Abstract
BackgroundAlthough TBX1 mutations have been identified in patients with 22q11.2 deletion syndrome (22q11.2DS)-like phenotypes including characteristic craniofacial features, cardiovascular anomalies, hypoparathyroidism, and thymic hypoplasia, the frequency of TBX1 mutations remains rare in deletion-negative patients. Thus, it would be reasonable to perform a comprehensive genetic analysis in deletion-negative patients with 22q11.2DS-like phenotypes.Methodology/Principal FindingsWe studied three subjects with craniofacial features and hypocalcemia (group 1), two subjects with craniofacial features alone (group 2), and three subjects with normal phenotype within a single Japanese family. Fluorescence in situ hybridization analysis excluded chromosome 22q11.2 deletion, and genomewide array comparative genomic hybridization analysis revealed no copy number change specific to group 1 or groups 1+2. However, exome sequencing identified a heterozygous TBX1 frameshift mutation (c.1253delA, p.Y418fsX459) specific to groups 1+2, as well as six missense variants and two in-frame microdeletions specific to groups 1+2 and two missense variants specific to group 1. The TBX1 mutation resided at exon 9C and was predicted to produce a non-functional truncated protein missing the nuclear localization signal and most of the transactivation domain.Conclusions/SignificanceClinical features in groups 1+2 are well explained by the TBX1 mutation, while the clinical effects of the remaining variants are largely unknown. Thus, the results exemplify the usefulness of exome sequencing in the identification of disease-causing mutations in familial disorders. Furthermore, the results, in conjunction with the previous data, imply that TBX1 isoform C is the biologically essential variant and that TBX1 mutations are associated with a wide phenotypic spectrum, including most of 22q11.2DS phenotypes.
Highlights
Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a developmental disorder associated with characteristic craniofacial features with velopharyngeal incompetence, cardiovascular anomalies primarily affecting the outflow tracts, hypoparathyroidism and resultant hypocalcemia, and thymic hypoplasia leading to susceptibility to infection [1]
Expressivity and penetrance of these features are highly variable and, consistent with this, chromosome 22q11.2 deletions have been identified in DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS) with overlapping but different patterns of clinical features [1]
The c.1253delA (p.Y418fsX459) appears to be a disease-causing mutation, because it is predicted that this variant escapes nonsense-mediated mRNA decay due to its position on the final exon [18] and produces a truncated protein lacking the nuclear localization signal (NLS) and most of the transactivation domain (TAD) on exon 9C (Fig. 3) [19]
Summary
Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a developmental disorder associated with characteristic craniofacial features with velopharyngeal incompetence, cardiovascular anomalies primarily affecting the outflow tracts, hypoparathyroidism and resultant hypocalcemia, and thymic hypoplasia leading to susceptibility to infection [1]. This condition is frequently accompanied by non-specific clinical features such as developmental retardation [1]. It would be reasonable to perform a comprehensive genetic analysis in deletion-negative patients with 22q11.2DS-like phenotypes
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