EP262: De novo heterozygous variant in the RAB11B gene presenting with combined cardiac defect and neurodevelopmental disorder: A case report

Abstract

The RAB11B gene (OMIM: 604198) encodes for a GTP-binding protein within the Rab11 GTPase subfamily which is associated with the regulation of exocytic and endocytic pathways. It also plays an essential role in ciliogenesis and vesicular trafficking. Pathogenic variants in RAB11B were first described in five patients in 2017. Subsequently, an additional patient was diagnosed through the Korean Undiagnosed Diseases Program (KUDP) in 2019. Clinical features shared by these patients were predominantly a neurological phenotype, including global developmental delay, epilepsy, hypotonia and gait disturbances. Ophthalmological, musculoskeletal, dermatological, and urological findings were also reported in some patients. MRI brain abnormalities were present in many of these patients and include decrease in white matter volume, patchy white matter signals, cerebellar hypoplasia, ventriculomegaly, thin corpus callosum and atypical partial rhombencephalosynapsis. Here we describe a 6-year-old male with previously unreported clinical findings of congenital heart defect in this disorder. A 5-year-old term male presented with prenatal complications of fetal congenital heart disease, maternal hypertension and maternal gestational diabetes. Fetal echocardiogram identified a tetralogy of Fallot (TOF) and post-natal echocardiogram confirmed the TOF with pulmonary valve atresia and 2 aorto-pulmonary collateral vessels from the descending aorta. Clinical examination at birth revealed bilateral congenital vertical talus but no other dysmorphic features. Fluorescent in-situ hybridization test for 22q11.2 deletion was negative. Chromosomal microarray analysis revealed a 133kb deletion of uncertain significance on chromosome 5q14.3. A head and renal ultrasound was normal at birth. He was diagnosed with congenital nystagmus and microcoria at 6 months of age with low amplitude on visual evoked potential testing. MRI brain revealed an extremely hypoplastic corpus callosum and brainstem, bilateral optic nerve hypoplasia, marked depletion of white matter and delayed myelination. He requires a G-tube for feeding. He has significant global developmental delays and is non-verbal. A clinical trio exome sequencing revealed a de novo, heterozygous, missense variant of unknown significance in the RAB11B gene (c.64 G>A; p.al22Met). This variant has since been re-classified as a pathogenic variant based on the published case series of 6 other individuals with similar phenotype. Given the fact that RAB11B is highly expressed in brain, cardiac and testicular tissue with various roles in ciliogenesis and vesicular trafficking, this patient’s cardiac defect is likely secondary to the pathogenic variant the RAB11B gene. We present this case of a de novo, heterozygous RAB11B variant presenting with a congenital heart defect in addition to a neurodevelopmental phenotype, thus expanding the phenotypic spectrum of this rare disorder.