Clinical Reports

The index case is a 4-year-old boy (III:1, Fig. ​Fig.1A)1A) presenting with clinically isolated SVAS. He is the first born of a twin bichorial biamniotic pregnancy, an eutrophic premature at 32 weeks of amenorrhea. The neonatal period was uneventful. A rough aortic murmur 3/6 was found at 11 months of age, fully symptom free. The echocardiography showed an isolated SVAS measured at 5.7 mm with a maximal gradient at 118 mmHg and a mean gradient at 64 mmHg. The prestenotic aorta was measured at 15.8 mm for a poststenotic aorta at 13.8 mm. The left ventricle was not dilated, normokinetic, but hypertrophied, without mitral insufficiency. The aortic valve appeared asymmetric but tricuspid, without valvular stenosis. There was a micro aortic insufficiency 0.5/4 and a common origin of the innominate artery and the left primary carotid artery. The coronary arteries looked anatomically normal. A scan showed an SVAS of approximately 50% of the diameter without further anomalies of the thoracic aorta. He underwent a patch aortoplasty and plasty of the Valsalva sinuses at 32 months of age, without complications. Functional result was excellent. The last echocardiography, at 4 years of age, found no persistent SVAS, but an acceleration of the flow in the tubular aorta (2.6 m/s) with stable mild aortic insufficiency. Psychomotor development was normal, with regular schooling. Growth was normal as well, with a weight of 15 kg (-1 SD) and a height of 106 cm (average) at the last observation, 4 years of age. Blood pressure was normal. Serum calcium level was normal. There were no dysmorphic features suggestive of WBS. The twin sister of the index case (III:2, Fig. ​Fig.1A)1A) is healthy. Both of the boy's parents (II:5 and II:4) have a heart murmur, with normal echocardiographic values as well as the maternal grandparents and 2 maternal aunts. Likewise among 3 paternal aunts, the eldest one (II:1) was monitored since infancy for an isolated symptom-free SVAS. The middle (II:2) is healthy, and the youngest (II:3) has a heart murmur, with normal echocardiographic values. The paternal grandmother (I:2) is healthy. The paternal grandfather (I:1) has a mitral valve prolapse in the context of a ballooned dystrophic mitral valve, with no left ventricle impact.

A Family pedigree. B R-banded chromosome 7 showing a paracentric inversion inv(7)(q11.2;q31) (arrows). C FISH using RP11-644H24 probe (7q11.23) in green (FITC) and 7qter control probe in red showing a split green signal on derivative chromosome 7 (arrows). D FISH using RP11-560I19 BAC (7q31.32) in green (FITC) and 7qter control probe in red showing a split green signal on derivative chromosome 7 (arrows). E Amplification of junction fragments by PCR and migration on a 2% agarose gel. P, patient; C, control; B, blank; ATP1A3, positive control; 7q11.23, proximal junction fragment; 7q31.32, distal junction fragment. F Sanger sequencing determining the breakpoints at bp level: sequence of proximal junction fragment (7q11.23) and sequence of distal junction fragment (7q31.32). The 7q11.23 sequence is in green, 7q31.32 is in black. Genomic coordinates are given according to hg19 and strand orientation is indicated (+ or -). Regions of microhomology are underlined. Note that there is a loss of 2 bp at the 7q11.23 breakpoint and of 49 bp at the 7q31.32 breakpoint.