Skeletal dysplasia

Gene: BTRC

I don't know

Comment on list classification: Rating this gene as amber as there is some evidence that duplications encompassing this gene as well as nearby re-arrangements which may impact the expression of this gene, are linked to Split-hand/foot malformation 3.

Created: 27 Jan 2025, 12:36 a.m. | Last Modified: 27 Jan 2025, 12:36 a.m.

Panel Version: 7.16

In OMIM Split-hand/foot malformation 3, gene duplication syndrome (OMIM:246560) is linked to a duplication at 10q24q25 inherited in an autosomal dominant manner and is characterized by the absence of central digits. Gene2Phenotype and ClinGen do not list this gene associated with any phenotype.

Multiple publications have reported patients with SHFM3 and rearrangements covering a 500 kb region encompassing five genes of the locus (LBX1, BTRC, POLL, DPCD, and a partial portion of FBXW4) but excluding the neighbouring FGF8 e.g. PMID: 12913067 (2003), PMID: 16681918 (2006). Subsequent reports have reported various re-arrangements involving different sets of genes in the region. Examples are:

PMID: 27600068 Li et al 2015 - mapped the breakpoints of cases with duplications in the 10q24 region with and without a SHFM3 phenotype and concluded that the critical region responsible for the SHFM phenotypes is most likely located at exon 1 of BTRC gene, which is duplicated in all cases with SHFM phenotypes.

PMID: 30622331 Holder-Espinasse et al 2019 - used array CGH or qPCR to analyse 32 new index cases of 10q24 duplication (22 SHFM including 3 with preaxial polydactyly, 7 monodactylies and 3 patients presenting overlapping phenotypes). 17 cases were familial and 15 occurred de novo. Studies in 4 families showed that the duplication segregated with the phenotype. All cases tested by array-CGH had duplication of at least BTRC and POLL genes. Seven cases had duplication of LBX1 gene as well and 12 patients had duplications comprising the FBXW4 gene (although partially for cases 24 and 27).

PMID: 35908152 - Qui et al 2022 - using trio clinical exome sequencing, a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3. The duplication co-segregated with SHFM phenotypes in the family. Transcription levels of BTRC mRNA in lymphocytes of the proband was significantly higher than in the healthy control.

PMID: 36928426 Cova et al 2023 - show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. By re-engineering a human SHFM3-associated duplication in mice they observed ectopic interactions between the Fgf8 apical ectodermal ridge (AER) enhancers and two other genes in the locus, Lbx1 and Btrc. The same ectopic interactions were present in fibroblasts from a SHFM3 affected individual with duplication. In mice with the duplication a limb malformation was not observed. They also report a case of SHFM3 malformation associated with an inversion encompassing the DPDC, POLL and FBXW4 genes which when re-engineered in mice results in increased expression of genes, Lbx1 and Btrc, in an Fgf8-like pattern in the apical ectodermal ridge. Mice with the inversion were observed to have a digit phenotype.

In conclusion, point mutations in BTRC in association with SHFM3 have not been reported. It appears that changed expression of gene BTRC is related to the phenotype, but that expression levels can be impacted by both duplication of the region itself and inversion of other nearby regions, likely by disruption of regulatory domains.
Sources: Literature

Created: 27 Jan 2025, 12:34 a.m.

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

Phenotypes
Split-hand/foot malformation 3, gene duplication syndrome, OMIM:246560; split hand-foot malformation 3, MONDO:0009525

Publications

• 19584065
• 18067070
• 12913067
• 16681918
• 27600068
• 30622331
• 35908152
• 36928426
• 18392654

Mode of pathogenicity
Other