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CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 3; CHTD3

CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 3; CHTD3

Alternative titles; symbolsCONGENITAL HEART DEFECTS, MULTIPLE TYPES, WITH CARDIAC RHYTHM AND CONDUCTION DISTURBANCESCytogenetic location: 9q31.1 Genomic coor...

Alternative titles; symbols

  • CONGENITAL HEART DEFECTS, MULTIPLE TYPES, WITH CARDIAC RHYTHM AND CONDUCTION DISTURBANCES

Cytogenetic location: 9q31.1 Genomic coordinates (GRCh38): 9:99,800,000-105,400,000

▼ Description
Multiple types of congenital heart defects-3 (CHTD3) is an autosomal dominant condition characterized by various types of congenital heart defects and low atrial rhythm (van de Meerakker et al., 2011).

For a general phenotypic description and a discussion of genetic heterogeneity of multiple types of congenital heart defects, see 306955.

▼ Clinical Features
Van de Meerakker et al. (2011) studied a 4-generation family in which 13 individuals had various types of congenital cardiac defects and/or cardiac arrhythmias and/or conduction disturbances. All affected individuals exhibited 'low atrial rhythm' on electrocardiography (ECG), consisting of a p-wave frontal axis oriented in a superior direction, reflecting atrial pacemaker tissue located in the lower part of the atrium. The proband was a 33-year-old woman who was diagnosed in the first year of life with an incomplete atrioventricular septal defect (AVSD) consisting of a common atrium and a small communication between the left and right ventricles. During surgical correction of those defects at age 2.5 years, the presence of bilateral left atria with bilateral left atrial appendages was observed. At 33 years of age, she was asymptomatic. MRI demonstrated normal situs of the lungs and abdominal organs, and ECG consistently showed left QRS axis deviation and low atrial rhythm. Her asymptomatic sister and father both had normal echocardiography but low atrial rhythm on ECG; the father had bradycardia. The paternal aunt, who had bradycardia with AV-junctional escape rhythms in infancy and later developed intermittent complete AV dissociation, had no structural abnormalities on repeat echocardiograms. However, during placement of a cardiac pacemaker at 39 years of age due to chronic fatigue, the lead could not be placed in the right atrial appendage, which was assumed therefore to be absent. Imaging studies showed normal situs of lungs and abdominal organs. Her daughter was born with a large incomplete AVSD and secundum-type atrial septal defect (ASD II), and at the time of surgical correction was also found to have absence of the coronary sinus and a persistent left superior vena cava (LSVC); situs of lungs and abdominal organs was normal. ECG consistently showed low atrial rhythm. Cardiac defects present in other family members included tetralogy of Fallot with LSVC, aortic hypoplasia, LSVC with aberrant right subclavian artery, and secundum ASD. ECG abnormalities in addition to low atrial rhythm included bradycardia, incomplete or complete right bundle branch block, atrial fibrillation, and paroxysmal supraventricular tachycardia. Noting that the spectrum of congenital heart defects seen in this family was compatible with that seen in left isomerism, Van de Meerakker et al. (2011) suggested that their phenotype resembled a developmental laterality defect, albeit with mild expression that appeared to be restricted to the heart. The authors also suggested that the phenotype might represent an underlying developmental defect of the sinus node.

▼ Mapping
In a 4-generation family segregating autosomal dominant congenital heart defects with disturbances of cardiac rhythm and conduction, in which linkage to the candidate cardiac transcription factor genes GATA4 (600576), TBX5 (601620), and NKX2-5 (600584) had been excluded, van de Meerakker et al. (2011) performed genomewide linkage analysis and identified significant linkage to a single locus on chromosome 9q shared by all affected individuals and absent from unaffected family members. The shared locus had a maximum multipoint lod score of 4.1 at marker D9S1690 at 9q31.1, and was delineated by markers D9S167 and D9S1682 based on haplotype analysis.

Tags: 9q31.1