TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome.
Holt-Oram syndrome (HOS) is an autosomal dominant heart-hand syndrome characterized by congenital heart disease (CHD) and upper limb deformity, and caused by mutations in the TBX5 gene. To date, the sensitivity of TBX5 genetic testing for HOS has been unclear. We now report mutational analyses of a nongenetically selected population of 54 unrelated individuals who were consecutively referred to our center with a clinical diagnosis of HOS. TBX5 mutational analyses were performed in all individuals, and clinical histories and findings were reviewed for each patient without reference to the genotypes. Twenty-six percent of the complete cohort was shown to have mutations of the TBX5 gene. However, among those subjects for whom clinical review demonstrated that their presentations met strict diagnostic criteria for HOS, TBX5 mutations were identified in 74%. No mutations were identified in those subjects who did not meet these criteria. Thus, these studies validate our clinical diagnostic criteria for HOS including an absolute requirement for preaxial radial ray upper limb malformation. Accordingly, TBX5 genotyping has high sensitivity and specificity for HOS if stringent diagnostic criteria are used in assigning the clinical diagnosis.
McDermott
Deborah A
DA
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Bressan
Michael C
MC
He
Jie
J
Lee
Joseph S
JS
Aftimos
Salim
S
Brueckner
Martina
M
Gilbert
Fred
F
Graham
Gail E
GE
Hannibal
Mark C
MC
Innis
Jeffrey W
JW
Pierpont
Mary Ella
ME
Raas-Rothschild
Annick
A
Shanske
Alan L
AL
Smith
Wendy E
WE
Spencer
Robert H
RH
St John-Sutton
Martin G
MG
van Maldergem
Lionel
L
Waggoner
Darrel J
DJ
Weber
Matthew
M
Basson
Craig T
CT
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D017931:DNA Primers; D005799:Genes, Dominant; D005820:Genetic Testing; D005838:Genotype; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010641:Phenotype; D013577:Syndrome; D020825:T-Box Domain Proteins / Q000235:genetics*
D017931:DNA Primers; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5