Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms

Abstract

A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation (P < 0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty-nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1, TGFBR2, and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable. In these families, routine cerebral and aortic imaging for at risk members could prevent cerebral hemorrhages and aortic dissections.

Figure 1

Families with multiple members with thoracic aortic aneurysms and dissections (TAAD) with one or more members with saccular intracranial aneurysms (ICAs). a. Pedigrees with multiple individuals with TAAD and at least two members at risk for inheriting the TAAD gene who had ICAs (TAA288 and TAA549), and AAAs in addition to ICAs (TAA062 and TAA395). b. Pedigrees with an inheritance pattern of TAAD and ICAs similar to family TAA288 and TAA549. c. Pedigrees with TAAD, ICAs and AAAs inherited in an autosomal dominant manner. d. Pedigrees with many members with TAAD and only one member with ICAs. e. Pedigrees with TAAD and ICAs that do not follow a Mendelian pattern for inheritance of a combined TAAD and ICA predisposition gene. Squares represent males, circles represent females and triangles represent miscarriages. A line through the symbol represents a deceased person. TAAD means thoracic aortic aneurysm/dissection, ICA means intracranial aneurysm, and AAA means abdominal aortic aneurysm. “d” indicates age at death, “dx” indicates age at diagnosis. The asterisks (*) on a pedigree symbol indicates that the cause of death was verified by medical records, autopsy report or death certificate. The legend explains the designations for the other symbols used.

Figure 1

Families with multiple members with thoracic aortic aneurysms and dissections (TAAD) with one or more members with saccular intracranial aneurysms (ICAs). a. Pedigrees with multiple individuals with TAAD and at least two members at risk for inheriting the TAAD gene who had ICAs (TAA288 and TAA549), and AAAs in addition to ICAs (TAA062 and TAA395). b. Pedigrees with an inheritance pattern of TAAD and ICAs similar to family TAA288 and TAA549. c. Pedigrees with TAAD, ICAs and AAAs inherited in an autosomal dominant manner. d. Pedigrees with many members with TAAD and only one member with ICAs. e. Pedigrees with TAAD and ICAs that do not follow a Mendelian pattern for inheritance of a combined TAAD and ICA predisposition gene. Squares represent males, circles represent females and triangles represent miscarriages. A line through the symbol represents a deceased person. TAAD means thoracic aortic aneurysm/dissection, ICA means intracranial aneurysm, and AAA means abdominal aortic aneurysm. “d” indicates age at death, “dx” indicates age at diagnosis. The asterisks (*) on a pedigree symbol indicates that the cause of death was verified by medical records, autopsy report or death certificate. The legend explains the designations for the other symbols used.