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| Ehlers Danlos syndrome with a likely monogenic cause v4.12 | P4HA1 |
Ida Ertmanska gene: P4HA1 was added gene: P4HA1 was added to Ehlers Danlos syndrome with a likely monogenic cause. 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 |
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| Ehlers Danlos syndrome with a likely monogenic cause v4.8 | LOX | Ida Ertmanska commented on gene: LOX: Comment on mode of inheritance: There are 2 unrelated probands reported with biallelic missense LOX variants and a shared phenotype of cutis laxa, arterial dilatation, thickened heart, bone fragility, and respiratory failure. Mouse models are supportive, with knockout mouse showing abnormal collagen fibers in skin, impaired airway development, aneurysms and aortic wall dysplasia, with death occuring shortly after birth. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.8 | OLA1 |
Ida Ertmanska changed review comment from: PMID: 41887223 Alabdi et al., 2026 14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder. All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in unrelated 6 individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome. Microcephaly was noted in 4 individuals from unrelated families (severity details: -4.49 SD, -3SD, -4.6SD, and "HC 45cm at 9 years") Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons. Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping. Sources: Literature; to: PMID: 41887223 Alabdi et al., 2026 14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder. All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in 6 unrelated individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome. Microcephaly was noted in 4 individuals from unrelated families (severity details: -4.49 SD, -3SD, -4.6SD, and "HC 45cm at 9 years") Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons. Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping. Sources: Literature |
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| Ehlers Danlos syndrome with a likely monogenic cause v4.8 | OLA1 | Ida Ertmanska Added comment: Comment on list classification: There are 13 individuals reported from 9 unrelated families with biallelic variants in OLA1 and joint hypermobility, with additional features of skin laxity (5 cases) and scoliosis (6 cases), suggestive of EDS diagnosis. Hence, this gene should be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.7 | OLA1 |
Ida Ertmanska gene: OLA1 was added gene: OLA1 was added to Ehlers Danlos syndrome with a likely monogenic cause. Sources: Literature Q1_26_promote_green tags were added to gene: OLA1. Mode of inheritance for gene: OLA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OLA1 were set to 41887223 Phenotypes for gene: OLA1 were set to Ehlers-Danlos syndrome, hypermobility type, MONDO:0007523; neurodevelopmental disorder,MONDO:0700092; microcephaly, MONDO:0001149 Review for gene: OLA1 was set to GREEN Added comment: PMID: 41887223 Alabdi et al., 2026 14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder. All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in unrelated 6 individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome. Microcephaly was noted in 4 individuals from unrelated families (severity details: -4.49 SD, -3SD, -4.6SD, and "HC 45cm at 9 years") Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons. Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping. Sources: Literature |
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| Ehlers Danlos syndrome with a likely monogenic cause v4.2 | FLNA |
Ida Ertmanska changed review comment from: PMID: 34863227 Billon et al., 2021 Summary report of 3 patient cohorts: 10 French female index cases from the Rare Vascular Diseases Centre, aged 14-66, 23 cases from the filaminopathies diagnostic lab, and a literature review of 59 cases - total of 92 cases with monoallelic variants in FLNA and periventricular nodular heterotopia type 1 (X-linked dominant). 50% of patients did not have neurological symptoms. Most patients presented with combined cardiovascular (CV) and connective tissue disorder (CTD) features. CV anomalies, e.g. aortic aneurysm and/or dilation, were present in 75% of patients. CTD features were present in 75% of patients - e.g. joints hyperlaxity and skin hyperelasticity. Studies analysed in the literature review: PMIDs:11532987;15249610;15459826;15668422;15994863;15994863;16303888;16684786;19917821;20014127;20730588;20888935;21194575;21960593;22238415;22366253;23032111;24906659;26059841;27091362;27144976;27739212;28177866;28457522;29334594;29449050;30089473;30547349 PMID: 15668422 Sheen et al., 2005 - first report 2 families and 9 sporadic cases with periventricular nodular heterotopia associated with joint hyperlaxity, skin