Abstract:
:The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many structural malformations in DiGeorge syndrome caused by a chromosome 22q11.2 deletion. We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants. The p.R20Q variant is shared by three affected family members in an autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation. Bioinformatics analyses indicate that these variants are rare and predict them to be damaging. In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2. Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles. Hence, these and other data suggest that TBX2 is a novel candidate gene for a new multisystem malformation disorder.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Liu N,Schoch K,Luo X,Pena LDM,Bhavana VH,Kukolich MK,Stringer S,Powis Z,Radtke K,Mroske C,Deak KL,McDonald MT,McConkie-Rosell A,Markert ML,Kranz PG,Stong N,Need AC,Bick D,Amaral MD,Worthey EA,Levy S,Undiagnoseddoi
10.1093/hmg/ddy146subject
Has Abstractpub_date
2018-07-15 00:00:00pages
2454-2465issue
14eissn
0964-6906issn
1460-2083pii
4991966journal_volume
27pub_type
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