Genetic testing yield among patients with suspected primary heritable optic atrophy

Abstract

Purpose : The clinical and genetic heterogeneity of suspected primary heritable optic atrophy (phOA) poses genetic diagnostic challenges. Patients with suspected phOA were retrospectively analyzed to determine genetic testing yield and clinical correlates.

Methods : Medical records of patients with genetic testing for suspected phOA were reviewed. Sex, age at vision symptom onset (VSO) and OA diagnosis (OAD), clinical diagnosis subgroup, presence of syndromic features, and positive family history were analyzed. Clinical diagnosis subgroups included 1) Dominant Optic Atrophy (DOA) (OPA1 or OPA3), 2) Leber Hereditary Optic Neuropathy (LHON), 3) unspecified isolated OA, and 4) syndromic OA. Probands underwent Sanger Sequencing, Next Generation Sequencing, and/or whole exome sequencing. Molecular confirmation indicated presence of pathogenic variants

Results : Fifty unique probands with suspected phOA were identified (32 male, 18 female). Mean ages were 22±20 years (standard deviation) for VSO and 26±21 years for OAD. Testing confirmed molecular causes in 30% of cases (15/50), including 11/32 males and 4/18 females (not significant; Fisher’s exact test). Molecular testing result stratified by clinical diagnosis subgroup confirmed disease-causing genotypes in 6/23 with suspected DOA, 4/6 with suspected LHON, 2/8 with unspecified isolated OA, and 3/13 with suspected syndromic OA. Age at VSO and OAD between molecularly confirmed vs. unconfirmed cases were not statistically different. Isolated OA was reported in 42 probands (84%) and suspected syndromic OA in 8 probands (16%); genetic testing yield was not different between these groups (31% vs. 25% respectively; Fisher’s test). Genetic testing yield was 60% for probands with positive family history (9/15) and 19% for singletons (6/32) (p=0.0077; Fisher’s test).

Conclusions : Consistent with prior studies, family history was positively associated with testing yield, but was not significantly affected by sex, clinical diagnosis subgroup, or presence of syndromic features. A large prospective phOA cohort is needed to identify and refine clinical associations and drive gene discovery required to improve genetic diagnostic yield among unconfirmed patients.

This is a 2021 ARVO Annual Meeting abstract.