hyperelasticity, and aortic aneurysm/dissection. The authors suggested calling this condition Ehlers–Danlos variant of periventricular heterotopia. FLNA is putatively linked to FG syndrome 2, 300321, and associated with 9 X-linked conditions: Cardiac valvular dysplasia, X-linked, 314400; Congenital short bowel syndrome, 300048; Frontometaphyseal dysplasia 1, 305620; Heterotopia, periventricular, 1, 300049; Intestinal pseudoobstruction, neuronal, 300048; Melnick-Needles syndrome, 309350; Otopalatodigital syndrome, type I, 311300; Otopalatodigital syndrome, type II, 304120; Terminal osseous dysplasia, 300244 in OMIM (accessed 31st Oct 2025).; to: PMID: 34863227 Billon et al., 2021 Summary report of 3 patient cohorts: 10 French female index cases from the Rare Vascular Diseases Centre, aged 14-66, 23 cases from the filaminopathies diagnostic lab, and a literature review of 59 cases - total of 92 cases with monoallelic variants in FLNA and periventricular nodular heterotopia type 1 (X-linked dominant). 50% of patients did not have neurological symptoms. Most patients presented with combined cardiovascular (CV) and connective tissue disorder (CTD) features. CV anomalies, e.g. aortic aneurysm and/or dilation, were present in 75% of patients. CTD features were present in 75% of patients - e.g. joints hyperlaxity and skin hyperelasticity. Studies analysed in the literature review: PMIDs:11532987;15249610;15459826;15668422;15994863;15994863;16303888;16684786;19917821;20014127;20730588;20888935;21194575;21960593;22238415;22366253;23032111;24906659;26059841;27091362;27144976;27739212;28177866;28457522;29334594;29449050;30089473;30547349 PMID: 15668422 Sheen et al., 2005 - first report 2 families and 9 sporadic cases with periventricular nodular heterotopia associated with joint hyperlaxity, skin hyperelasticity, and aortic aneurysm/dissection. The authors suggested calling this condition Ehlers–Danlos variant of periventricular heterotopia. FLNA is putatively linked to FG syndrome 2, 300321, and associated with 9 X-linked conditions: Cardiac valvular dysplasia, X-linked, 314400; Congenital short bowel syndrome, 300048; Frontometaphyseal dysplasia 1, 305620; Heterotopia, periventricular, 1, 300049; Intestinal pseudoobstruction, neuronal, 300048; Melnick-Needles syndrome, 309350; Otopalatodigital syndrome, type I, 311300; Otopalatodigital syndrome, type II, 304120; Terminal osseous dysplasia, 300244 in OMIM (accessed 31st Oct 2025). |
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| Ehlers Danlos syndrome with a likely monogenic cause v4.2 | FLNA | Neeti Ghali edited their review of gene: FLNA: Added comment: Currently on R125 panel as well as other panels but I would argue that there is a connective tissue phenotype for a number of patients with missense variants in FLNA. A patient recently had R101 for connective tissue features, but went on to have R125 because of valvular disease and a FLNA pathogenic variant was identified. This is reasonable given the function of the protein Filamin A. Therefore, it would be beneficial for it to also be on R101 panel; Changed publications to: 34863227, 30089473, 40883083, 23032111; Changed phenotypes to: connective tissue phenotype eg. hypermobility, skin hyperextensibility, perforated ear drum, retinal detachment, arterial fragility, aortic dilatation, arterial tortuosity, valvular disease, PVL, lung | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v2.60 | SMAD3 |
Eleanor Williams commented on gene: SMAD3: Note one case with a biallelic variant reported: PMID: 32935439 - Baskin et al 2020 - first report of a LDS patient with biallelic SMAD3 variants (affecting splice site). Proband had classic Loeys-Dietz features, including dysmorphic facial features, significant scoliosis, and pectus excavatum, arachnodactyly, severe aortic root dilation, and diffuse arterial tortuosity. His parents are each heterozygous for the likely pathogenic variant and are more mildly affected. |
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| Ehlers Danlos syndrome with a likely monogenic cause v2.57 | LTBP1 |
Andžela Lazdāne changed review comment from: Based on the literature homozygous premature truncating LTBP1 variants was reported in eight affected individuals with connective tissue features. In vivo validation with two independent zebrafish lines carrying mutations in LTBP1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae. Sources: Literature; to: Based on the literature homozygous premature truncating LTBP1 variants was reported in eight affected individuals with connective tissue features. In vivo validation with two independent zebrafish lines carrying mutations in LTBP1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae. Sources: Literature |
