P475: Genome sequencing reveals a novel, homozygous in-frame deletion, c.367_375del, in CYP2U1 in twin sisters with early onset spastic paraplegia

Outcome and Follow-Up: The patient has been followed by genetics and was most recently seen at 2 years of age.She has global developmental delays.Though she has required formula supplementation and close nutritional monitoring, growth has been overall typical (parameters at three years of age on WHO girls, 2-5 yr curves: head circumference 84%ile, height 5-17%ile, weight 43%ile).Discussion: TUBA1A-associated tubulinopathies are characterized by abnormal neuronal migration resulting in malformations of the brain.Although ventriculomegaly is not rare, it is usually due to cortical atrophy in this condition.Two patients with different variants (c.656T>C, c.652G>A) have aqueductal stenosis, however these changes are located in the intermediate domain, whereas the variant for the present case is in the N-terminal domain.The present case, along with a previously documented fetus carrying the same TUBA1A variant, developed hydrocephalus due to aqueductal stenosis.This case suggests that this specific variant p.Ile93Thr may be associated with aqueductal stenosis leading to hydrocephalus. Conclusion:The present findings suggest that a specific variant in TUBA1A (p.Ile93Thr) may be associated with aqueductal stenosis leading to hydrocephalus, expanding the phenotypic diversity of TUBA1A-associated tubulinopathies.Further study of similar cases will help elucidate whether specific TUBA1A variants predispose to aqueductal stenosis and whether this can inform management.Introduction: Heterozygous pathogenic variants in TUBA1A are associated with a type of tubulinopathy.Tubulinopathies are congenital disorders of brain development featuring alterations in neuronal migration due to microtubule dysfunction.They exhibit varying degrees of lissencephaly, dysgenesis of the corpus callosum, cerebellar dysplasia, asymmetric hypoplasia of the brainstem, and dysgenesis of the basal ganglia.Although ventriculomegaly has been reported in tubulinopathies, this is generally secondary to cortical malformations.Here we document a case of TUBA1A-related tubulinopathy with aqueductal stenosis leading to obstructive hydrocephalus that has significant phenotypic overlap with a previously described fetal case carrying the same variant.Case Presentation: A newborn female was evaluated for prenatally identified ventriculomegaly and cerebellar hypoplasia.Postnatal brain MRI was notable for marked supratentorial ventriculomegaly due to aqueductal stenosis, absent septum pellucidum, agenesis of the corpus callosum, hypoplasia of the brainstem and cerebellum, and non-visualized olfactory bulbs.Physical exam was notable for low set and posteriorly rotated ears, downturned corners of the mouth, small chin, and sacral dimple.Spine MRI and evaluation for possible hypopituitarism given her midline defects were reassuring.Diagnostic Workup: Molecular panel testing identified a heterozygous variant of uncertain significance in the TUBA1A gene (c.278T>C,p.Ile93Thr), which was classified as likely pathogenic after it was confirmed to be de novo in the proband.This particular variant is located in a region regarded as a mutational hotspot for TUBA1A, and given the patient's phenotypic overlap, this finding was considered to be diagnostic for a TUBA1A-associated tubulinopathy.A literature review identified an abstract reporting a case in France of a fetus heterozygous for the same variant, which exhibited triventricular dilation from aqueductal stenosis, corpus callosum agenesis, dysmorphic cerebellum, and absent olfactory bulbs; the pregnancy was ultimately medically terminated.