Sinoatrial Node Dysfunction And Deafness

A number sign (#) is used with this entry because of evidence that sinoatrial node dysfunction and deafness (SANDD) is caused by homozygous mutation in the CACNA1D gene (114206) on chromosome 3p21.

Description

Patients with sinoatrial node dysfunction and deafness have congenital severe to profound deafness without vestibular dysfunction, associated with episodic syncope due to intermittent pronounced bradycardia (Baig et al., 2011).

See Jervell and Lange-Nielsen syndrome (220400) for discussion of another deafness syndrome with impaired cardiac conduction.

Clinical Features

Baig et al. (2011) studied 2 consanguineous Pakistani families in which affected individuals had congenital deafness that was severe (71- to 95-dB loss) to profound (greater than 95-dB loss), without vestibular dysfunction. Three brothers and a sister were affected in 1 family; the youngest brother, aged 15 years, reported episodes of syncope since early childhood that were triggered by enhanced physical activity and stress. In the other family, 2 brothers, aged 22 years and 20 years, were affected, as well as a more distant 24-year-old male relative; the older brother reported several syncopal episodes during normal physical activity between the ages of 3 years and 6 years. Electrocardiograms in all 7 affected individuals showed resting bradycardia with heart rates of 38 beats to 52 beats per minute in the daytime, and rates as low as 32 bpm during the night. QRS complexes were not widened and QT(c) intervals were not prolonged. P waves were visible in most of the recordings, but did not regularly precede QRS complexes, indicating that bradycardia was associated with alteration of atrioventricular conduction. In 3 of the 4 sibs, paired beats occurred during bradycardic episodes, probably triggered by P waves seen in the repolarization phase of the preceding junctional beats. Baig et al. (2011) designated the disorder SANDD, for 'sinoatrial node dysfunction and deafness.'

Mapping

By genomewide linkage analysis in a consanguineous Pakistani family in which 4 sibs had congenital deafness and bradycardia, Baig et al. (2011) obtained a maximum parametric lod score of 2.783 for 2 chromosomal regions that showed homozygosity by descent in all 4 affected sibs. One was a 3.5-Mb region on chromosome 1p31.3, containing only 14 annotated genes, none of which was an obvious candidate for deafness. The other was a 13-Mb region between SNPs rs33509 and rs373532 on chromosome 3p22.1-p14.3, overlapping the DFNB6 locus (600971); however, no mutations were identified in the DFNB6 gene, TMIE (607237).

Molecular Genetics

In a consanguineous Pakistani family in which 4 sibs had congenital deafness and bradycardia mapping to chromosome 3p21, Baig et al. (2011) sequenced the candidate gene CACNA1D and identified homozygosity for a 3-bp insertion (114206.0001) that segregated with disease in the family. Screening of 151 families with autosomal recessive deafness, including 75 from Pakistan, identified 1 Pakistani family from the same geographic region in which homozygosity for the insertion also segregated with disease. The mutation was found in heterozygous state in 1 of 255 healthy Pakistani controls; that control individual, whose family was from the same rural area as the other 2 families, had 3 sibs who also carried the insertion in heterozygous state, 1 of whom was deaf. However, electrocardiography in 2 of the heterozygous sibs, including the deaf sister, showed no abnormalities, and Baig et al. (2011) concluded that the 3-bp insertion represents a local founder allele, incidentally carried by the members of the third family.