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

Abstract

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.

Introduction

Hydrocephalus is a radiological and clinical diagnosis characterized by buildup of cerebrospinal fluid (CSF) due to increased production, decreased absorption, or impaired CSF flow. The symptomatology is broad, often manifesting with signs of increased intracranial pressure such as headache, vomiting, nausea, and papilledema. 1 The global prevalence averages around 85 cases per 100,000, with an incidence of 80–120 per 100,000 live births [2–4]. Owing to its heterogeneity and complex pathogenesis, hydrocephalus can be classified in various ways, including primary vs. secondary, congenital vs. acquired, acute vs. chronic, and communicating vs. non-communicating [1, 2].

Most cases are attributed to inflammatory backgrounds, such as posthemorrhagic and postinfectious hydrocephalus. While syndromic forms of primary congenital hydrocephalus are well described, non-syndromic inherited causes are less frequently reported [3, 4]. Over 100 genes have been implicated in hydrocephalus, notably X-linked L1CAM and AP1S2, and autosomal genes such as CCDC88C, MPDZ, TRIM71, SMARCC1, EML1, WDR81, PTCH1, and SHH. This case report suggests that MAP7D3 may also play a role in the pathogenesis of hydrocephalus [5–12]. The MAP7D3 gene encodes a member of the microtubule-associated protein 7 family, promoting the assembly and stability of microtubules. Expression is cell cycle dependent, with highest levels during G1, S, and M phases.

Case Presentation

A 38-year-old woman presented with a 6-month history of progressive predominantly occipital headache without nausea, vomiting, or diplopia. Her past medical history was unremarkable, with no history of central nervous system infection, intracranial hemorrhage, neurosurgical procedures, or head trauma requiring hospital admission. She had no known malignancy, coagulopathy, or chronic inflammatory disease and was not taking anticoagulants or antiplatelet agents. Neurological examination revealed no focal motor or sensory deficit and no signs of meningism. Neuro-ophthalmic examination confirmed unilateral right optic disc swelling consistent with papilledema, whereas the left disc was normal. Visual acuity was 1.0/1.0 with physiological intraocular pressure (Tn/Tn); color testing revealed red desaturation in the right eye; 30° perimetry was normal, and optical coherence tomography showed superior disc swelling in the right eye. Cranial CT and 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 signal abnormality (Fig. 1a–b). Cine phase-contrast MRI demonstrated impaired CSF flow through the aqueduct with no evidence of prior hemorrhage or infection (Fig. 2a–b). The patient reported no family history of hydrocephalus, macrocephaly, intraventricular hemorrhage, or known monogenic neurodevelopmental disorders.

Fig. 1.

Preoperative MRI. a Axial T2-weighted image demonstrating ventriculomegaly of the lateral and third ventricles. b Sagittal T2-weighted image showing third-ventricle floor depression and partially empty sella.

Fig. 2.

Aqueductal phase-contrast MRI. a Time-resolved CSF flow waveform across one cardiac cycle (ms) measured in the cerebral aqueduct. b ROI placement within the aqueduct on magnitude/phase images.

Endoscopic third ventriculostomy was performed in 04/2022. One month postoperatively, headache intensity decreased (visual analogue scale score reduced from 6 to 3). At 12-month follow-up, MRI showed a reduction in Evans index from 0.40 preoperatively to 0.36, and at approximately 24 months the ophthalmic findings remained stable without progression of papilledema (Fig. 3a–b). Given the absence of an identifiable acquired cause of hydrocephalus and emerging evidence for monogenic forms even in apparently sporadic cases [8–10], we offered exome sequencing in a research setting to explore a potential genetic contribution.

Fig. 3.

Postoperative MRI (12-month follow-up after endoscopic third ventriculostomy in 04/2022). a Axial T2-weighted image. b Sagittal T2-weighted image. Evans’ index decreased from 0.40 pre-operatively to 0.36 at 12 months, indicating radiologic improvement.

Methods

Genomic DNA was extracted from whole blood using a MagCore automated isolation station. DNA was enzymatically fragmented and prepared for deep, massively parallel sequencing using the SureSelect Focused Exome design, targeting over 4,800 disease-associated genes. Library preparation and enrichment followed standard protocols, and sequencing was performed on an Illumina NextSeq 500/550 system Table 1.

Table 1.

The main genetic findings summarized

Gene	Variant	Effect	ACMG classification	Notes
MAP7D3	c.30_40delinsCGTCTCT	Frameshift, premature stop codon	Variant of uncertain significance (VUS) — strong candidate	Possible alternative start codon; loss of signal peptide
HTR2A	c.154C>T	Stop gained	Uncertain significance	Role in cerebral cortex development

The in-house bioinformatic pipeline used hs38DH as the reference genome. Variant detection tools included Freebayes, GATK HaplotypeCaller, SPiP, CNVkit, and Manta. Annotation was performed with SnpEff and SnpSift using databases, such as dbNSFP, dbscSNV, ClinVar, gnomAD, CADD, and MSigDB. Variants were filtered for moderate or high impact, low population frequency (<0.01 in Europeans), high CADDphred score (>15), and predicted deleteriousness by at least eight tools, or classified as frameshift/stop gained. Preselected variants were checked in VarSome for ACMG classification and in ClinVar and UniProt for additional information. The CARE Checklist has been completed by the authors for this case report and is provided as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550933).

