Genetic Risk for Aortic Aneurysm in Adolescent Idiopathic Scoliosis.
BACKGROUND
Scoliosis is a feature of several genetic disorders that are also associated with aortic aneurysm, including Marfan syndrome, Loeys-Dietz syndrome, and type-IV Ehlers-Danlos syndrome. Life-threatening complications of aortic aneurysm can be decreased through early diagnosis. Genetic screening for mutations in populations at risk, such as patients with adolescent idiopathic scoliosis, may improve recognition of these disorders.


METHODS
The coding regions of five clinically actionable genes associated with scoliosis (COL3A1, FBN1, TGFBR1, TGFBR2, and SMAD3) and aortic aneurysm were sequenced in 343 adolescent idiopathic scoliosis cases. Gene variants that had minor allele frequencies of <0.0001 or were present in human disease mutation databases were identified. Variants were classified as pathogenic, likely pathogenic, or variants of unknown significance.


RESULTS
Pathogenic or likely pathogenic mutations were identified in 0.9% (three) of 343 adolescent idiopathic scoliosis cases. Two patients had pathogenic SMAD3 nonsense mutations consistent with type-III Loeys-Dietz syndrome and one patient had a pathogenic FBN1 mutation with subsequent confirmation of Marfan syndrome. Variants of unknown significance in COL3A1 and FBN1 were identified in 5.0% (seventeen) of 343 adolescent idiopathic scoliosis cases. Six FBN1 variants were previously reported in patients with Marfan syndrome, yet were considered variants of unknown significance based on the level of evidence. Variants of unknown significance occurred most frequently in FBN1 and were associated with greater curve severity, systemic features of Marfan syndrome, and joint hypermobility.


CONCLUSIONS
Clinically actionable pathogenic mutations in genes associated with adolescent idiopathic scoliosis and aortic aneurysm are rare in patients with adolescent idiopathic scoliosis who are not suspected of having these disorders, although variants of unknown significance are relatively common.


CONCLUSIONS
Routine genetic screening of all patients with adolescent idiopathic scoliosis for mutations in clinically actionable aortic aneurysm disease genes is not recommended on the basis of the high frequency of variants of unknown significance. Clinical evaluation and family history should heighten indications for genetic referral and testing.
Departments of Orthopaedic Surgery (G.H., D.M.A., K.H.B., M.K., L.G.L., S.J.L., C.A.G., and M.B.D.), Pediatrics (M.C.W. and C.A.G.), Cardiology (A.C.B.), and Neurology (C.A.G.), Washington University, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address for M.B. Dobbs: dobbsm@wudosis.wustl.edu.
Gabe
G
Haller
Departments of Orthopaedic Surgery (G.H., D.M.A., K.H.B., M.K., L.G.L., S.J.L., C.A.G., and M.B.D.), Pediatrics (M.C.W. and C.A.G.), Cardiology (A.C.B.), and Neurology (C.A.G.), Washington University, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address for M.B. Dobbs: dobbsm@wudosis.wustl.edu.
David M
DM
Alvarado
Departments of Orthopaedic Surgery (G.H., D.M.A., K.H.B., M.K., L.G.L., S.J.L., C.A.G., and M.B.D.), Pediatrics (M.C.W. and C.A.G.), Cardiology (A.C.B.), and Neurology (C.A.G.), Washington University, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address for M.B. Dobbs: dobbsm@wudosis.wustl.edu.
Marcia C
MC
Willing
Departments of Orthopaedic Surgery (G.H., D.M.A., K.H.B., M.K., L.G.L., S.J.L., C.A.G., and M.B.D.), Pediatrics (M.C.W. and C.A.G.), Cardiology (A.C.B.), and Neurology (C.A.G.), Washington University, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address for M.B. Dobbs: dobbsm@wudosis.wustl.edu.
Alan C
AC
Braverman
Departments of Orthopaedic Surgery (G.H., D.M.A., K.H.B., M.K., L.G.L., S.J.L., C.A.G., and M.B.D.), Pediatrics (M.C.W. and C.A.G.), Cardiology (A.C.B.), and Neurology (C.A.G.), Washington University, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address for M.B. Dobbs: dobbsm@wudosis.wustl.edu.
Keith H
KH
Bridwell
Departments of Orthopaedic Surgery (G.H., D.M.A., K.H.B., M.K., L.G.L., S.J.L., C.A.G., and M.B.D.), Pediatrics (M.C.W. and C.A.G.), Cardiology (A.C.B.), and Neurology (C.A.G.), Washington University, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address for M.B. Dobbs: dobbsm@wudosis.wustl.edu.
Michael
M
Kelly
Departments of Orthopaedic Surgery (G.H., D.M.A., K.H.B., M.K., L.G.L., S.J.L., C.A.G., and M.B.D.), Pediatrics (M.C.W. and C.A.G.), Cardiology (A.C.B.), and Neurology (C.A.G.), Washington University, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address for M.B. Dobbs: dobbsm@wudosis.wustl.edu.
Lawrence G
LG
Lenke
Departments of Orthopaedic Surgery (G.H., D.M.A., K.H.B., M.K., L.G.L., S.J.L., C.A.G., and M.B.D.), Pediatrics (M.C.W. and C.A.G.), Cardiology (A.C.B.), and Neurology (C.A.G.), Washington University, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address for M.B. Dobbs: dobbsm@wudosis.wustl.edu.
Scott J
SJ
Luhmann
Departments of Orthopaedic Surgery (G.H., D.M.A., K.H.B., M.K., L.G.L., S.J.L., C.A.G., and M.B.D.), Pediatrics (M.C.W. and C.A.G.), Cardiology (A.C.B.), and Neurology (C.A.G.), Washington University, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address for M.B. Dobbs: dobbsm@wudosis.wustl.edu.
Christina A
CA
Gurnett
Departments of Orthopaedic Surgery (G.H., D.M.A., K.H.B., M.K., L.G.L., S.J.L., C.A.G., and M.B.D.), Pediatrics (M.C.W. and C.A.G.), Cardiology (A.C.B.), and Neurology (C.A.G.), Washington University, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address for M.B. Dobbs: dobbsm@wudosis.wustl.edu.
Matthew B
MB
Dobbs
D000293:Adolescent; D001014:Aortic Aneurysm / Q000175:diagnosis / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics*; D024061:Collagen Type III / Q000235:genetics; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D055947:Loeys-Dietz Syndrome / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D012307:Risk Factors; D012600:Scoliosis / Q000235:genetics*; D051900:Smad3 Protein / Q000235:genetics; D054392:Adipokines
D018389:Codon, Nonsense; D024061:Collagen Type III; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; C439971:COL3A1 protein, human; C000605722:FBN1 protein, human; D054392:Adipokines; C000625841:TGFBR1 protein, human