Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts.

Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10-33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease.

Familial and syndromic forms of arachnoid cyst implicate genetic factors in disease pathogenesis.

Arachnoid cysts (ACs) are the most common space-occupying lesions in the human brain and present significant challenges for clinical management. While most cases of ACs are sporadic, nearly 40 familial forms have been reported. Moreover, ACs are seen with increased frequency in multiple Mendelian syndromes, including Chudley-McCullough syndrome, acrocallosal syndrome, and autosomal recessive primary ciliary dyskinesia. These findings suggest that genetic factors contribute to AC pathogenesis. However, traditional linkage and segregation approaches have been limited in their ability to identify causative genes for ACs because the disease is genetically heterogeneous and often presents asymptomatically and sporadically. Here, we comprehensively review theories of AC pathogenesis, the genetic evidence for AC formation, and discuss a different approach to AC genomics that could help elucidate this perplexing lesion and shed light on the associated neurodevelopmental phenotypes seen in a significant subset of these patients.

PKD1-Associated Arachnoid Cysts in Autosomal Dominant Polycystic Kidney Disease.

OBJECTIVES: the prevalence of intracranial aneurysms and arachnoid cysts is higher in patients with autosomal dominant polycystic kidney disease (ADPKD) than in the general population. A genotype correlation was reported for intracranial aneurysms, but it is unclear for arachnoid cysts. Therefore, the genotype correlation with intracranial aneurysms and arachnoid cysts was investigated in ADPKD. MATERIALS AND METHODS: intracranial aneurysms and arachnoid cysts were screened by magnetic resonance imaging (MRI), and PKD genotypes were examined using next-generation sequencing for 169 patients with ADPKD. RESULTS: PKD1-, PKD2- and no-mutation were identified in 137, 24 and 8 patients, respectively. Intracranial aneurysms and arachnoid cysts were found in 34 and 25 patients, respectively, with no significant difference in frequency. Genotype, sex, estimated glomerular filtration rate and age at ADPKD diagnosis significantly affected the age at brain MRI. The proportional hazard risk analyzed using the age at brain MRI adjusted by these four variables was 5.0-times higher in the PKD1 group than in the PKD2 group for arachnoid cysts (P = 0.0357), but it was not different for intracranial aneurysms (P = 0.1605). Arachnoid cysts were diagnosed earlier in the PKD1 group than in the PKD2 group (54.8 vs 67.7 years, P = 0.0231), but no difference was found for intracranial aneurysms (P = 0.4738) by Kaplan-Meier analysis. CONCLUSIONS: this study demonstrated the correlation between arachnoid cysts and PKD1 mutation. The reported association of arachnoid cysts with advanced renal disease may be due to the common correlation of these factors with PKD1 mutation.

Deleterious fibronectin type III-related gene variants may induce a spinal extradural arachnoid cyst: an exome sequencing study of identical twin cases.

PURPOSE: Despite numerous studies, the etiology of spinal extradural arachnoid cyst (SEDAC), a lesion associated with neurological symptoms, remains unknown. In this genomic twin study, we investigated the genetic etiology of SEDACs. METHODS: The subjects were identical twins who developed notably similar SEDACs at the same vertebral level. Accordingly, we performed whole-exome sequencing analyses of genomic material from the twins and their parents using a next-generation sequencer. Additionally, we determined their detailed family history and analyzed the family pedigree. RESULTS: The pedigree analysis suggested the potential presence of SEDACs in certain family members, indicating a genetic disease. Sequenced data were analyzed and filtered using a purpose-built algorithm, leading to the identification of 155 novel single-nucleotide polymorphisms (SNPs), of which 118 encoded missense or nonsense variants. A functional analysis of the proteins encoded by these SNP alleles revealed strong enrichment for the fibronectin type III (FN3) protein domain (q = 0.00576). Specifically, the data indicated that a missense variant affecting the FN3 protein domain of fibronectin 1 (FN1, p.P969S) can be the causal mutation underlying the SEDACs. CONCLUSION: The data suggest that deleterious mutations in fibronectin-related genes may cause SEDACs. In particular, it was suspected that a variant of FN1 may be the cause of the SEDACs in the twin cases studied herein. Detailed studies with a larger number of cases are needed.

