TBX1 mutation identified by exome sequencing in a Japanese family with 22q11.2 deletion syndrome-like craniofacial features and hypocalcemia.

[22q11.2 deletion syndrome]

Although TBX 1 mutations have been identified in patients with 22 q 11 .2 deletion syndrome (22 q 11 .2 DS )-like phenotypes including characteristic craniofacial features , cardiovascular anomalies , hypoparathyroidism , and thymic hypoplasia , the frequency of TBX 1 mutations remains rare in deletion-negative patients . Thus , it would be reasonable to perform a comprehensive genetic analysis in deletion-negative patients with 22 q 11 .2 DS -like phenotypes .We 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 22 q 11 .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 TBX 1 frameshift mutation (c .1253 delA , p .Y 418 fsX 459 ) 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 TBX 1 mutation resided at exon 9 C and was predicted to produce a non-functional truncated protein missing the nuclear localization signal and most of the transactivation domain .Clinical features in groups 1 +2 are well explained by the TBX 1 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 TBX 1 isoform C is the biologically essential variant and that TBX 1 mutations are associated with a wide phenotypic spectrum , including most of 22 q 11 .2 DS phenotypes .

Diseases
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Diseases presenting "while the clinical effects of the remaining variants are largely unknown" symptom

22q11.2 deletion syndrome

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