A, Axial computed tomography of the head in an affected mother with bilateral middle fossa ACs. B-D, Axial T2 magnetic resonance imaging of the brain in the mother’s 3 affected children with nearly identical bilateral middle fossa ACs. E and F, Axial T2 magnetic resonance imaging of the brain in the mother’s unaffected children.
A, First generation. B, Second generation. Family members I-1, II-1, II-3, and II-5 all exhibit bilateral middle fossa ACs and harbor the maternally inherited 720-kb duplication of Xp22.2, which is not present in the unaffected family members (I-2, I-3, II-2, II-4, and II-6).
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Furey CG, Timberlake AT, Nelson-Williams C, et al. Xp22.2 Chromosomal Duplication in Familial Intracranial Arachnoid Cyst. JAMA Neurol. 2017;74(12):1503–1504. doi:10.1001/jamaneurol.2017.3399
Arachnoid cysts (ACs) are congenital fluid-filled malformations that account for approximately 1% of all intracranial, space-occupying lesions in the central nervous system.1 Despite an estimated prevalence of 1.4%, little is known about the pathogenesis of these presumed developmental anomalies of the arachnoid.2 The coincidence of ACs in known mendelian cystic disorders, such as autosomal dominant polycystic kidney disease,3 along with rare clinical reports of familial AC occurrence,4,5 suggests a genetic basis for the disorder. However, no gene or chromosomal abnormalities have been detected in familial intracranial AC. We present a familial form of isolated intracranial AC showing an X-linked dominant inheritance pattern and characterized by the presence of large, bilateral, and symmetric middle fossa ACs (Figure 1) in 4 family members of a nuclear kindred (Figure 2).
To identify potential rare causal variants in this phenotype, we performed whole-exome sequencing of the 2 most distantly related individuals (II-1 and II-5). We assessed for extremely rare variants (Exome Aggregation Consortium minor allele frequency < 2 × 10−5) and damaging variants (loss-of-function or predicted deleterious per MetaSVM); however, none of the identified variants segregated within all affected individuals, significantly decreasing the likelihood of their pathogenicity in AC formation. Therefore, we performed array comparative genomic hybridization analysis on DNA that was obtained from all the known affected and unaffected family members. Institutional review board approval was granted by Yale University and all participants provided written consent.
The array comparative genomic hybridization results revealed a maternally inherited 720-kb duplication of Xp22.2 that segregated with the disease phenotype in all affected individuals (I-1, II-1, II-3, and II-5) and was not present in any of the unaffected family members (I-2, II-2, II-4, and II-6). The duplicated region (X chromosome: 10 605 711-11 325 964) included the genes MID1, HCCS, AMELX, and ARHGAP6. Breakpoints for the duplication were found within the intron following the first of 9 coding exons of MID1, and within the intron following the first of 13 coding exons of ARHGAP6, thereby causing the interruption and likely loss of function of these 2 genes. By contrast, the entire coding sequence and 5 untranslated regions of HCCS and AMELX were duplicated, suggesting an increased gene dosage at these 2 loci. Interestingly, patients with type 1 Opitz/BBB syndrome (OMIM: 300000) that resulted from deletions or loss-of-function mutations in MID1 exhibited ocular hypertelorism, a phenotype that is shared by all patients that have ACs and harbor MID1 interruption in this article. A substantially larger 9-Mb Xp22.2 duplication that encompassed this region was recently reported in a family who presented with intellectual disability, hypotonia, and developmental delay; however, the presence or absence of AC was not noted.6
To our knowledge, these results present the first plausible genetic locus for intracranial AC. Sequencing a larger cohort of intracranial AC kindreds will be necessary to determine how heterogeneous the genetic contribution to AC may be. Further investigation of the genes in the duplicated Xp22.2 region may help elucidate the factors that contribute to the pathogenesis of intracranial ACs in this family. This could then have diagnostic and therapeutic implications for more common forms of sporadic intracranial ACs.
Corresponding Author: Kristopher T. Kahle, MD, PhD, Yale University School of Medicine, 300 Cedar St, Room S311, New Haven, CT 06519 (email@example.com).
Published Online: October 10, 2017. doi:10.1001/jamaneurol.2017.3399
Author Contributions: Dr Kahle had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Furey, Timberlake, Jackson, Kahle.
Acquisition, analysis, or interpretation of data: Furey, Timberlake, Nelson-Williams, Li, Jackson.
Drafting of the manuscript: Furey, Timberlake, Kahle.
Critical revision of the manuscript for important intellectual content: Furey, Nelson-Williams, Li, Jackson.
Administrative, technical, or material support: Furey, Nelson-Williams, Duran, Li.
Supervision: Jackson, Kahle.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank Brittany Grommisch, BS, Yale University, for her contribution to the array comparative genomic hybridization analysis. She was not compensated for her contribution.
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