Chudley-McCullough Syndrome: A Recognizable Clinical Entity Characterized by Deafness and Typical Brain Malformations.

Chudley-McCullough syndrome, a rare autosomal recessive disorder due to pathogenic variants in the GPSM2 (G-protein signaling modulator 2) gene, is characterized by early-onset sensorineural deafness and a typical combination of brain malformations, including ventriculomegaly, (partial) agenesis of the corpus callosum, cerebellar dysplasia, arachnoid cysts, frontal subcortical heterotopia, and midline polymicrogyria. When hearing loss is managed early, most patients have minor or no impairment of motor and cognitive development, despite the presence of brain malformations. We report 2 cases of Chudley-McCullough syndrome, one presenting with congenital deafness and normal development except for speech delay and one presenting prenatally with ventriculomegaly and an atypical postnatal course characterized by epileptic spasms, deafness, and moderate intellectual disability. These highlight the challenges faced by clinicians when predicting prognosis based on pre- or postnatal imaging of brain malformations. We have also reviewed the phenotype and genotype of previous published cases to better understand Chudley-McCullough syndrome.

Low-grade developmental and epilepsy associated brain tumors: a critical update 2020.

Brain tumors represent the second most frequent etiology in patients with focal seizure onset before 18 years of age and submitted to epilepsy surgery. Hence, this category of brain tumors, herein defined as low-grade, developmental, epilepsy-associated brain tumors (LEAT) is different from those frequently encountered in adults as (A): 77% of LEAT occur in the temporal lobe; (B): the vast majority of LEAT are of low malignancy and classified as WHO I°; (C): LEAT are often composed of mixed glial and neuronal cell components and present with variable growth patterns including small cysts or nodules; (D): LEAT do not share common gene driving mutations, such as IDH1 or 1p/19q co-deletions. Characteristic entities comprise the ganglioglioma (GG), the dysembryoplastic neuroepithelial tumor (DNT), the angiocentric glioma (AG), the isomorphic diffuse glioma (IDG) and the papillary glio-neuronal tumor (PGNT), representing 73.2% of 1680 tumors collected in a large German series of 6747 patients submitted to epilepsy surgery. In the realm of exciting discoveries of genetic drivers of brain tumors new genes have been also reported for LEAT. BRAF V600E mutations were linked to GG with CD34 expression, FGFR1 mutations to DNT, MYB alterations to AG and also IDG and PRKCA fusions to PGNT, suggesting the possibility to also develop a genetically driven tumor classification scheme for LEAT. Rare availability of LEAT in a single center is a challenging obstacle, however, to systematically unravel the neurobiological nature and clinical behavior of LEAT. Other challenges in need of clarification include malignant tumor progression of LEAT entities, seizure relapse in patients following bulk tumor resection and the controversial issue of associated focal cortical dysplasia as additional pathomechanism. In order to advance our understanding and promote reliable diagnostic work-up of LEAT, we recommend, therefore, international collaboration to achieve our goals.

Association between ELP4 rs986527 polymorphism and the occurrence and development of intracranial arachnoid cyst.

OBJECTIVE: The association between ELP4 rs986527 polymorphism and the occurrence and development of intracranial arachnoid cyst was studied in this paper. METHODS: Eighty-five patients diagnosed with intracranial arachnoid cysts by cerebral computed tomography scan were selected. Sixty-three healthy volunteers for medical examination in hospitals served as controls. The cognition, depressive symptoms, and the likelihood of headache, dizziness, head trauma history, dementia, depression, and epilepsy were assessed. ELP4 genotypes and its allele frequency were determined by PCR, endonuclease restriction analysis, and gel electrophoresis. RESULTS: ELP4 rs986527 had three genotypes: TT, TC, and CC. The intracranial arachnoid cyst group showed no statistically significant difference in genotype frequencies compared with healthy controls. There was no significant correlation between ELP4 rs986527 polymorphism and location of intracranial arachnoid cyst. TC and C genotype frequencies were associated with a higher incidence of clinical symptoms than TT genotype frequencies, and C allele frequencies were associated with a significantly higher incidence of clinical symptoms compared with T allele frequencies. There was no significant difference in TNF-α and IL-1ß levels between TT/TC/CC genotypes before treatment. After treatment, the levels of TNF-α and IL-1ß were significantly decreased in different genotypes, and the decrease in CC was the greatest. The frequency of TT and TC genotypes was higher than that of CC genotypes. CONCLUSION: ELP4 rs986527 polymorphism affected the incidence of clinical symptoms and the levels of TNF-α and IL-1ß in patients with intracranial arachnoid cysts.

