Myocilin Mutation N480K Leads to Early Onset Juvenile and Adult-onset Primary Open Angle Glaucoma in Six Generations of a Family

Precis: A pathogenic autosomal dominant MYOC mutation N480K detected in six generations of an Indian family is primarily responsible for JOAG and adult-onset POAG, emphasizing the importance of screening this mutation at a younger age. Purpose: To screen myocilin mutations in a large South Indian family with early-onset Juvenile (JOAG) and adult-onset primary open-angle glaucoma (POAG) Methods: In a large South Indian family with 20 members, eight members diagnosed as JOAG, seven members as POAG, four members as JOAG suspect, and one member as POAG suspect were screened for myocilin ( MYOC) mutations using Sanger sequencing. Whole exome sequencing was performed on clinically suspected JOAG/ POAG individuals. Results: Myocilin gene mutation N480K (c.1440C>G) was detected in 20 family members including proband, of whom 8 were JOAG and 7 were POAG patients, three JOAG suspects and two were unaffected. Among the unaffected carriers, one was less than five years old, and another was 25 years old. The earliest to develop the disease was a ten-year-old child. The penetrance of the mutation was 95% over ten years of age. This family had JOAG/POAG suspects with no N480K MYOC mutation and they were further screened for other mutations using whole-exome sequencing. Polymorphisms CYP1B1 L432V and MYOC R76K were detected in three JOAG/POAG suspects, and among these three, one had another CYP1B1 polymorphic variant R368H. The presence of the CYP1B1 polymorphism along with a MYOC polymorphic variant among the JOAG/POAG suspects needs additional studies to explore their combined role in the onset of glaucoma. Conclusions: This study reveals that MYOC mutation is primarily responsible for JOAG and adult-onset POAG in the Kadaladi family, emphasizing the importance of screening for this mutation at a younger age for early treatment.