Identification of a Mutation in MAP7D3 in a Patient with Hydrocephalus and Optic Nerve Edema: Case Report.

INTRODUCTION: Hydrocephalus is an etiologically heterogeneous disorder that may result from acquired insults or monogenic causes. More than 100 genes have been implicated in congenital and early-onset hydrocephalus, but MAP7D3 has not previously been associated with disturbances of cerebrospinal fluid (CSF) circulation. We report an adult patient with obstructive hydrocephalus in whom a novel frameshift variant in MAP7D3 was identified by exome sequencing.

CASE PRESENTATION: A 38-year-old woman presented with a 6-month history of progressive predominantly occipital headache without nausea, vomiting, or diplopia. Neurological examination was normal, whereas neuro-ophthalmic assessment showed unilateral right optic disc swelling consistent with papilledema. Brain MRI demonstrated ventriculomegaly of the lateral and third ventricles with depression of the third-ventricle floor and a partially empty sella, without mass lesion, venous sinus thrombosis, or parenchymal abnormalities. Cine phase-contrast MRI revealed impaired CSF flow through the aqueduct, and there was no clinical or radiological evidence of prior intracranial hemorrhage or central nervous system infection. The patient had no relevant comorbidities, was not taking anticoagulants or antiplatelet agents, and reported no family history of hydrocephalus, macrocephaly, intraventricular hemorrhage, or monogenic neurodevelopmental disorders. Endoscopic third ventriculostomy performed in 04/2022 led to improvement in headache intensity (visual analogue scale 6 to 3) and a decrease in Evans index from 0.40 to 0.36 at 12-month follow-up, with stable ophthalmic findings at approximately 24 months. Research exome sequencing identified a novel frameshift variant in MAP7D3 (c.30_40delinsCGTCTCT; p.Gly11ValfsTer5), absent from population databases and predicted to result in loss of function. Based on ACMG/AMP criteria and the current literature, we classified this variant as a strong candidate variant of uncertain significance.

CONCLUSION: This case illustrates how a carefully phenotyped adult patient with obstructive hydrocephalus and no identifiable acquired cause may benefit from exploratory exome sequencing, which can reveal rare variants in emerging candidate genes such as MAP7D3. Although a causal role for MAP7D3 loss-of-function in hydrocephalus has not yet been established, our findings support further functional studies and highlight the need for cautious interpretation of single-patient variants of uncertain significance.