A Boy with Holt-Oram Syndrome Caused by Novel Mutation c.1304delT in the TBX5 Gene.

[holt-oram syndrome]

Holt-Oram syndrome (HOS ) is an autosomal dominant developmental defect involving preaxial radial ray upper limb deformity and variable cardiac defects . It has been demonstrated that HOS is caused by mutations in the T -box transcription factor gene TBX 5 . Numerous germline mutations (more than 60 ) of this gene produce preterminal stop codons , which lead to synthesis of a truncated nonfunctional TBX 5 protein . The haplo-insufficiency of the TBX 5 gene is the most significant cause of HOS . We report on a sporadic patient with clinical features of HOS . Our patient had a cardiac anomaly - a muscular ventricular and atrial septal defect , patent ductus arteriosus and a conduction defect (a first -step atrioventricular block ). Upper limb anomalies in our patient were relatively mild and unusual to HOS - distally displaced thumbs , narrow shoulders and hypotrophy of the muscles in the shoulder region . Molecular analysis identified a novel and unusual heterozygous frameshift mutation - c .1304 delT (p .Leu 435 fsX 146 ) - in exon 9 of the TBX 5 gene , which is predicted to cause an elongated TBX 5 protein with 84 miscoding amino acids and 62 supernumerary C-terminal amino acids . To the best of our knowledge , only one such type of elongation mutation has thus far been reported in the TBX 5 gene .