Loss-of-function variants in tbc1d32 underlie syndromic hypopituitarism

Abstract

Context: Congenital pituitary hormone deficiencies with syndromic phenotypes and/or familialoccurrence suggest genetic hypopituitarism; however, in many such patients the underlyingmolecular basis of the disease remains unknown.Objective: To describe patients with syndromic hypopituitarism due to biallelic loss-of-functionvariants in TBC1D32, a gene implicated in Sonic Hedgehog (Shh) signaling.Setting: Referral center.Patients: A Finnish family of 2 siblings with panhypopituitarism, absent anterior pituitary, andmild craniofacial dysmorphism, and a Pakistani family with a proband with growth hormonedeficiency, anterior pituitary hypoplasia, and developmental delay.Interventions: The patients were investigated by whole genome sequencing. Expressionprofiling of TBC1D32 in human fetal brain was performed through in situ hybridization. Stableand dynamic protein-protein interaction partners of TBC1D32 were investigated in HEK cellsfollowed by mass spectrometry analyses. Main Outcome Measures: Genetic and phenotypic features of patients with biallelic loss-offunction mutations in TBC1D32.Results: The Finnish patients harboured compound heterozygous loss-of-function variants(c.1165 1166dup p.(Gln390Phefs*32) and c.2151del p.(Lys717Asnfs*29)) in TBC1D32; thePakistani proband carried a known pathogenic homozygous TBC1D32 splice-site variantc.1372 + 1G > A p.(Arg411 Gly458del), as did a fetus with a cleft lip and partial intestinalmalrotation from a terminated pregnancy within the same pedigree. TBC1D32 was expressed inthe developing hypothalamus, Rathke's pouch, and areas of the hindbrain. TBC1D32 interactedwith proteins implicated in cilium assembly, Shh signaling, and brain development.Conclusions: Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the underlyingmechanism may be via disrupted Shh signaling.