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| Skeletal dysplasia v4.2 | PKDCC | Eleanor Williams Added comment: Comment on list classification: Further expert review from Alistair Pagnamenta supports the green rating of this gene. No change in rating needed as is green already. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.184 | MBTPS2 | Eleanor Williams commented on gene: MBTPS2: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed. It has been agreed to keep this gene as amber at this time. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.165 | LPIN2 | Arina Puzriakova Phenotypes for gene: LPIN2 were changed from Majeed syndrome (Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia) 609628 to Majeed syndrome, OMIM:609628; Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.107 | FLNA | Arina Puzriakova Phenotypes for gene: FLNA were changed from Terminal osseous dysplasia 300244; Otopalatodigital syndrome, type II -304120; Otopalatodigital syndrome, type II 304120 XLD; Otopalatodigital syndrome, type I -311300; Melnick Needles syndrome 309350; Frontometaphyseal dysplasia 305620; Frontometaphyseal dysplasia 305620 XLR; Osteodysplasty Melnick Needles 309350 XLD to Frontometaphyseal dysplasia 1, OMIM:305620; Melnick-Needles syndrome, OMIM:309350; Otopalatodigital syndrome, type I, OMIM:311300; Otopalatodigital syndrome, type II, OMIM:304120; Terminal osseous dysplasia, OMIM:300244 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.3 | TBXAS1 | Tracy Lester edited their review of gene: TBXAS1: Added comment: Variants in the AD form are associated with a bleeding disorder - no evidence of skeletal dysplasia in these patients. Mode of inheritance should just be biallelic for the skeletal dysplasia panel.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.290 | WRN | Eleanor Williams changed review comment from: Comment on list classification: Keeping red for now. Associated with Werner syndrome with Osteoporosis and slender limbs listed as clinical features in OMIM. Short stature.; to: Comment on list classification: Keeping red for now. Associated with Werner syndrome with Osteoporosis and slender limbs listed as clinical features in OMIM. Short stature. But need confirmation that this is considered strong enough a skeletal dysplasia phenotype before promoting to green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.281 | DPAGT1 | Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. It is green on the Congenital disorders of glycosylation panel (panel ID:25, version 1.32). Decision agreed with Prof Lyn Chitty. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.278 | B3GLCT | Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. It is green on the Congenital disorders of glycosylation panel (panel ID:25, version 1.32). Decision agreed with Prof Lyn Chitty. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.276 | SLC35C1 | Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. It is green on the Congenital disorders of glycosylation panel (panel ID:25, version 1.32). Decision agreed with Prof Lyn Chitty. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.219 | CKAP2L |
Eleanor Williams commented on gene: CKAP2L: Associated with Filippi syndrome #272440 (AR) in OMIM. Mainly a digital phenotype. PMID: 25439729 - Hussain et al 2014 - performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two children with Filippi syndrome and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfsā6), in CKAP2L which segregated with the disease in the family. They then sequenced CKAP2L in eight additional Filippi-syndrome-affected families (one from Italy, one from Poland, one from Turkey, and five from the UK) and identified five additional mutations in four of the further eight families affected by Filippi syndrome. Sufficient cases reported, but need to assess whether the phenotype is appropriate for the skeletal dysplasia panel. It is green on the Limb disorders panel. |
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| Skeletal dysplasia v1.159 | RASGRP2 |
Eleanor Williams commented on gene: RASGRP2: PMID: 18709451 - Kilic et al 2009 - 3 families with 4 individuals with Leukocyte adhesion deficiency (LAD) type III (severe recurrent infections, leukocytosis, and increased bleeding tendency). All patients had increased bone density on X-ray similar to that seen in patients with osteopetrosis, and variants in the CalDAG-GEF1 gene (now called RASGRP2). A splice junction mutation was found in families 1 and 3. The patient from family 2 had very low levels of CalDAG-GEF1. . Knock out CalDAG-GEFI deficient mice exhibit the same platelet and neutrophil adhesion defect but NO abnormalities in bone density on X-ray. PMID: 24958846 - Canault et al 2014 - three siblings affected by severe bleeding - whole-exome sequencing identified the culprit mutation (cG742T) in RASGRP2 - couldn't find any mention of a bone density/skeletal dysplasia phenotype. |
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| Skeletal dysplasia v1.153 | FLNA | Eleanor Williams Added phenotypes Terminal osseous dysplasia 300244; Melnick Needles syndrome 309350; Frontometaphyseal dysplasia 305620; Otopalatodigital syndrome, type II -304120; Otopalatodigital syndrome, type I -311300 for gene: FLNA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.153 | LPIN2 |
Eleanor Williams Added phenotypes Majeed syndrome (Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia) 609628 for gene: LPIN2 Publications for gene LPIN2 were changed from to 29912021 |
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| Skeletal dysplasia v1.153 | FBLIM1 |
