Based on a survey of case reports both maternal and paternal uniparental disomy (UPD) for chromosome 14 have different and specific phenotypes. This suggests that there are imprinted genes on chromosome 14. Features that have been reported in association with maternal UPD 14 include: Hypotonia, dysmorphic facial features, mental retardation/developmental delay, early puberty, prenatal and postnatal growth delay and hypercholesterolemia. Features that have been reported in association with paternal UPD 14 include: Blepharophimosis and other dysmorphic facial features, mental retardation/developmental delay, laryngomalacia, small thorax, joint contractures, short long bones, congenital heart disease and prenatal growth delay. We believe that imprinted genes are located on chromosome 14 and that overexpression or absence of expression of these imprinted genes causes the different and distinct phenotypic features associated with maternal and paternal uniparental disomy for chromosome 14. In order to prove this hypothesis, local IRB approval and GCRC support has been obtained for careful and systematic characterization of the clinical features associated with both maternal and paternal UPD 14. We will recruit individuals with both maternal and paternal UPD 14 and enroll them in our GCRC protocol. Studies will include: Clinical evaluation, digital imaging or photography of relevant physical features and imaging anthropometrics of each patient; sex and growth hormone levels and pituitary function tests; brain imaging studies; serum cholesterol, triglyceride and total plasma sterol levels; ophthalmologic exam; laryngoscopy; echocardiography; complete skeletal survey; IQ and developmental testing; peripheral blood UPD studies and establishment of a fibroblast cell line. We will compare both groups with one another and with the general population to prove that maternal and paternal UPD 14 are distinct genetic disorders with specific phenotypes. The study of human disorders, such as Angelman, Prader-Willi,. Beckwith-Wiedemann and Russell-Silver syndromes, has led both to the identification of imprinted genes and to an understanding of the effects of those imprinted genes. To date, there has been no systematic characterization of the phenotypic features of maternal and paternal UPD 14. Through careful and systematic characterization of the features of UPD 14 we will test the hypothesis that maternal and paternal UPD 14 are distinct and different disorders. We will establish the frequency of phenotypic features, which will allow clinicians to provide prognostic information and treatment guidelines for UPD 14. This phenotype delineation will lay the foundation for understanding the effects and pathogenesis of imprinted genes on chromosome 14.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HD040843-04
Application #
6760205
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Oster-Granite, Mary Lou
Project Start
2001-08-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
4
Fiscal Year
2004
Total Cost
$121,008
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Rosa, Alberto L; Wu, Yuan-Qing; Kwabi-Addo, Bernard et al. (2005) Allele-specific methylation of a functional CTCF binding site upstream of MEG3 in the human imprinted domain of 14q32. Chromosome Res 13:809-18
Murphy, S K; Wylie, A A; Coveler, K J et al. (2003) Epigenetic detection of human chromosome 14 uniparental disomy. Hum Mutat 22:92-7
Coveler, K J; Sutton, V R; Knox-DuBois, C et al. (2003) Comprehensive microsatellite marker analysis contradicts previous report of segmental maternal heterodisomy of chromosome 14. J Med Genet 40:e26
Sutton, V Reid; Coveler, Karen J; Lalani, Seema R et al. (2002) Subtelomeric FISH uncovers trisomy 14q32: lessons for imprinted regions, cryptic rearrangements and variant acrocentric short arms. Am J Med Genet 112:23-7
McGowan, Kathryn D; Weiser, Joseph J; Horwitz, Juli et al. (2002) The importance of investigating for uniparental disomy in prenatally identified balanced acrocentric rearrangements. Prenat Diagn 22:141-3
Coveler, Karen J; Yang, Sam P; Sutton, ReidV et al. (2002) A case of segmental paternal isodisomy of chromosome 14. Hum Genet 110:251-6