Molecular genetics of heterotaxy syndromes.
OBJECTIVE
Heterotaxy is a complex set of birth defects in which the normal concordance of asymmetric thoracic and abdominal organs is disturbed. In this review the authors summarize recent research on the etiology of heterotaxy syndromes. Improved understanding of the genetic control of left-right patterning in the early embryo is leading to the identification of candidate genes that may be mutated in heterotaxy patients, and epidemiologic studies are helping to define nongenetic mechanisms of embryopathy.


RESULTS
Several genes have now been implicated in heterotaxy and related isolated congenital heart malformations. These studies indicate that heterotaxy can be caused by single gene mutations. They also demonstrate that there is probably extensive locus heterogeneity. Heterotaxy may be caused by teratogenic exposures, especially maternal diabetes. Isolated congenital heart defects resulting from isomerisms and disturbed looping may be caused by mutations in genes that control early left-right patterning and the earliest steps in cardiogenesis. Genes currently implicated in human heterotaxy include ZIC3, LEFTYA, CRYPTIC, and ACVR2B. Roles for NKX2.5 and CRELDA are suggested by recent case reports.


CONCLUSIONS
Active research on the etiology of heterotaxy is leading to a reformulation of the likely etiologies. Its complex inheritance likely results from a mix of teratogenic and single gene disorders with variable expression and incomplete penetrance.
Belmont
John W
JW
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. jbelmont@bcm.tmc.edu
Mohapatra
Bhagyalaxmi
B
Towbin
Jeffrey A
JA
Ware
Stephanie M
SM
D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics*; D030301:Activin Receptors, Type II / Q000235:genetics; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D055458:Left-Right Determination Factors; D013154:Spleen / Q000002:abnormalities; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
C491268:CFC1 protein, human; C465506:CRELD1 protein, human; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C526161:LEFTY1 protein, human; D055458:Left-Right Determination Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C491595:ZIC3 protein, human; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B