GENE LOCALIZATION TO 12Q2 IN THE ATRIO-DI GITAL HOLT-ORAM SYNDROME

The Holt-Oram syndrome, first described in 1960, consists of non-cyano tic congenital heart disease, usually an atrial septal defect, arrhyth mias and malformations of the upper limbs affecting the radial segment . The transmission of the syndrome is autosomal dominant with almost c omplete penetrance. The authors report the localisation of a genetic a bnormality of the Holt-Oram syndrome on the long arm of chromosome 12 (12q21-q3) by analysis of linkage in 9 multiplex families (Z(max) = 8. 19 at locus D12S354). Multipoint analysis showed a genetic interval of 7 centimorgans containing a gene of the Holt-Oram syndrome between lo ci D12S84 and D12S79 (multipoint lod score, 10 g base 10 = 8.96). In s itu hybridization of artificial yeast chromosomes containing the surro unding markers showed that a gene of the Holt-Oram syndrome is located in 12q23-q24. The genetic heterogeneity was demonstrated in 3 familie s of the Holt-Oram syndrome with polydactyly or without cardiac diseas e (homogtest: chi 2 = 13.28; p = 0.0001). The localisation of a gene o f the Holt-Oram syndrome is, to the authors' knowledge, the first chro mosomal localisation of a cardiac malformation with septal defects in man. The identification of this gene should open wide perspectives for genetic research of cardiac morphogenesis and clarify the molecular m echanisms which govern cardiac septation during embryogenesis.