title: 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.forename: Katarzyna E
authors.initials: KE
authors.lastname: Kolodziejska
authors.forename: Michael M
authors.initials: MM
authors.lastname: Quach
authors.forename: Varina Louise
authors.initials: VL
authors.lastname: Wolf
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Ramocki
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
mesh_terms: D055028:Comparative Genomic Hybridization; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D057895:Haploinsufficiency; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D009030:Mosaicism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II