: 8731679 Hamm, 1996 and PMID: 29409814 Günther et al., 2018 PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 32769257 Alruwaili & Hai, 2019 Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform. PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026). Sources: Literature
08 Jun 2026	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
11 May 2026	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.226Argext170 (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.226Argext170 (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.
11 May 2026	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.226Argext170 (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.226Argext170 (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.
11 May 2026	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.226Argext170 (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.226Argext170 (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.
11 May 2026	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.226Argext170 (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.226Argext170 (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).
13 Mar 2026	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
25 May 2023	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.
04 Jun 2021	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).
16 Jan 2017	Arthrogryposis	SKI	Alice Gardham marked SKI as ready
16 Jan 2017	Arthrogryposis	SKI	Alice Gardham classified SKI as green
16 Jan 2017	Arthrogryposis	SKI	Alice Gardham reviewed SKI