Eleanor Williams Added phenotypes Majeed syndrome (Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia) 609628 for gene: FBLIM1 Publications for gene FBLIM1 were changed from to 29912021 |
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| Skeletal dysplasia v1.153 | EED |
Eleanor Williams Added phenotypes Cohen-Gibson syndrome 617561 for gene: EED Publications for gene EED were changed from 25787343; 27193220; 27868325; 28229514 to 25787343; 27193220; 27868325; 28229514 |
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| Skeletal dysplasia v1.153 | RASGRP2 |
Eleanor Williams Added phenotypes Bleeding disorder, platelet-type, 18 615888 for gene: RASGRP2 Publications for gene RASGRP2 were changed from 18709451; 24958846 to 24958846; 18709451 |
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| Skeletal dysplasia v1.147 | RASGRP2 | Tracy Lester reviewed gene: RASGRP2: Rating: GREEN; Mode of pathogenicity: ; Publications: 18709451, 24958846; Phenotypes: Bleeding disorder, platelet-type, 18 615888; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.147 | LPIN2 | Tracy Lester reviewed gene: LPIN2: Rating: GREEN; Mode of pathogenicity: ; Publications: 29912021; Phenotypes: Majeed syndrome (Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia) 609628; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.147 | FLNA | Tracy Lester reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: Other - please provide details in the comments; Publications: ; Phenotypes: Melnick Needles syndrome 309350, Otopalatodigital syndrome, type I -311300, Otopalatodigital syndrome, type II -304120, Frontometaphyseal dysplasia 305620, Terminal osseous dysplasia 300244; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.147 | FBLIM1 | Tracy Lester reviewed gene: FBLIM1: Rating: AMBER; Mode of pathogenicity: ; Publications: 29912021; Phenotypes: Majeed syndrome (Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia) 609628; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.147 | EED | Tracy Lester reviewed gene: EED: Rating: GREEN; Mode of pathogenicity: ; Publications: 25787343, 27193220, 27868325, 28229514; Phenotypes: Cohen-Gibson syndrome 617561; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.146 | EED | Eleanor Williams reviewed gene: EED: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.145 | EED |
Eleanor Williams Source NHS GMS was added to EED. Rating Changed from Green List (high evidence) to Green List (high evidence) |
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| Skeletal dysplasia v1.139 | TRPV6 |
Helen Brittain gene: TRPV6 was added gene: TRPV6 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: TRPV6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRPV6 were set to 29861107 Phenotypes for gene: TRPV6 were set to Hyperparathyroidism, transient neonatal, 618188 Penetrance for gene: TRPV6 were set to unknown Review for gene: TRPV6 was set to GREEN Added comment: 6 unrelated children with skeletal abnormalities detected in the third trimester of pregnancy, who presented at birth with elevated serum PTH and alkaline phosphatase activity, with normal or low ionized calcium. Skeletal anomalies included generalized osteopenia, narrow chest, short ribs with multiple healing fractures, and bowing or fractures of long bones. All affected individuals experienced postnatal respiratory difficulties requiring ventilatory support in the first few weeks to months of life. In addition, most showed poor feeding, with some requiring tube feeding. Sources: Literature |
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| Skeletal dysplasia v1.131 | ABL1 |
Rebecca Foulger gene: ABL1 was added gene: ABL1 was added to Skeletal dysplasia. 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 Added comment: Added to Skeletal dysplasia panel with Amber rating as suggested by Helen Brittain. 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. They report 2 variants in 4 families (6 individuals). Helen Brittain, clinical fellow, notes that: "the broader skeletal manifestations (scoliosis / pectus) are classically thought of as part of the Marfan / FTAAD spectrum rather than a skeletal dysplasia. Therefore do not think that skeletal dysplasia (or limb panel) would be the primary route for diagnosis here and would opt for amber on the basis that we need to see the phenotype across other cases first." Sources: Literature |
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| Skeletal dysplasia v1.105 | ISCA-37418-Loss |
Louise Daugherty Region: ISCA-37418-Loss was added Region: ISCA-37418-Loss was added to Unexplained skeletal dysplasia. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37418-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for Region: ISCA-37418-Loss were set to Potocki-Lupski syndrome; hypotonia, poor feeding, failure to thrive, developmental delay particularly cognitive and language deficity, mild-moderate intellectual deficit, and neuropsychiatric disorders; Smith-Magenis syndrome; Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance; 182290; moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems; hypotonia, failure to thrive, mental retardation, pervasive developmental disorders, congenital anomalies; Dental abnormalities |
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| Skeletal dysplasia | EED | Sarah Leigh classified EED as green | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia | EED | Sarah Leigh classified EED as green | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia | EED | Sarah Leigh added EED to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia | EED | Sarah Leigh reviewed EED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||