Case report: a novel mutation in ZIC2 in an infant with microcephaly, holoprosencephaly, and arachnoid cyst.

RATIONALE: Holoprosencephaly (HPE) is a severe congenital brain malformation resulting from failed or incomplete forebrain division in early pregnancy. PATIENT CONCERNS: In this study, we reported a 9-month old infant girl with mild microcephaly, semilobor HPE, and arachnoid cyst. DIAGNOSES: Potential genetic defects were screened directly using trio-case whole exome sequencing (WES) rather than traditional karyotype, microarray, and Sanger sequencing of select genes. OUTCOMES: A previous unpublished de novo missense mutation (c.1069C >G, p.H357D) in the 3rd zinc finger domain (ZFD3) of the ZIC2 gene was identified in the affected individual, but not in the parents. Sanger sequencing using specific primers verified the mutation. Extensive bioinformatics analysis confirmed the pathogenicity of this extremely rare mutation. Phenotype-genotype analysis revealed significant correlation between the 3rd zinc-finger domain with semilobor HPE. LESSONS: These findings expanded the spectrum of the ZIC2 gene mutations and associated clinical manifestations, which is the first identification of a mutated ZIC2 gene in a Han infant girl with mild microcephaly, semilobor HPE, and arachnoid cyst.

Familial arachnoid cysts: a review of 35 families.

INTRODUCTION: Arachnoid cysts are commonly considered congenital lesions, but this has not been proven. With the development of neuroimaging and DNA testing technology, more cases of familial arachnoid cysts have been reported. Herein, we review such cases. MATERIALS AND METHODS: The PubMed, Embase, and Web of Science databases were searched for case reports of arachnoid cysts published through April 2018. Case reports were included only if two or more related patients were diagnosed with an arachnoid cyst by neuroimaging or intraoperatively. For each report, the following data were extracted: first author name, date of publication, number of families, number of patients, location of the arachnoid cysts, patient age, patient sex, and genetic mutations and associated disease. RESULTS: Our searches identified 33 case reports involving 35 families and 115 patients. The locations of arachnoid cysts were similar in 25 of the 35 families. Spinal extradural arachnoid cysts were reported most often, followed by arachnoid cysts in the middle fossa and posterior fossa. A left-sided predominance was noticed for arachnoid cysts of the middle fossa. Mutation of the FOXC2 gene was reported most often, and arachnoid cysts may be associated with mutations on chromosome 16. CONCLUSIONS: Although the origin of arachnoid cysts is believed to have a genetic component by some researchers, the genes associated with arachnoid cysts remain unknown. Unfortunately, the evidence remains insufficient.

Familial intracranial arachnoid cysts with a missense mutation (c.2576C > T) in RERE: A case report.

RATIONALE: Arachnoid cysts are relatively common intracranial space-occupying lesions; nevertheless, familial intracranial arachnoid cysts are extremely rare, with only a few cases having been reported. PATIENT CONCERNS: The proband was a 7-year-old girl who had experienced generalized tonic-clonic seizures 5 times in the 8 days prior to admission. Nine months later, her 6-year-old younger female cousin presented to us with a 3-day history of headache. DIAGNOSES: Brain magnetic resonance imaging (MRI) confirmed the diagnosis of arachnoid cyst for both of the girls. INTERVENTIONS: A cyst-peritoneal shunting and cyst fenestration were performed for the 7-year-old girl and her cousin separately. Sanger sequencing revealed a heterozygous missense mutation (c.2576C > T) in the Arginine-Glutamic Acid Dipeptide Repeats gene (RERE). OUTCOMES: The outcome was favorable and the follow-up was uneventful. LESSONS: We hypothesize that the mutation in RERE may be associated with the pathogenesis of familial intracranial arachnoid cysts.

