Limb disorders

Gene: KIAA0586

Comment on list classification: Gene made grey as it is green on the Rare multisystem ciliopathy disorders panel (v1.78) and the ciliopathy panel will be applied if a patient is suspected of having a ciliopathy, or the possibility of a ciliopathy cannot be excluded.

Created: 2 Dec 2018, 10:56 p.m.

Comment on list classification: Rated green because three different variants have been reported in individuals presenting with a polydactyly phenotype as part of Joubert syndrome or Short-rib thoracic dysplasia 14 with polydactyly. 1 variant is thought to be a founder mutation but functional studies support this being the causative mutation.

Created: 7 Nov 2018, 11:30 a.m.

Associated with Joubert syndrome 23 and Short-rib thoracic dysplasia 14 with polydactyly in OMIM and Joubert syndrome in Gene2Phenotype.

4 families described in PMID: 26166481 for Short-rib thoracic dysplasia 14 with polydactyly. One family is a consanguineous Lebanese family in which 2 fetuses exhibited severe hydrocephaly, polydactyly, and skeletal abnormalities. A homozygous nonsense mutation was identified (S77X). They identified 3 further unrelated Eastern European families with cerebral anomalies, polydactyly, and long-bone shortening, including short ribs, who were all homozygous for the same splice site variant in KIAA0586 (c.1815G-A). Haplotype analysis of these 3 families was consistent with a common ancestor, estimated to have lived 16 generations (480 years) earlier. Functional studies using fibroblasts from one of the Eastern European families showed a reduced number of cells presenting with cilia compared to wild type cells.

Bachmann-Gagescu et al. (2015) (PMID: 26096313) identified homozygous or compound heterozygous mutations in the KIAA0586 gene in individuals with Joubert syndrome-23 from 9 unrelated families. Only 1 patient of Middle eastern origin had polydactyly (D566V variant).

Akawi et al (2015)(PMID: 26437029) also report 8 individuals from 6 families with variants in KIAA0586 and a clinical diagnosis of Joubert syndrome in 7 individuals. No limb phenotypes are reported.

In summary, three different variants have been reported in individuals presenting with a polydactyly phenotype as part of Joubert syndrome or Short-rib thoracic dysplasia 14 with polydactyly. 1 variant is thought to be a founder mutation.

Created: 6 Nov 2018, 10:45 p.m.

Genomics England clinical team notes - Agree with amber rating. Not primarily limb. On appropriate panels already

Created: 9 Sep 2018, 6:13 p.m.

Comment on publications: 4 families described in PMID: 26166481 for Short-rib thoracic dysplasia 14 with polydactyly.

Created: 9 Apr 2018, 2:38 p.m.