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| Ehlers Danlos syndrome with a likely monogenic cause v2.57 | LTBP1 |
Andžela Lazdāne gene: LTBP1 was added gene: LTBP1 was added to Ehlers Danlos syndromes. Sources: Literature Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LTBP1 were set to PMID: 33991472 Phenotypes for gene: LTBP1 were set to Cutis laxa; craniofacial dysmorphism; altered skeletal development, including short stature; brachydactyly; clinodactyly Penetrance for gene: LTBP1 were set to Complete Review for gene: LTBP1 was set to GREEN Added comment: Based on the literature homozygous premature truncating LTBP1 variants was reported in eight affected individuals with connective tissue features. In vivo validation with two independent zebrafish lines carrying mutations in LTBP1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae. Sources: Literature |
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| Ehlers Danlos syndrome with a likely monogenic cause v2.42 | SKI | Ivone Leong Phenotypes for gene: SKI were changed from Shprintzen-Goldberg syndrome, 182212 to Shprintzen-Goldberg syndrome, OMIM:182212 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v2.8 | ATP6V0A2 | Ivone Leong Phenotypes for gene: ATP6V0A2 were changed from Cutis laxa, autosomal recessive, type IIA, 219200; Wrinkly skin syndrome, 278250 to Cutis laxa, autosomal recessive, type IIA, OMIM:219200; Wrinkly skin syndrome, OMIM:278250 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v2.4 | EFEMP1 |
Zornitza Stark gene: EFEMP1 was added gene: EFEMP1 was added to Ehlers Danlos syndromes. Sources: Literature Mode of inheritance for gene: EFEMP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EFEMP1 were set to 32006683; 31792352 Phenotypes for gene: EFEMP1 were set to Connective tissue disorder Review for gene: EFEMP1 was set to AMBER Added comment: Monoallelic variants in this gene are associated with a retinal dystrophy. New publications linking bi-allelic variants to a connective tissue disease phenotype: PMID 31792352 reports one individual with a pronounced connective tissue phenotype presenting multiple and recurrent abdominal and thoracic herniae, myopia, hypermobile joints, scoliosis, and thin translucent skin. This individual has no clinical signs of retinal dystrophy. PMID 32006683 reports 2 homozygous siblings (consanguinous) with multiple and recurrent herniae, pelvic and rectal prolapse, huge diverticula, marfanoid habitus, joint laxity, dorsal scoliosis, advanced bone age, pectus excavatum, dysmorphic facial features, and myopia. Both papers mention that studies on EFEMP1−/− mice revealed a phenotypic resemblance. Sources: Literature |
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| Ehlers Danlos syndrome with a likely monogenic cause v1.43 | SKI | Duncan Baker reviewed gene: SKI: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v1.42 | SKI | Eleanor Williams reviewed gene: SKI: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v1.41 | SKI |
Eleanor Williams Source NHS GMS was added to SKI. Rating Changed from Green List (high evidence) to Green List (high evidence) |
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| Ehlers Danlos syndrome with a likely monogenic cause v1.36 | ABL1 |
Rebecca Foulger gene: ABL1 was added gene: ABL1 was added to Ehlers Danlos syndromes. Sources: Literature missense tags were added to gene: ABL1. Mode of inheritance for gene: ABL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ABL1 were set to 28288113 Phenotypes for gene: ABL1 were set to Congenital heart defects and skeletal malformations syndrome, 617602 Mode of pathogenicity for gene: ABL1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: ABL1 was set to GREEN Added comment: Added ABL1 to EDS panel as requested by Helen Brittain, clinical fellow. Wang et al, 2017 (PMID:28288113) report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities and failure to thrive. 2 variants reported in 4 families, including c.734A>G (p.Tyr245Cys) found to occur in 3 famililes. Included on this EDS panel on advice from Helen Brittain: the kyphosis / scoliosis / velvety skin could overlap with the EDS syndromes panel as a mimic of kyphoscoliotic EDS. Sources: Literature |
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| Ehlers Danlos syndrome with a likely monogenic cause | SKI | Angela Brady reviewed SKI | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause | SKI | Neeti Ghali reviewed SKI | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause | SKI | Louise Daugherty edited their review of SKI | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause | SKI | Louise Daugherty classified SKI as green | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause | SKI | Louise Daugherty commented on SKI | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||