A de novo NR2F1 c.330 C > A variant in Bosch-Boonstra-Schaaf optic atrophy syndrome presenting with early-onset developmental and epileptic encephalopathy.

BACKGROUND

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare autosomal dominant neurodevelopmental disorder caused by pathogenic variants in the NR2F1 gene. The syndrome is characterized by a complex phenotype including optic nerve atrophy, global developmental delay, intellectual disability, and seizures. We report a patient with this syndrome whose prominent clinical presentation included developmental and epileptic encephalopathy (DEE). Due to overlapping clinical features with other neurodevelopmental disorders, clinical diagnosis remains challenging, necessitating molecular genetic studies.

PATIENT PRESENTATION: The proband was a 14.5-month-old female who presented with early-onset neurological symptoms, including severe hypotonia, global developmental delay, drug-resistant seizures, bilateral optic atrophy, hearing loss, and structural brain anomalies.

METHODS AND

RESULTS

Whole-exome sequencing (WES) revealed two novel heterozygous variants: a nonsense variant in ARF3 (NM_001659.3:c.295C>T, p.Arg99*) and a missense variant in NR2F1 (NM_005654.6: c.330C>A, p.Phe110Leu). Sanger sequencing segregation analysis demonstrated that the ARF3 variant was inherited from the clinically unaffected father, indicating it is unlikely to be the primary causative variant. In contrast, the NR2F1 variant was confirmed to be de novo. The NR2F1 variant was absent in a local control cohort of 500 healthy individuals and in major population databases.

CONCLUSION

The novel NR2F1 variant was classified as likely pathogenic according to ACMG guidelines, confirming the diagnosis of BBSOAS. The ARF3 variant, identified as a secondary finding of uncertain clinical significance, is unlikely to account for the patient's phenotype; however, reporting this variant may facilitate future interpretation of ARF3-associated disease. This is the first reported case of BBSOAS in an Iranian patient.