| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Skeletal dysplasia v3.10 | KIF5B |
Achchuthan Shanmugasundram gene: KIF5B was added gene: KIF5B was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: KIF5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KIF5B were set to 35342932 Phenotypes for gene: KIF5B were set to kyphomelic dysplasia, MONDO:0008881 Review for gene: KIF5B was set to GREEN Added comment: 4 individuals were reported with Kyphomelic dysplasia, which is characterised by severe bowing of the limbs, sharp angulation of the femora and humeri, short stature, narrow thorax, distinctive facial features, and neonatal respiratory distress. All these individuals harboured a de novo heterozygous missense variant in KIF5B gene ( two with c.272A>G (p.Lys91Arg), one with c.584C>A (p.Thr195Lys), and the other with c.701G>T(p.Gly234Val)). All three variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.195 | PRKAR1A |
Eleanor Williams edited their review of gene: PRKAR1A: Added comment: Looking at the mode of inheritance of this gene on the Skeletal dysplasia panel where it is Both mono and bi-allelic. In OMIM and Gene2Phenotype the relevant phenotypes of Acrodysostosis 1, with or without hormone resistance, OMIM:101800 and ACRODYSOSTOSIS respectively are listed with autosomal dominant/monoallelic inheritance. There are several reports of heterozygous variants in PRKAR1A in patients with Acrodysostosis (PMIDs: 21651393, 22464250, 22464252, 28804209, 23425300, 25075981, 26763073). No reports of biallelic variants were found in a search of PubMed. Therefore the recommendation is for the mode of inheritance to be changed to monoallelic only.; Changed mode of pathogenicity: Other; Changed publications to: 21651393, 22464250, 22464252, 28804209, 23425300, 25075981, 26763073; Changed phenotypes to: Acrodysostosis 1, with or without hormone resistance, OMIM:101800; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.130 | ARCN1 | Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Andžela Lazdāne. ARCN1 is associated with a relevant phenotype in OMIM (MIM# 617164) which is characterised by rhizomelic short stature. At least 6 individuals from 5 unrelated families reported in literature (PMIDs: 27476655; 31075182; 33154040), which is sufficient to rate this gene as Green at the next GMS panel update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.97 | NEPRO |
Zornitza Stark gene: NEPRO was added gene: NEPRO was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: NEPRO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEPRO were set to 26633546; 29620724; 31250547 Phenotypes for gene: NEPRO were set to Anauxetic dysplasia 3, MIM618853 Review for gene: NEPRO was set to AMBER Added comment: PMIDs 26633546, 29620724: 2 families with the same homozygous missense variant, haplotype analysis confirmed the founder nature of the variant. PMID 31250547: 1 family with homozygous novel missense All 5 affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. No functional studies. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.91 | FBN2 | Sarah Leigh commented on gene: FBN2: It would appear from PMIDs 33571691, 25558065 & 28383543 that biallelic variants should be considered for this gene and as such the MOI should be changed to BOTH monallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.91 | FBN2 | Sarah Leigh edited their review of gene: FBN2: Added comment: It would appear from PMIDs 33571691, 25558065 & 28383543 that biallelic variants should be considered for this gene and as such the MOI should be changed to BOTH monallelic and biallelic, autosomal or pseudoautosomal.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.220 | COG1 |
Eleanor Williams changed review comment from: Associated with Congenital disorder of glycosylation, type IIg #611209 (AR) in OMIM.; to: Associated with Congenital disorder of glycosylation, type IIg #611209 (AR) in OMIM. Clinical features include short stature, several skeletal features such as scoliosis and vertebral abnormalities. PMID: 16537452 - Foulquier et al 2006 - describe a patient with a mild form of congenital disorder of glycosylation type II with a homozygous insertion of a single nucleotide (2659-2660insC), which is predicted to lead to a premature translation stop and truncation of the C terminus of the Cog1 protein by 80 amino acids. Both parents were shown to be heterozygous for this mutation. Her skeletal features included small hands and feet, rhizomelic short stature. PMID: 19008299 - Zeevaert et al 2009 - two patients (one with consanguineous Greek-Turkish parents, the other with unrelated Bulgarian parents) with a cerebrocostomandibular-like syndrome and an intronic mutation, c.1070+5G>A, that disrupts a splice donor site and leads to skipping of exon 6, a frameshift and a premature stopcodon in exon 7. Patient 1's characteristics included multiple congenital abnormalities including Pierre-Robin sequence (cleft palate, micrognathia and glossoptosis), costovertebral anomalies including osteopenia, ribfusions and posterior rib gaps, butterfly vertebrae, misalignment of the vertebrae and a clubfoot on the right. Patient 2 presented with rhizomelic shortening of upper limbs, ulnar deviation of fingers, thoracic scoliosis, hypospadias-I and left-side cryptorchidism among other features. 3 unrelated cases. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.172 | ADAMTS17 |
Eleanor Williams commented on gene: ADAMTS17: Associated with Weill-Marchesani 4 syndrome, recessive #613195 in OMIM. This condition is characterized by short stature and brachydactyly as well as eye-associated clinical features. PMID: 19836009 - Morales et al. 2009 - 3 cases from Saudi Arabia, 2 familial and 1 sporadic. 7 affected individuals. All had short stature and ocular manifestations but not brachydactyly so are described as WMS-like. 3 different homozygous variants were detected (1 bp insertion, a splice-site mutation, and a nonsense mutation). PMID: 22486325 - Khan et al. 2012 - 1 case. A sister and brother with WMS from a consanguineous Saudi family were found to have a 1-bp deletion that segregated with disease. The probands presented with high myopia and had spherophakia. Although both had short stature, neither had short hands, short feet, joint stiffness, or non-ocular congenital abnormalities PMID: 24940034 - Shah et al. 2014 - 1 case. In an Indian family WES analysis identified a homozygous novel splice-site mutation c.873+1G>T in ADAMTS1 in a 21 year old proband. RT-PCR analysis in the patient showed that exon 5 was skipped, which resulted in the deletion of 28 amino acids in the ADAMTS17 protein. The proband presented with decreased vision. She had short stature, brachydactyly, but no joint stiffness. PMID: 31019231 - Yi et al 2019 - 1 case. In a consanguineous Chinese family, a nonsense mutation c.1051 A > T in ADAMTS17 was identified. (Abstract only accessed). More than 3 cases. Short stature reported but brachydactyly only in 1 case. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.153 | IDS | Eleanor Williams Added phenotypes Mucopolysaccharidosis II 309900 for gene: IDS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.147 | IDS | Tracy Lester reviewed gene: IDS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Mucopolysaccharidosis II 309900; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.146 | IDS | Eleanor Williams reviewed gene: IDS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.145 | IDS |
Eleanor Williams Source NHS GMS was added to IDS. Rating Changed from Green List (high evidence) to Green List (high evidence) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||