The LARS2 gene was first associated with autosomal recessive Perrault syndrome in 2013 (Pierce et al., PMID: 23541342). At least 27 unique variants (missense, frameshift) have been reported in 18 probands in 12 publications (PMIDs: 23541342, 26970254, 27650058, 26657938, 29205794, 30737337, 31274036, 32442335, 32399598, 32767731, 32842620, 36450801). Variants in this gene segregated with disease in 7 additional members in one family (PMID: 32842620). An additional internal case at the Laboratory for Molecular Medicine involves two young sisters with profound sensorineural hearing loss, who are compound heterozygous for a missense variant and exon 22 deletion (NM_015340.3(LARS2):c.(?2533)-70*(70_?)del, SCV000731480.1). This gene-disease relationship is supported by relevant expression studies, biochemical function studies, a mouse model and a rescue (PMIDs: 23541342, 26537577, 28263850). In summary LARS2 is definitively associated with autosomal recessive Perrault syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally classified as Strong by the ClinGen Hearing Loss Working Group on 6/26/2018 as per SOP v5. It was reevaluated on 6/1/2023 as per SOP v9. As a result of this reevaluation, the classification increased from Strong to Definitive due to additional case level evidence from new literature (PMIDs: 30737337, 31274036, 32442335, 32399598, 32767731, 32842620, 36450801).
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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