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Molecular genetics of atrioventricular septal defects

Maslen, Cheryl L.

Current Opinion in Cardiology: May 2004 - Volume 19 - Issue 3 - p 205-210
Molecular Genetics

Purpose of review Atrioventricular septal defects (AVSDs) occur as a clinical feature of several different syndromes, as autosomal dominant defects, and as sporadically occurring malformations. Consequently, it is clear that there is genetic heterogeneity, but until recently, little else was known about the genes involved in the pathogenesis of AVSD. Recent advances in understanding the molecular genetic basis of AVSD are reviewed.

Recent findings Atrioventricular septal defect is most often found associated with trisomy 21 (Down syndrome), but the responsible gene or genes on chromosome 21 have not been identified. However, promising candidates exist, and the current status of those efforts is presented. AVSD not associated with trisomy 21 usually occurs as a sporadic trait with no indication of the genetic basis. The discovery of cysteine rich with EGF domains (CRELD) 1 as the first recognized genetic risk factor for AVSD provides new insight into the genetic basis of sporadically occurring AVSD and the potential for genetic overlap with syndromic AVSD. Mutation of CRELD1 increases susceptibility to AVSD but is not alone sufficient to cause the defect, indicating that AVSD is multigenic. Consequently, additional genes must be identified to understand the genetic basis of AVSD.

Summary Because most nonsyndromic cases of AVSD are sporadic, opportunities for genetic analyses in humans are limited. An abundance of candidate genes have been identified through animal models and biochemical studies, but determining which actually contribute to the pathogenesis of AVSD will be difficult. Painstaking investigation of these candidate genes in humans may ultimately be necessary to identify the remaining genetic risk factors for AVSD.

Department of Medicine, Heart Research Center, Oregon Health and Science University, Portland, Oregon, USA, and the Department of Molecular and Medical Genetics, Heart Research Center, Oregon Health and Science University, Portland, Oregon, USA

Correspondence to Cheryl L. Maslen, PhD, Department of Medicine, L465, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA Tel: 503 494 2011; fax: 503 494 6986; e-mail:

Supported in part by March of Dimes grant 1-FY02-20 and Public Health Service (PHS) grant 5 M01 RR000334.

© 2004 Lippincott Williams & Wilkins, Inc.