Introduction: Arachnoid cysts (AC) are congenital fluid-filled malformations that account for approximately 1% of all intracranial, space-occupying lesions in the central nervous system . Despite an estimated prevalence of 1.4%, little is known about the pathogenesis of these presumed developmental anomalies of the arachnoid . Co-incidence of arachnoid cysts in known Mendelian cystic disorders such as autosomal dominant polycystic kidney disease [3, 4], along with rare clinical reports of familial AC occurrence [5, 6], suggests a genetic basis for the disorder. However, to date, no gene or chromosomal abnormalities have been detected in familial intracranial AC. Here, we present a familial form of isolated intracranial AC showing autosomal dominant inheritance pattern and characterized by the presence of large, bilateral middle fossa arachnoid cysts [Figure 1] in four different family members of a nuclear kindred [Figure 2].
Methods: To investigate genetic determinants for this phenotype, we performed whole-exome sequencing and a SNP microarray on DNA obtained from all individuals with known bilateral, intracranial arachnoid cysts, as well their unaffected family members.
Results: Combined genetic analysis revealed a maternally-inherited 737kb duplication of Xp22.2 that segregated with the disease phenotype in all tested individuals and was not present in tested unaffected family members.
Conclusions: These results present the first evidence that a genetic mutation underlies the pathogenesis of intracranial AC. Further investigation of the genes in the duplicated Xp22.2 region may help elucidate the factors that contribute to intracranial arachnoid cystogenesis, with diagnostic and potentially therapeutic implications for more common forms of sporadic intracranial AC.
Patient Care: Despite an estimated prevalence of 1 in every 100 births, arachnoid cysts remain understudied and their pathogenesis is largely unknown. Subsequently, our treatments for symptomatic AC remain primitive and predominantly symptomatic, consisting most commonly of surgical cyst fenestration. This research advances our understanding of cellular and genetic drivers of AC formation, and thus, aims to provide opportunities for improved therapeutic targets and non-invasive therapies for affected patients.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the epidemiology and genetic basis of Arachnoid Cyst, 2) Discuss, in small groups, potential causal mechanisms of AC in the context of genes contained within the Xp22.2 region and recognize the potential of genetic study of rare disorders (familial intracranial AC) to elucidate disease-causing pathways underlying more common disease (sporadic intracranial AC).
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