Skeletal dysplasia

Gene: THPO

Red List (low evidence)

Limb hypoplasia-reduction defects gp of SD - ?secondary to blood disorder.; Review on behalf of Tracy Lester/Michael Oldridge

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Thrombocythemia 1 187950 (rare presentation with congenital limb defects)

Publications

• 22453305
• 19553636

I don't know

Comment on list classification: Demoted from Green to red. Only two cases reported with a limb defect and no clear wider skeletal phenotype.

Created: 20 Nov 2019, 12:15 p.m. | Last Modified: 20 Nov 2019, 12:15 p.m.

Panel Version: 1.218

Associated with Thrombocythemia 1 #187950 (AD) in OMIM.


PMID: 19553636 - Graziano et al 2009 - report where the father has thrombocythemia and limb defects (absence of forearm and hand, absence of foot). Two sons had milder lower limb defects. A G185T heterozygous mutation was detected in THPO. The grandfather was found to have the variant and had thrombocythemia but no limb defect.

PMID: 22453305 - Stockklausner et al 2012 - report two families with Hereditary thrombocythemia resulting from a THPO c.13+1 G>C mutation in the splice donor of intron 3. In one family there were coexisting distal limb defects in 2 out of 4 individuals with thrombocythemia (complex limb defects of the left hand in one individual, and absent proximal, middle, and distal phalanges at digits 3–5, a dysplastic proximal phalanx at digit 2 with absent middle and distal phalanx and shortened metacarpal bones at digits 3 and 4, carpal bones were partly fused to metacarpal bones at digits 2–5 in the other).

Created: 20 Nov 2019, 12:13 p.m. | Last Modified: 20 Nov 2019, 12:13 p.m.

Panel Version: 1.217

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: THPO; Initial rating suggestion: red

Created: 6 Mar 2019, 11:37 a.m.

Comment when marking as ready: At least two reports of variants associated with Thrombocythemia 1 187950 with congenital limb defects

Created: 12 Jul 2016, 1:56 p.m.

Comment on mode of pathogenicity: Gain of function

Created: 12 Jul 2016, 1:55 p.m.

Green List (high evidence)

Tier 2

Created: 17 Jun 2016, 8:09 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Thrombocythemia 1 187950; Stockklausner C et al. Hereditary thrombocythemia caused by a thrombopoietin (THPO) gain-of-function mutation associated with multiple myeloma and congenital limb defects. Ann Hematol. 2012 Jul, 91(7):1129-33; Graziano C et al. Association of hereditary thrombocythemia and distal limb defects with a thrombopoietin gene mutation. Blood. 2009 Aug 20, 114(8):1655-7

Variants in this GENE are reported as part of current diagnostic practice