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Mendeliome v1.4861 PITX1 upstream regulatory region Sarah Milton Classified Region: PITX1 upstream regulatory region as Green List (high evidence)
Mendeliome v1.4861 PITX1 upstream regulatory region Sarah Milton Region: pitx1 upstream regulatory region has been classified as Green List (High Evidence).
Mendeliome v1.4860 PITX1 upstream regulatory region Sarah Milton Classified Region: PITX1 upstream regulatory region as Green List (high evidence)
Mendeliome v1.4860 PITX1 upstream regulatory region Sarah Milton Region: pitx1 upstream regulatory region has been classified as Green List (High Evidence).
Mendeliome v1.4729 PITX1 upstream regulatory region Sarah Milton Tag regulatory region was added to Region: PITX1 upstream regulatory region.
Mendeliome v1.4625 PITX1 upstream regulatory region Sarah Milton Region: PITX1 upstream regulatory region was added
Region: PITX1 upstream regulatory region was added to Mendeliome. Sources: Literature
Mode of inheritance for Region: PITX1 upstream regulatory region was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for Region: PITX1 upstream regulatory region were set to PMID: 30711920; 23022097; 25124102; 23587911
Phenotypes for Region: PITX1 upstream regulatory region were set to Liebenberg syndrome, MIM#186550
Review for Region: PITX1 upstream regulatory region was set to GREEN
Added comment: PITX1 is a transcription factor expressed solely in the hindlimb during limb development where it ensures proper outgrowth and patterning of this tissue.

Over 25 individuals have been reported in the literature with deletions upstream of PITX1 presenting with Liebenberg syndrome characterised by dysplastic elbow joints and the fusion of wrist bones and the consequent radial deviation. With upper limb features resembling some of those seen in the lower limb.

The deletions seen in affected individuals range from 8kb to 134kb in size and are thought to result in overexpression of PITX1 by affecting the proximity between the coding sequence and an upstream enhancer (referred to variably as 'Pen' or 'hs1473').
The deletion removes part of a different protein coding gene - MACROH2A1 which is not thought to contribute to the pathogenesis (knockout mice do not present with a similar phenotype to Liebenberg).
Authors of PMID: 30711920 suggest the promoter of MACROH2A1 acts as an insulator between the upstream enhancer and PITX1 however further functional studies are required to establish this.

Functional studies involving transgenic mice with the enhancer element just upstream of PITX1 resulting in a similar phenotype to affected individuals.

Note: Maximal reported deletion coordinates at time of writing: chr5:135288912-135423802
Minimum: chr5:135393716-135402219:
Sources: Literature
Mendeliome v0.10674 PITX1 Zornitza Stark Marked gene: PITX1 as ready
Mendeliome v0.10674 PITX1 Zornitza Stark Gene: pitx1 has been classified as Green List (High Evidence).
Mendeliome v0.10674 PITX1 Zornitza Stark Phenotypes for gene: PITX1 were changed from to Brachydactyly-elbow wrist dysplasia syndrome, MONDO:0008520; Clubfoot, MONDO:0007342; Liebenberg syndrome, OMIM:186550; Clubfoot, congenital, with or without deficiency of long bones and/or mirror-image polydactyly, OMIM:119800
Mendeliome v0.10673 PITX1 Zornitza Stark Publications for gene: PITX1 were set to
Mendeliome v0.10672 PITX1 Zornitza Stark Mode of inheritance for gene: PITX1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.10671 PITX1 Zornitza Stark reviewed gene: PITX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21775501, 22258522, 18950742; Phenotypes: Brachydactyly-elbow wrist dysplasia syndrome, MONDO:0008520, Clubfoot, MONDO:0007342, Liebenberg syndrome, OMIM:186550, Clubfoot, congenital, with or without deficiency of long bones and/or mirror-image polydactyly, OMIM:119800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.0 PITX1 Zornitza Stark gene: PITX1 was added
gene: PITX1 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: PITX1 was set to Unknown