P732: Identification of pathogenic expansions within FXN in individuals with suspected Friedreich ataxia diagnoses

Data Interpretation Network (ODIN).CNV analysis was completed using Biodiscovery's NxClinical software (BioDiscovery, El Segundo, CA).All variants were classified according to ACMG/AMP guidelines.Results: Molecular diagnosis was established in a total of 110 cases (16.0%) by identifying pathogenic (P) or likely pathogenic (LP) variants in the DYSF gene.Out of 110 cases, 75 (68.2%)individuals underwent NGS panel testing and 35 (31.8%) individuals underwent exome or genome testing.Probands were compound heterozygous for two LP/P variants in 56 (50.1%) cases and homozygous for an LP/P variant in 54 (49.1%) cases.An additional 24 (3.5%) cases were compound heterozygous for an LP/P variant and a variant of uncertain significance (VOUS) and 12 (1.7%)cases were homozygous for a VOUS, of which 33 probands had a strong clinical suspicion of dysferlinopathy.Two VOUS were identified in 30 cases, although only 8 probands presented with features consistent with dysferlinopathy.A single LP/P variant or VOUS was reported in 45 (6.6%) and 465 (67.8%) cases, respectively.Conclusion: Overall, this comprehensive analysis of both SNVs and CNVs greatly helped in establishing a molecular diagnosis and better understanding the complex variant spectrum of dysferlinopathies.In total, 439 unique SNVs were identified in this cohort, including 357 missense, 2 nonsense, 33 frameshift, and 39 splice variants, as well as 6 in-frame insertions or deletions.Three common, pathogenic variants, c.4253G>A, c.2643+1G>A, and c.5979dup, were each identified in more than 15 cases.Deep intronic variants in the DYSF gene were identified in a total of 7 cases.CNVs were identified in 7 cases, including 4 intragenic deletions and 3 duplications.