TY - JOUR
T1 - Cleft palate, retrognathia and congenital heart disease in velo-cardio-facial syndrome
T2 - A phenotype correlation study
AU - Friedman, Marcia A.
AU - Miletta, Nathanial
AU - Roe, Cheryl
AU - Wang, Dongliang
AU - Morrow, Bernice E.
AU - Kates, Wendy R.
AU - Higgins, Anne Marie
AU - Shprintzen, Robert J.
N1 - Funding Information:
National Institutes of Health ; Grant numbers: 5R01MH064824-03 , 1R01MH065481-01A2 , and 1R01HL084410-01A1 ; Grant sponsors: VCFS International Center , The Joseph and Annette Cooper Fund and the VCFS Research Fund .
PY - 2011/9
Y1 - 2011/9
N2 - Objective: Velo-cardio-facial syndrome (VCFS) is caused by a microdeletion of approximately 40 genes from one copy of chromosome 22. Expression of the syndrome is a variable combination of over 190 phenotypic characteristics. As of yet, little is known about how these phenotypes correlate with one another or whether there are predictable patterns of expression. Two of the most common phenotypic categories, congenital heart disease and cleft palate, have been proposed to have a common genetic relationship to the deleted T-box 1 gene (TBX1). The purpose of this study is to determine if congenital heart disease and cleft palate are correlated in a large cohort of human subjects with VCFS. Methods: This study is a retrospective chart review including 316 Caucasian non-Hispanic subjects with FISH or CGH microarray confirmed chromosome 22q11.2 deletions. All subjects were evaluated by the interdisciplinary team at the Velo-Cardio-Facial Syndrome International Center at Upstate Medical University, Syracuse, NY. Each combination of congenital heart disease, cleft palates, and retrognathia was analyzed by Chi square or Fisher exact test. Results: For all categories of congenital heart disease and cleft palate or retrognathia no significant associations were found, with the exception of submucous cleft palate and retrognathia (nominal p=0.0325) and occult submucous cleft palate and retrognathia (nominal p=0.000013). Conclusions: Congenital heart disease and cleft palate do not appear to be correlated in human subjects with VCFS despite earlier suggestions from animal models. Possible explanations include modification of the effect of TBX1 by genes outside of the 22q11.2 region that may further influence the formation of the palate or heart, or the presence of epigenetic factors that may effect genes within the deleted region, modifying genes elsewhere, or polymorphisms on the normal copy of chromosome 22. Lastly, it is possible that TBX1 plays a role in palate formation in some species, but not in humans. In VCFS, retrognathia is caused by an obtuse angulation of the skull base. It is unknown if the correlation between retrognathia and cleft palate in VCFS indicates a developmental sequence related to skull morphology, or direct gene effects of both anomalies. Much work remains to be done to fully understand the complex relationships between phenotypic characteristics in VCFS.
AB - Objective: Velo-cardio-facial syndrome (VCFS) is caused by a microdeletion of approximately 40 genes from one copy of chromosome 22. Expression of the syndrome is a variable combination of over 190 phenotypic characteristics. As of yet, little is known about how these phenotypes correlate with one another or whether there are predictable patterns of expression. Two of the most common phenotypic categories, congenital heart disease and cleft palate, have been proposed to have a common genetic relationship to the deleted T-box 1 gene (TBX1). The purpose of this study is to determine if congenital heart disease and cleft palate are correlated in a large cohort of human subjects with VCFS. Methods: This study is a retrospective chart review including 316 Caucasian non-Hispanic subjects with FISH or CGH microarray confirmed chromosome 22q11.2 deletions. All subjects were evaluated by the interdisciplinary team at the Velo-Cardio-Facial Syndrome International Center at Upstate Medical University, Syracuse, NY. Each combination of congenital heart disease, cleft palates, and retrognathia was analyzed by Chi square or Fisher exact test. Results: For all categories of congenital heart disease and cleft palate or retrognathia no significant associations were found, with the exception of submucous cleft palate and retrognathia (nominal p=0.0325) and occult submucous cleft palate and retrognathia (nominal p=0.000013). Conclusions: Congenital heart disease and cleft palate do not appear to be correlated in human subjects with VCFS despite earlier suggestions from animal models. Possible explanations include modification of the effect of TBX1 by genes outside of the 22q11.2 region that may further influence the formation of the palate or heart, or the presence of epigenetic factors that may effect genes within the deleted region, modifying genes elsewhere, or polymorphisms on the normal copy of chromosome 22. Lastly, it is possible that TBX1 plays a role in palate formation in some species, but not in humans. In VCFS, retrognathia is caused by an obtuse angulation of the skull base. It is unknown if the correlation between retrognathia and cleft palate in VCFS indicates a developmental sequence related to skull morphology, or direct gene effects of both anomalies. Much work remains to be done to fully understand the complex relationships between phenotypic characteristics in VCFS.
KW - 22q11 Deletion
KW - Aortic arch anomalies
KW - Cleft palate
KW - Conotruncal heart anomalies
KW - Occult submucous cleft palate
KW - Retrognathia
KW - Submucous cleft palate
KW - TBX1
KW - Tetralogy of Fallot
KW - VCFS
KW - Velo-cardio-facial syndrome
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U2 - 10.1016/j.ijporl.2011.06.013
DO - 10.1016/j.ijporl.2011.06.013
M3 - Article
C2 - 21763005
AN - SCOPUS:80051890270
SN - 0165-5876
VL - 75
SP - 1167
EP - 1172
JO - International journal of pediatric otorhinolaryngology
JF - International journal of pediatric otorhinolaryngology
IS - 9
ER -