The Genetics of Chiari 1 Malformation

Abstract

Chiari malformation type 1 (CM1) is a structural defect that involves the herniation of the cerebellar tonsils through the foramen magnum, causing mild to severe neurological symptoms. Little is known about the molecular and developmental mechanisms leading to its pathogenesis, prompting current efforts to elucidate genetic drivers. Inherited genetic disorders are reported in 2-3% of CM1 patients; however, CM1, including familial forms, is predominantly non-syndromic. Recent work has focused on identifying CM1-asscoiated variants through the study of both familial cases and de novo mutations using exome sequencing. This article aims to review the current understanding of the genetics of CM1. We discuss three broad classes of CM1 based on anatomy and link them with genetic lesions, including posterior fossa-linked, macrocephaly-linked, and connective tissue disorder-linked CM1. Although the genetics of CM1 are only beginning to be understood, we anticipate that additional studies with diverse patient populations, tissue types, and profiling technologies will reveal new insights in the coming years.

Keywords: Chiari malformation; cerebellum; familial aggregation; genetics; posterior fossa; sequencing.

Figure 1

Chiari 1 Malformation (CM1). Sagittal MRI (a) Male, 24 years; CM1 is defined as a displacement of the cerebellar tonsils greater than five millimeters below the basion–opisthion line (red line); (b) Female, 38 years; CM1 with long segment syringomyelia (red arrow).

Figure 2

Overview of key genes linked with CM1 and CM1-associated syndromes. Genes were summarized from studies on individual patients, families, and larger cohort analyses [8,9,12,13,14,15,16,17,18,19,20,22,23,24,25,26,28,37,45,62,66,67,68,69,71,72,73,74,75,76,78,79,80,83,88,93,100,104,105,106,107,108,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163]. Genes linked to syndromes associated with CM1 were included. Black/grey: heterochromatin; red: centromere; blue: variable regions [164].