A screening method to distinguish syndromic from sporadic spinal extradural arachnoid cyst.

BACKGROUND: Spinal extradural arachnoid cyst (SEDAC) is a cystic lesion that protrudes into the epidural space from a small dural defect. Early diagnosis of SEDAC is important because its expansion causes neurological damage. Two types of SEDAC, syndromic and sporadic, are present. Syndromic SEDAC is inherited as a part of lymphedema-distichiasis syndrome caused by mutations in the FOXC2 gene; however, it is often mistaken as sporadic because of low penetrance. It is not reasonable to conduct a genetic testing for all SEDAC patients and their family members. The aim of this study is to establish an effective screening method to distinguish syndromic SEDAC from sporadic SEDAC. METHODS: We performed a retrospective review of medical records and imaging studies of 29 subjects who were diagnosed with SEDAC. Clinical features, family history and magnetic resonance imaging (MRI) were analyzed. Mutations in FOXC2 were examined by Sanger-sequencing of the entire coding region of the genes. SEDAC having a mutation in FOXC2 gene was defined with syndromic SEDAC. RESULTS: Eleven subjects had a heterozygous mutation in FOXC2. They were all familial and hence syndromic SEDAC. Only one proband had known family history of SEDAC at diagnosis. MRI findings and physical examinations, especially eye and leg examinations, were quite useful to screen syndromic SEDAC. Physical examination often showed accompanying lymphedema and distichiasis in syndromic SEDAC. Syndromic SEDAC tended to have multiple cysts out of the thoracolumbar area. CONCLUSIONS: We established an effective screening method based on physical examinations and MRI findings.

Defective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.

Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gαi3, a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gαi3, myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gαi3 in the regulation of actin dynamics in epithelial and neuronal tissues.

A novel nonsense GPSM2 mutation in a Yemeni family underlying Chudley-McCullough syndrome.

Mutations in the G Protein Signaling Modulator 2 (GPSM2) cause the autosomal recessive disorder Chudley-McCullough syndrome (CMS), which is characterized by profound congenital sensorineural hearing loss with various abnormalities in the brain. This phenotypic combination is attributed to the role played by GPSM2 in the establishment of planar polarity and spindle orientation during asymmetric cell divisions. Here we present two brothers from a Yemeni family who were diagnosed clinically with CMS then tested for GPSM2 mutations using Sanger sequencing. Consequent to sequencing, in silico tools (such as CADD) were utilized to assess functional consequences. Molecular analysis revealed a previously unreported homozygous mutation in GPSM2 in both brothers (c.1055C > A) leading to a truncating protein change; (p.Ser352*). This mutation is predicted to abolish all four GoLoco domains in GPSM2 and this explains the bioinformatic prediction for this mutation to be functionally damaging. Full clinical and molecular accounts of the novel mutation are provided in this paper.

Chudley-McCullough Syndrome: Variable Clinical Picture in Twins with a Novel GPSM2 Mutation.

Chudley-McCullough syndrome (CMS) is a rare autosomal recessive disorder characterized by sensorineural deafness, agenesis of the corpus callosum, frontal polymicrogyria, interhemispheric cyst, and ventricular enlargement. CMS is caused by mutations in the GPSM2 gene, but until now no more than eight different mutations are on record. We describe two dizygotic twins with a novel homozygous loss-of-function mutation (c.1093C > T; p.Arg365*). While one child developed hydrocephalus-prompting shunt implantation immediately after birth, the other sibling did not. The combination of sensorineural hearing loss and partial agenesis of the corpus callosum is a highly recognizable clinico-radiological entity that should prompt mutational analysis of the GPSM2 gene.

Outcome of Fetuses with Supratentorial Extra-Axial Intracranial Cysts: A Systematic Review.

