TRIM32

Inheritance Pattern: AR

Disease ID:MONDO:0009683

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009683

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0015229

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009683

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014439

Submitter: ClinGen

*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).

Inheritance Pattern: AR

Disease ID:MONDO:0014439

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009683

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: ClinGen

TRIM32 was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 2002 (Frosk et al., PMID:11822024). At least five unique variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. A founder variant in this gene, D487N, was first characterized by Frosk et al as causative for an LGMD in a Hutterite population, stemming from Eastern Europe. A follow-up publication by Schoser et al (PMID:15786463) observed that Hutterite LGMD probands and German sarcotubular myopathy probands shared this same variant and similar phenotypic features, concluding that both were part of the same spectrum of disorder. Since this initial characterization, several isolated variants have been reported in at least five other probands in four publications (PMIDs: 17994549, 19492423, 19303295, 31309175). In the initial pubication the D487N variant also segregated with disease in 18 additional probands in four families, yielding a maximum LOD score of 7.61. The mechanism for disease appears to be biallelic loss of function, with the disruption of the c-terminal NHL repeats impacting protein interactions and affecting proteins important to the skeletal muscle. However, no exact protein has been implicated. Of note, a variant in the TRIM32 B-box domain has also been implicated in Bardet-Biedl Syndrome. Due to the significant phenotypic and mechanistic differences, this assertion will be assessed separately. This gene-disease association is primarily supported by multiple animal models, with both a TRIM32 Knock-Out model and a D487N Knock-In model recapitulating phenotypes of the human probands such as muscle weakness and atrophy. In summary, TRIM32 is definitively associated with autosomal recessive limb-girdle muscular dystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on Nov. 5, 2020 (SOP Version 7). This gene curation was re-approved and published on 11/14/24 by the Muscular Dystrophies and Myopathies GCEP to reflect the change in the panel's name from LGMD GCEP to MDM GCEP. As part of this process, the genetic evidence was re-scored in accordance with SOP version 11.

Inheritance Pattern: AR

Disease ID:MONDO:0014439

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009683

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014439

Submitter: G2P

Inheritance Pattern: Unknown

Disease ID:MONDO:0014439

Submitter: Natera