Palmoplantar keratoderma and erythrokeratodermas

Gene: TRPV3

Green List (high evidence)

Comment when marking as ready: Sufficient cases to support causation. Mode of inheritance supported by OMIM and G2P.

Created: 13 Mar 2017, 10:16 a.m.

Comment on list classification: Updated rating from Amber to Green: 1 Green expert review plus at least 3 unrelated cases (from China and India) supporting causation for Olmsted Syndrome (which presents with PPK) from OMIM and additional literature. Plus one family reported for Palmoplantar keratoderma, nonepidermolytic, focal 2 (MIM:616400).

Created: 13 Mar 2017, 10:16 a.m.

>3 TRPV3 variants listed in OMIM for Olmsted syndrome (OMIM:614594; also known as mutilating palmoplantar keratoderma with periorificial keratotic plaques). This includes 6 Chinese patients with OMIM:614594 identified by Lin et al., 2012 (PMID: 22405088), and a girl of unspecified ethnicity (PMID:24452206, Duchatelet et al., 2014). It's not specified whether the Chinese patients in Lin et al, are related or not.

Created: 13 Mar 2017, 9:36 a.m.

TRPV3 is a PROBABLE DD gene for Olmsted syndrome (OMIM:614594).

Created: 13 Mar 2017, 9:16 a.m.

PMID:25989441 (Agarwala, 2016) present a 28 year old Indian male with Olmsted syndrome and thickening of palmar and plantar skin (diffuse PPK). They detected four heterozygous variants in TRPV3. Only one of these was unique to the affected proband: c.1246Ins6 (a 6 nucleotide insertion) appears to be a de novo change that is only expressed in the proband's DNA. Other heterozygous changes are present in the unaffected parents and sister.

Created: 10 Jan 2017, 3:05 p.m.

Comment on mode of inheritance: Mode of inheritance confirmed by OMIM (for both OMIM:614594 and OMIM:616400) and G2P (for Olmsted syndrome, OMIM:614594).

Created: 9 Jan 2017, 9:55 a.m.

1 TRPV3 variant listed in OMIM for 'Palmoplantar keratoderma, nonepidermolytic, focal 2 (OMIM:616400)' for 1 family (also a Chinese family- a father and son with focal palmoplantar keratoderma). The mutation (a T-G transversion resulting in a Q580P substitution) occurred de novo in the father; it was not detected in the unaffected paternal grandparents, an unaffected paternal uncle, or an unaffected sister. Transfection studies suggest that Q580P is a gain-of-function change.

Created: 9 Jan 2017, 9:52 a.m.

Comment on mode of pathogenicity: The T-G transversion (rs786205869) resulting in a Q580P substitution in a Chinese father and son (PMID:25285920, He et al., 2015) is a gain-of-function change.

Created: 9 Jan 2017, 9:52 a.m.