OBJECTIVE: To investigate the incidence of associated anomalies, aneuploidy, cyst progression, need for surgery and neurodevelopmental outcome in fetuses with extra-axial supratentorial intracranial cysts. DATA SOURCES: Medline, Embase and CINAHL databases were searched and the following outcomes analyzed: associated central nervous system (CNS) and extra-CNS anomalies detected at the scan, chromosomal anomalies, additional CNS anomalies detected only at prenatal MRI, additional CNS anomalies detected only after birth, cyst progression in utero, neurological outcome and need for surgery. Two authors reviewed all abstracts independently. Results were reported as proportions, and between-study heterogeneity was explored using the I² statistic; fixed or random effect models were used accordingly. RESULTS: Ten studies involving 47 fetuses were included in the meta-analysis. Arachnoid cysts (n = 24) had associated CNS anomalies and extra-CNS in 73% (95% CI 56-88) and 14% (95% CI 4-29), respectively. The most common associated anomalies were ventriculomegaly and callosal abnormalities. Chromosomal abnormalities were present in 6% (95% CI 0-30), but fetuses with isolated cysts were always euploid (0/7; 95% CI 0-29). Fetal MRI and postnatal examination identified 5 additional cases (21%, 95% CI 1-57). Cavum veli interpositi (CVI) cysts had associated CNS and extra-CNS anomalies in 31% (95% CI 13-52) and 6% (95% CI 0-29), respectively. No chromosomal or callosal anomalies were found in these cases. In isolated CVI cysts, no cases of associated anomalies were detected postnatally. Intrauterine regression occurred in 23% of CVI cysts and in none of the arachnoid cysts. In children with arachnoid cyst, the occurrence of hydrocephaly and mass effect on the adjacent structures were observed in 23.9% (95% CI 8.3-4.4) and 26.8% (95% CI 4.0-60.1), respectively. None of the cases included had abnormal motor outcome or intelligence. The rate of surgery was 34.7% (95% CI 16.0-56.4). None of the children with a prenatal diagnosis of isolated CVI cyst experienced any of the adverse outcomes explored in this review. CONCLUSIONS: Extra-axial supratentorial cysts diagnosed in utero are frequently associated with other neural and extra-neural anomalies. However, this may represent the consequence of a selection bias. Interhemispheric arachnoid cysts were typically associated with callosal anomalies. Abnormal karyotypes were seen only in fetuses with multiple anomalies. Arachnoid, but not CVI, cysts frequently increased in size throughout gestation.

Identification of HOXD4 Mutations in Spinal Extradural Arachnoid Cyst.

Spinal extradural arachnoid cyst (SEDAC) is a cyst in the spinal canal that protrudes into the epidural space from a defect in the dura mater and leads to neurological disturbances. We previously showed that familial SEDAC is caused by FOXC2 mutation; however, the causal gene of sporadic SEDAC has not been identified. To identify the causal gene of sporadic SEDAC, we performed whole exome sequencing for 12 subjects with sporadic SEDAC and identified heterozygous HOXD4 loss-of-function mutations in three subjects. HOXD4 haplo-insufficiency causes SEDAC and a transcriptional network containing HOXD4 and FOXC2 is involved in the development of the dura mater and the etiology of SEDAC.

Arachnoid cysts in tuberous sclerosis complex.

OBJECTIVE: Some clinical findings in tuberous sclerosis complex (TSC), such as hypomelanotic macules or angiofibromas are related to problems in development of the neural crest, which is also the origin of cranial leptomeninges. Arachnoid cysts have been reported in two TSC patients to date. The purpose of this study was to assess the prevalence and characteristics of arachnoid cysts in a large cohort of TSC. MATERIALS AND METHOD: We performed a review of brain MRIs of 220 TSC patients searching for arachnoid cysts. RESULTS: Arachnoid cysts were found in 12 (5.5%) (general population: 0.5%), including ten males (83.3%). Four patients (33.3%) had also autosomal dominant polycystic kidney disease (ADPKD) due to a contiguous deletion of the TSC2-PKD1 genes. Three patients (25%) had two or more arachnoid cysts, of whom two also had ADPKD. One patient with an arachnoid cyst did not have tubers, subependymal nodules or white matter migration lines. CONCLUSION: Our study suggests that arachnoid cysts are part of the clinical spectrum of TSC and may be also present in TSC patients without other typical TSC brain lesions.