Expanding the spectrum of TBX5 mutations in Holt-Oram syndrome: detection of two intragenic deletions by quantitative real time PCR, and report of eight novel point mutations.

[holt-oram syndrome]

Mutations in the gene TBX 5 cause Holt-Oram syndrome (HOS ), an autosomal dominant disorder characterized by anterior (i .e ., radial ray ) upper limb malformations and congenital heart defects and /or cardiac conduction anomalies . The detection rate for TBX 5 mutations in HOS patients has been given as 30 -35 % in most reports . However , a detection rate of 74 % was reported when strict clinical inclusion criteria for HOS were applied prior to TBX 5 analysis . Still , in a significant proportion of typical HOS cases no mutation can be found within the TBX 5 coding region and flanking intronic sequences . One explanation could be that large but submicroscopic deletions of TBX 5 could cause HOS , yet only one such TBX 5 deletion has been reported to date . We developed a quantitative Real Time PCR strategy to detect large , submicroscopic deletions in TBX 5 . Using this assay , we screened a total of 102 TBX 5 mutation negative patients and discovered two novel intragenic deletions . One deletion of 7756 bp removes exon 6 and a considerable part of the neighboring intronic sequences , and the other of 3695 bp removes exon 9 with the stop codon and the 3 'UTR completely as well as a part of the preceding intron 8 . We conclude that quantitative Real Time PCR is a reliable method to detect submicroscopic deletions within TBX 5 . However , such deletions explain only approximately 2 % of the TBX 5 mutational spectrum in HOS cases . In addition , we also present eight novel TBX 5 mutations (three nonsense , one splice mutation , four short deletions ) as detected by direct sequencing in 21 families not previously analyzed for mutations .

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Diseases presenting "tbx5 mutations" symptom

holt-oram syndrome

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