TGFBR2 deletion in a 20-month-old female with developmental delay and microcephaly

Abstract

To date, over 70 mutations in the TGFBR2 gene have been reported in patients with Loeys-Dietz syndrome (LDS), Marfan syndrome type 2 (MFS2), or other hereditary thoracic aortic aneurysms and dissections. Whereas almost all of mutations analyzed thus far are predicted to disrupt the constitutively active C-terminal serine/threonine kinase domain of TGFBR2, mounting evidence suggests that the molecular mechanism underlying these diseases is more complex than simple haploinsufficiency. Using exon-targeted oligonucleotide array comparative genomic hybridization, we identified an ∼896 kb deletion of TGFBR2 in a 20-month-old female with microcephaly and global developmental delay, but no stigmata of LDS. FISH analysis showed no evidence of this deletion in the parental peripheral blood samples; however, somatic mosaicism was detected using PCR in the paternal DNA from peripheral blood lymphocytes and lymphoblasts. Our data suggest that TGFBR2 haploinsufficiency may cause a phenotype, which is distinct from LDS. Moreover, we propose that somatic mosaicism below the detection threshold of FISH analysis in asymptomatic parents of children with genomic disorders may be more common than previously recognized.

FIG. 1

A: Patient at age 19 months. B: Sagittal FFE magnetic resonance image demonstrating a thin and abnormally shaped corpus callosum, hypoplasia of the brainstem, hypoplasia of the inferior cerebellar vermis, and a prominent cisterna magna [Color figure can be viewed in the online issue, which is available at www.wileyonlinelibrary.com].

FIG. 2

A: Clinical aCGH (CMA V8.1 OLIGO) plot showing a deletion on chromosome 3q24.1-q23. The proximal breakpoint was mapped between 31,214,839 and 31,176,203 and the distal breakpoint between 30,287,071 and 30,325,687. B: Chromatogram showing DNA sequence of the junction fragment. Dashed lines show possible breakpoints. C: 1% Agarose gel demonstrating the presence of the family-specific fragment amplified from the patient’s and the father’s peripheral blood lymphocytes. Note the weaker intensity of the PCR band for a given reaction volume in the father indicating a low level mosaicism. D: Schematic diagram of the genomic structure of the deleted region. Red boxes represent CGH oligonucleotides with log ratios below −0.30 [Color figure can be viewed in the online issue, which is available at www.wileyonlinelibrary.com].