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.

Genetic Dissection of Marfan Syndrome and Related Connective Tissue Disorders: An Update 2012

“…The authors concluded that TGFBR2 haploinsufficiency may cause a phenotype that is different from LDS. Duplication of TGFBR1 on the other hand was found in a patient with symptoms suggestive of LDS [Campbell et al, 2011]. These findings are in line with the hypothesis that an increase in TGF ␤ signalling, rather than haploinsufficiency, is the main pathogenetic mechanism underlying LDS, and in part also MFS.…”

“…So far, no phenotypic differences have been reported between patients with mutations in TGFBR1 or TGFBR2. Recently, a 20-month-old female with microcephaly and developmental delay, but no typical features of LDS, was found to carry a microdeletion including TGFBR2 [Campbell et al, 2011]. The authors concluded that TGFBR2 haploinsufficiency may cause a phenotype that is different from LDS.…”

The Genetic Basis of Aortic Aneurysm

“…Patients with FSD experience multiple spontaneous self-healing epitheliomas, but do not show craniofacial dysmorphism or vascular disease (Goudie et al 2011). Additionally, a deletion of TGFBR2 has been described in a 20 mo old with microcephaly and developmental delay, but without features of LDS (Campbell et al 2011). In this light, receptor mutations in LDS seemingly select for receptors that must manifest a function separable from simple kinase-mediated signal transduction.…”

Genetics of Thoracic Aortic Aneurysm

“…For TGFBR1/2 mutations in LDS, it is becoming increasingly evident that, although the mutations in the serine/ threonine kinase domains of these proteins lead to a loss of function of the kinase activity, a complete haploinsufficiency of TGFBR1 or TGBFR2 does not seem to cause an aortic aneurysm phenotype. 160,161 Furthermore, the currently described nonsense mutations in LDS are all predicted to escape nonsense-mediated decay, and true nonsense mutations in TGFBR1 cause a skin cancer phenotype, multiple self-healing squamous epithelioma. 162 As such, having some mutant protein expressed seems to be a prerequisite to cause an aortic aneurysm phenotype.…”