Ulnar–mammary syndrome with dysmorphic facies and mental retardation caused by a novel 1.28 Mb deletion encompassing the TBX3 gene

Abstract

Ulnar -mammary syndrome (UMS) is a rare autosomal-dominant disorder caused by mutations in TBX3. The condition is characterized by hypoplasia or aplasia of upper limbs on the ulnar side, mammary glands and nipples, and of apocrine glands in both sexes (MIM #181450). We report on a girl presenting with an UMS like phenotype, a dysmorphic facies, and mental retardation. Mutation analysis of TBX3 and G-banded chromosome analysis from lymphocytes were performed. We used microarray-based comparative genomic hybridization (array CGH) to investigate the patient's genomic DNA for submicroscopic aberrations. No mutation of the TBX3 gene was detected in our patient and chromosome analysis revealed a normal female karyotype (46,XX). Hybridization of a whole-genome tiling path array consisting of more than 36 000 BAC clones revealed an interstitial 1.28 Mb deletion within chromosomal band 12q24.21. The deleted region encompasses one known gene, TBX3. The deletion and haploinsufficiency of TBX3 was confirmed by fluorescence in situ hybridization using BAC clones representing the deletion on the BAC array. To our knowledge, this is the first description of TBX3 haploinsufficiency caused by a genomic deletion in a patient with UMS. We suggest that the UMS phenotype in conjunction with the characteristic facial changes and mental retardation observed in our patient is owing to the deletion of TBX3 and the involvement of neighbouring genes.

Identification of loci affecting teat number by genome-wide association studies on three pig populations

“…T-box3 , a member of the T-box gene family, has been reported to influence the development of mammary gland placodes via interacting with Wnt family member 10 ( Wnt10 ), lymphoid enhancer binding factor 1 ( lef-1 ), and fibroblast growth factor 10 ( Fgf10 ) [32–34]. Moreover, T-box3 variants have been implicated in the Ulnar-Mammary Syndrome in humans, a genetic disease characterized by nipple and breast hypoplasia or aplasia [35,36]. Given that KDM6B is located in the confidence interval of the genome-wide significant locus and has a potential role in the development of nipples, we highlight it as an interesting candidate gene for pig teat number that warrant further investigations.…”

Detection of pathogenic gene copy number variations in patients with mental retardation by genomewide oligonucleotide array comparative genomic hybridization

“…The application of aCGH has enhanced the ability of localization of the genes associated with developmental disorders, e.g., the CHD7 genes in CHARGE [Vissers et al, 2004. Several other genes have recently been identified or proposed to be associated with mental retardation or abnormal brain development recently, including MCPH1, FBXW11, TBX3, and MAPT [Garshasbi et al, 2006;Koolen et al, 2006;Klopocki et al, 2006;Shaw-Smith et al, 2006]. Genomewide arrays with increasing density of probes will provide a powerful investigational tool for such efforts.…”

Basal transcription of the human TBX3 gene, a key developmental regulator which is overexpressed in several cancers, requires functional NF-Y and Sp1 sites

“…During embryogenesis, TBX3 plays critical roles in the development of several organs such as the heart, limb and mammary gland (Davenport et al, 2003;Hoogaars et al, 2007). Its importance in these processes is emphasized by haploinsufficiency of TBX3 resulting in Ulnar-Mammary Syndrome (UMS), a disorder characterized by several defects including the development of the limbs, mammary glands, and in extreme cases, heart (Bamshad et al, 1997;Klopocki et al, 2006;Meneghini et al, 2006). The degree of deformities which UMS patients suffer is dependent on the impact of the mutation on functional TBX3 levels.…”