Novel RAB3GAP1 compound heterozygous mutations in Japanese siblings with Warburg Micro syndrome.

ABSTRACT

BACKGROUND: Warburg Micro syndrome (WARBM) is a rare autosomal recessive disease characterized by postnatal growth retardation, microcephaly, severely delayed motor and intellectual development, microcornea, congenital cataracts, optic atrophy, and hypogonadism. While WARBM is a genetically heterogeneous condition, RAB3GAP1 mutations account for ∼40% of WARBM patients, and 69 different mutations of various types (nonsense, missense, frameshift, and splice site mutations) have been identified to date. PATIENTS Japanese siblings (a 7 years 3 months old male and a 2 years 1month old female) were found to have WARBM-compatible phenotypes. Direct sequencing of RAB3GAP1 revealed novel compound heterozygous mutations in the siblings a paternally inherited missense mutation (c.560G>C; p.Arg187Pro) in exon 7 and a maternally derived nonsense mutation (c.1009C>T; p.Arg337Ter) in exon 12. CONCLUSION: The siblings had WARBM caused by novel mutations in RAB3GAP1. Since molecular diagnosis permits adequate genetic counseling and appropriate management for predicted complications such as adequate sex steroid supplementation therapy for hypogonadism, in addition to standard supportive therapies for developmental delay and visual dysfunction, we recommend molecular studies for this rare condition.