Results

Thirty-two variants were subjected to further assessment. Two variants were selected as potentially associated with the phenotype:

• HTR2A: A stop-gained variant (c.154C>T; p.Arg52Ter) in exon 2, not previously reported in major databases, was detected in a heterozygous state. The transcript is predicted to undergo nonsense-mediated decay, resulting in loss-of-function. HTR2A encodes a serotonin receptor involved in mood, cognition, and may influence neuronal trafficking relevant to ependymal function and CSF dynamics.

In the genetic differential, HTR2A p.Arg52Ter was deprioritized because human evidence links HTR2A chiefly to neuropsychiatric traits and pharmacogenomics, with no established association with obstructive hydrocephalus or with our patient’s presentation.

• MAP7D3: A distinct haplotype in exon 1 (c.30_40delinsCGTCTCT; p.Gly11ValfsTer5) leads to a frameshift and premature stop codon. This variant is classified as likely pathogenic.

Variant Classification

The MAP7D3 variant was classified as variant of uncertain significance (VUS, strong candidate) according to ACMG/AMP criteria. We did not apply PVS1 beyond supporting, given that a gene-disease mechanism for MAP7D3 in hydrocephalus is not established; PM2 and PP3 are met; PS4 and PP1 are not met in a single case.

• PVS1: predicted null variant (frameshift/stop-gain).

• PM2: absent from population controls.

• PP3: multiple lines of computational evidence supporting a deleterious effect.

Discussion

We refrain from causal claims and classify the MAP7D3 frameshift as a VUS (strong candidate) pending functional validation or additional reports. The patient’s improvement after endoscopic third ventriculostomy – Evans index 0.40→0.36 at 12 months with stabilization of papilledema – is consistent with outcomes in adult obstructive hydrocephalus. Roles of MAP7-family proteins in kinesin-1 activation and microtubule transport provide biological plausibility but do not establish gene-disease causality.

Because a disease mechanism for MAP7D3 in human hydrocephalus has not been established, loss of function cannot be assumed disease-causing; accordingly, we classify the variant as a VUS (strong candidate) under ACMG/AMP. We note the presence of a downstream in-frame alternative start codon (approximately 33 nucleotides downstream) that could, in principle, produce an N-terminally truncated protein. If expressed, such an isoform would lack the extreme N-terminus – an area implicated within the MAP7 family in microtubule interaction and kinesin-1 recruitment – potentially modifying localization or stability. This remains a hypothesis to be tested.

Several independent truncating variants in MAP7D3 have been reported in males with X-linked neurodevelopmental disorders. Nogueira et al. [13] described a hemizygous frameshift mutation p.Thr821ArgfsTer8 (c.2461_2462insGGACA) in an 11-year-old boy with global developmental delay, attention-deficit/hyperactivity disorder, and autism spectrum disorder, without structural brain malformations on MRI. Monies et al. [14] identified a nonsense variant p.Asp304Ter (c.909_910insTA, reported as c.804_805insTA in an alternative transcript) in an 8-year-old boy with global developmental delay in a large diagnostic exome cohort and proposed MAP7D3 as a candidate gene for X-linked neurodevelopmental disorder. More recently, Kharrat et al. [15] reported a familial frameshift mutation p.Thr725MetfsTer2 (c.2174_2177del) in two siblings with severe intellectual disability and autistic traits. In addition, ClinVar lists several MAP7D3 variants classified as of uncertain significance with limited or no phenotype annotation (for example, VCV002220636 and VCV000980872). To our knowledge, no published case links MAP7D3 loss-of-function to hydrocephalus, and we therefore classify our patient’s frameshift as a variant of uncertain significance (strong candidate) rather than a confirmed disease-causing allele.

Adult-onset hydrocephalus is frequently secondary to non-genetic causes such as subarachnoid or intraventricular hemorrhage, central nervous system infection, neoplasia, or complications of neurosurgery. In our patient, these acquired etiologies were not supported by history, imaging, or laboratory work-up. The radiological pattern of long-standing aqueductal obstruction with a partially empty sella, in the absence of an identifiable secondary cause, is compatible with intrinsic or developmental (“idiopathic” obstructive) hydrocephalus. In parallel, exome-wide studies have shown that de novo or inherited variants in more than 100 genes can underlie congenital and early-onset hydrocephalus, including ostensibly sporadic cases without family history [8–10]. On this background, we regarded exome sequencing as a reasonable exploratory approach to search for candidate variants while carefully avoiding over-interpretation of single-patient findings.

Statement of Ethics

This study was performed in accordance with the Declaration of Helsinki. This human study was approved by Ethics Committee of the Military University Hospital Prague – approval: 108/17-62/2022. All adult participants provided written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was supported by the Charles University Research Program Cooperatio – Neurosciences and by the MO1012 program of the Ministry of Defence of the Czech Republic. The funding sources had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author Contributions

Conceptualization: Tomas Moravec and David Netuka. Methodology and data curation: Tomas Moravec and Zdenek Musil. Investigation: Tomas Moravec, Zdenek Musil, and Ondra Petr.Formal analysis: Zdenek Musil and Tomas Moravec. Supervision: David Netuka. Writing – original draft: Tomas Moravec. Writing – review and editing: Tomas Moravec, Zdenek Musil, Ondra Petr, and David Netuka.

Funding Statement

This study was supported by the Charles University Research Program Cooperatio – Neurosciences and by the MO1012 program of the Ministry of Defence of the Czech Republic. The funding sources had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability Statement

The data that support the findings of this study are not publicly available due to privacy and ethical restrictions but are available from the corresponding author (T.M.) upon reasonable request.