» Articles » PMID: 11562466

Genetic Factors Are Major Determinants of Phenotypic Variability in a Mouse Model of the DiGeorge/del22q11 Syndromes

Overview
Specialty Science
Date 2001 Sep 20
PMID 11562466
Citations 26
Authors
Affiliations
Soon will be listed here.
Abstract

The del22q11 syndrome is associated with a highly variable phenotype despite the uniformity of the chromosomal deletion that causes the disease in most patients. Df1/+ mice, which model del22q11, present with reduced penetrance of cardiovascular defects similar to those seen in deleted patients but not with other del22q11-like findings. The reduced penetrance of cardiovascular defects is caused by the ability of mutant embryos to recover from a fourth pharyngeal arch artery growth abnormality that is fully penetrant in early embryos. Here we show that genetic background has a major effect on penetrance of cardiovascular defects by affecting this embryonic recovery process. This effect could not be explained by allelic variation at the haploid locus, and it is likely to be caused by genetic modifiers elsewhere in the genome. We also show that genetic factors control extension of the Df1/+ phenotype to include thymic and parathyroid anomalies, establishing the Df1 mouse as a model for the genetic analysis of three major features of human del22q11 syndrome. We found that in Df1/+ mice, as in human patients, expression of the heart and thymic phenotypes are essentially independent from each other, suggesting that they may be controlled by different genetic modifiers. These data provide a framework for our understanding of phenotypic variability in patients with del22q11 syndrome and the tools for its genetic dissection.

Citing Articles

Beyond genomic studies of congenital heart defects through systematic modelling and phenotyping.

Henderson D, Alqahtani A, Chaudhry B, Cook A, Eley L, Houyel L Dis Model Mech. 2024; 17(11).

PMID: 39575509 PMC: 11603121. DOI: 10.1242/dmm.050913.


Mesenchymal cell replacement corrects thymic hypoplasia in murine models of 22q11.2 deletion syndrome.

Bhalla P, Du Q, Kumar A, Xing C, Moses A, Dozmorov I J Clin Invest. 2022; 132(22).

PMID: 36136514 PMC: 9663160. DOI: 10.1172/JCI160101.


Single cell multi-omic analysis identifies a Tbx1-dependent multilineage primed population in murine cardiopharyngeal mesoderm.

Nomaru H, Liu Y, De Bono C, Righelli D, Cirino A, Wang W Nat Commun. 2021; 12(1):6645.

PMID: 34789765 PMC: 8599455. DOI: 10.1038/s41467-021-26966-6.


Prenatal sonographic and cytogenetic/molecular findings of 22q11.2 microdeletion syndrome in 48 confirmed cases in a single tertiary center.

Sarac Sivrikoz T, Basaran S, Has R, Karaman B, Kalelioglu I, Kirgiz M Arch Gynecol Obstet. 2021; 305(2):323-342.

PMID: 34145474 DOI: 10.1007/s00404-021-06125-4.


Distinct immune trajectories in patients with chromosome 22q11.2 deletion syndrome and immune-mediated diseases.

Crowley T, Campbell I, Liebling E, Lambert M, Katz L, Heimall J J Allergy Clin Immunol. 2021; 149(1):445-450.

PMID: 34144109 PMC: 11853714. DOI: 10.1016/j.jaci.2021.06.007.


References
1.
Lindsay E, Goldberg R, Jurecic V, Morrow B, Carlson C, Kucherlapati R . Velo-cardio-facial syndrome: frequency and extent of 22q11 deletions. Am J Med Genet. 1995; 57(3):514-22. DOI: 10.1002/ajmg.1320570339. View

2.
Goodship J, Cross I, Scambler P, Burn J . Monozygotic twins with chromosome 22q11 deletion and discordant phenotype. J Med Genet. 1995; 32(9):746-8. PMC: 1051680. DOI: 10.1136/jmg.32.9.746. View

3.
Carlson C, Sirotkin H, Pandita R, Goldberg R, McKie J, Wadey R . Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am J Hum Genet. 1997; 61(3):620-9. PMC: 1715959. DOI: 10.1086/515508. View

4.
Ryan A, Goodship J, Wilson D, Philip N, Levy A, Seidel H . Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997; 34(10):798-804. PMC: 1051084. DOI: 10.1136/jmg.34.10.798. View

5.
Puech A, Funke B, Gilbert D, Sirotkin H, Copeland N, Jenkins N . Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization. Proc Natl Acad Sci U S A. 1998; 94(26):14608-13. PMC: 25069. DOI: 10.1073/pnas.94.26.14608. View