TRIM32 was first asserted in relation to autosomal recessive Bardet-Biedl syndrome in a family reported in 2006 (Chiang et al., PMID: 16606853). The phenotypes were consistent with other forms of Bardet-Biedl syndrome, including obesity, pigmentary retinopathy, polydactyly, hypogonadism, kidney and heart abnormalities, and/or intellectual impairment. TRIM32 variants have separately been asserted in relation to autosomal recessive limb-girdle muscular dystrophy as early as 2002 (Frosk et al., PMID: 11822024). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the cases diagnosed as Bardet-Biedl syndrome were found to be distinguishable from the limb-girdle muscular dystrophy cases based on phenotype and disease mechanism, despite their matching mode of inheritance (autosomal recessive). Therefore, a split curation was recommended for Bardet-Biedl syndrome 11 ()MIM# 615988), while TRIM32 has already been separately curated for autosomal recessive limb-girdle muscular dystrophy (MIM# 254110, MONDO:0015152).
This curation includes one missense variant identified in the homozygous state in four affected patients from one consanguineous Israeli Bedouin family in one publication (PMID: 16606853). Interestingly, the variant is located in the B-box-2 domain, in which variants have not yet been observed to be involved in the pathogenesis of limb-girdle muscular dystrophy (PMID: 16606853, PMID: 38304327).
The experimental evidence supporting the relationship of TRIM32 to Bardet-Biedl syndrome includes data from expression studies and animal models. TRIM32 is also known as BBS11 and encodes tripartite motif-containing protein 32, an E3 ubiquitin ligase that is responsible for protein degradation (PMID: 19349376) and known to regulate autophagy (PMID: 33802079). TRIM32 is expressed in a pattern that matches other BBS-related genes (PMID: 11822024). Knockdown of the trim32 ortholog in zebrafish results in a phenotype consistent with BBS (PMID: 16606853).
In summary, TRIM32 has limited evidence of association with autosomal recessive Bardet-Biedl syndrome 11 (MIM#615988, MONDO:0014439). Additional case evidence will be requried for this gene-disease association to reach a mroe definitive classification. This clinical validity classification was approved by the ClinGen Retina Gene Curation Expert Panel on July 11th, 2024 (SOP version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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