LGMD and VUS Resolution: Compound Heterozygous (CH) and Digenic Variants (DV). Are We Looking?


Clinical Management

Poster Number: Virtual


William Lowery, MD, LGMD-1D DNAJB6 Foundation

ABSTRACT: LGMDs are among a subset of rare genetic disorders which can be diagnosed by specific genetic panels. A panel may show a pathogenic or likely pathogenic result and the diagnosis is likely secured. The majority of these tests will fall into the VUS category which leaves a patient in a diagnostic limbo. Steps toward VUS resolution should include (CH) and (DV) investigation. Through routine segregation analysis and online databases, these variants can be screened as possible causes of LGMD and are often overlooked.

METHODS: From 2019 to July 2022 we reviewed 223 NM gene panels of individuals with LGMD symptoms of a chronic nature. These panels tested from 150 to 330 neuromuscular variants. Segregation analysis where available was performed on an additional 129 family members. All results from benign to pathogenic were shared with patients and their doctors. Access to genetic counseling was facilitated in all cases.

RESULTS: The combined results from 2021 of 128 patients are now totaling 223 symptomatic patients in 2022, showing a similar proportion of 25- 30% pathogenic results achieving a confirmed genetic diagnosis. The rest of the results were VUS with roughly half suspicious enough for further family testing. The average VUS variants per symptomatic patient was 4.

Of the 223 symptomatic individuals, 25 had CH variants in a trans or cis position. We excluded probands whose parents had cis position CH variants and were asymptomatic. Most had 150 to 330 NM variants tested. The CH variants were almost all VUS and no other variants seemed a likely explanation for their weakness.

The OLIDA: Oligogenic Diseases Database was used to screen for digenic and oligogenic matches for the 223 symptomatic patients. No exact variant matches were found. However, there were 2- COL6A1-COL6A3 ,
2- CACNAS1-COL12A1, 1- COL6A1-COL6A2 , 1- CAPN3-COL6A1, 1-COL6A3-COL12A1, 1-COL6A2-COL6A3-COL12A1. Although similar to those variants found in OLIDA, they have not been verified as causative.

CONCLUSION: The majority of patients with suspected LGMD will show VUS on genetic testing. The gene panels are expanding in number of variants tested each year and seem to catch ever diminishing rare forms of myopathic and neuropathic conditions. We believe closer examination VUS results for CH and DV is warranted and referral for RNA seq or muscle biopsy where indicated.