Limb disorders

Gene: BTRC

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.

Created: 27 Jan 2025, 12:38 a.m. | Last Modified: 27 Jan 2025, 12:38 a.m.

Panel Version: 6.6

Comment when marking as ready: Review of literature in October 2018 - no new publications. So keeping rating as Amber.

Created: 17 Oct 2018, 3:06 p.m.

Publications

• 35908152
• 36928426

Comment on publications: PMID: 16691619 - use different techniques to narrow down the SHFM3 (10q24) to a minimal 325 kb duplication containing two genes BTRC and POLL. Expression analysis of 13 candidate genes within and flanking the duplicated region shows that BTRC (present in three copies) and SUFU (present in two copies) are overexpressed in SHFM3 patients compared to controls.

Created: 5 Apr 2018, 9:55 a.m.

Comment on mode of pathogenicity: Microduplications reported, not SNVs within this gene, in patients with split hand-split foot malformation.

Created: 5 Apr 2018, 9:51 a.m.

Comment on publications: PMID: 29263051 - two Chinese patients with Split hand/foot malformation with a 534kb microduplication at 10q24 encompassing TLX1, LBX1, BTRC and POLL, and a 600kb duplication with TLX1, LBX1, BTRC, POLL, and FBXW4 located. PMID: 28777841 (article in Chinese, abstract available in English) - 3 families with Split hand/foot malformationMicroarray and real-time PCR analysis has identified a duplication in all patients from pedigrees 1 and 3, which have spanned FKSG40, TLX1, LBX1, BTRC, POLL and FBXW4 (exons 6-9) and LBX1, BTRC, POLL and FBXW4 (exons 6-9) genes, respectively. A missense mutation of the TP63 gene, namely c.692A>G (p.Tyr231Cys), was found in two patients from pedigree 2. PMID: 27600068 - A 514 kb gain at 10q24.31-q24.32 (chr10:102,962,134-103,476,346, hg19) was identified using 6.0 Single nucleotide polymorphism (SNP) microarray, resulting in the duplication of nine genes, including BTRC and FBXW4. A detailed systematic review of literature and mapping of breakpoints using microarray data from all reported cases in PubMed and DECIPHER were conducted, and exon 1 of BTRC gene was identified as the critical region responsible for the SHFM3 phenotype.

Created: 5 Apr 2018, 9:49 a.m.

Comment on list classification: Not associated with a disease in OMIM or Gene2Phenotype.

Created: 5 Apr 2018, 9:41 a.m.