ESPE Abstracts (2015) 84 FC2.2

Identification of Mutations in TBX1 and AIRE in Isolated Hypoparathyroidism Patients

Dong Lia, Sarah Schnellbacherb, Lifeng Tiana, Cuiping Houa, Cecilia Kima, Hakon Hakonarsona,c & Michael Levineb,c


aThe Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; bDivision of Endocrinology and Diabetes, Center for Bone Health, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; cDepartment of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA


Background: Hypoparathyroidism may manifest either as an isolated disorder or as a component of a more complex syndrome. Molecular genetic studies indicate that mutations in PTH, CASR, GCM2 and GNA11 are causes of isolated hypoparathyroidism (IH) and mutations in GATA3, TBCE, FAM111A, AIRE and TBX1 are associated with different complex syndromes with hypoparathyroidism.

Objective and hypotheses: To identify the underlying genetic basis for IH two multigenerational families with negative PTH, CASR, GCM2 and GNA11 sequencing.

Method: Whole exome sequencing (WES) was performed in three affecteds in family 1 and five affecteds from two generations in family 2.

Results: WES analysis in family 1 revealed that affecteds were compound heterozygotes for two previously identified mutations (c.967_979delGCCTGTCCCCTCC:p.L323SfsX51 and c.995+(3_5)delGAGinsTAT) in AIRE, which is implicated in autoimmune polyglandular syndrome type 1 (PGA1). In PGA1 hypoparathyroidism is usually associated with adrenal insufficiency and candidiasis, which were not present in the three affected patients now aged 40-50 years. For family 2, all affecteds carried a novel heterozygous splice-altering mutation in TBX1, which is located at 22q11. This mutation showed reduced penetrance – 8 affecteds all have splicing mutation and some unaffecteds as well. Previously studies showed either gain of function or loss of function TBX1 mutations can lead to DGS or a DGS-like syndrome with craniofacial features, but the prevalence of hypoparathyroidism is only about 30%. A similarly low prevalence of hypoparathyroidism occurs in DGS due to the 3Mb deletion. The limited phenotype of IH in family 2 suggests that manifestation of the splicing defect may be tissue-specific, a hypothesis we are now testing in zebrafish.

Conclusion: Our identification of mutations in AIRE and TBX1 in patients with IH refines the phenotypic spectrum of clinical and endocrine abnormalities associated with these genes, and extends the number of candidate genes that can cause IH.

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