Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland.

A.K Nicholas,G Lyons,S Jaleel,E.F Roche,N Schoenmakers,J Kirk,V.K Chatterjee,B Bernhard,M.T Dattani,E Crowne,E Schoenmakers

doi:10.1111/cen.13149

Abstract

SummaryObjectiveHomozygous mutations in the TSH beta subunit gene (TSHB) result in severe, isolated, central congenital hypothyroidism (CCH). This entity evades diagnosis in TSH‐based congenital hypothyroidism (CH) screening programmes in the UK and Ireland. Accordingly, genetic diagnosis, enabling ascertainment of affected relatives in families, is critical for prompt diagnosis and treatment of the disorder.Design, Patients and MeasurementsFour cases of isolated TSH deficiency from three unrelated families in the UK and Ireland were investigated for mutations or deletions in TSHB. Haplotype analysis, to investigate a founder effect, was undertaken in cases with identical mutations (c.373delT).ResultsTwo siblings in kindred 1 were homozygous for a previously described TSHB mutation (c.373delT). In kindreds 2 and 3, the affected individuals were compound heterozygous for TSHB c.373delT and either a 5·4‐kB TSHB deletion (kindred 2, c.1‐4389_417*195delinsCTCA) or a novel TSHB missense mutation (kindred 3, c.2T>C, p.Met1?). Neurodevelopmental retardation, following delayed diagnosis and treatment, was present in 3 cases. In contrast, the younger sibling in kindred 1 developed normally following genetic diagnosis and treatment from birth.ConclusionsThis study, including the identification of a second, novel, TSHB deletion, expands the molecular spectrum of TSHB defects and suggests that allele loss may be a commoner basis for TSH deficiency than previously suspected. Delayed diagnosis and treatment of profound central hypothyroidism in such cases result in neurodevelopmental retardation. Inclusion of thyroxine (T4) plus thyroxine‐binding globulin (TBG), or free thyroxine (FT4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae.

Highlights

Isolated congenital central hypothyroidism is rare,[1] with genetic causes comprising mutations in the TSH beta subunit (TSHB), the immunoglobulin superfamily member 1 (IGSF1) or, less frequently, the TRH receptor (TRHR) genes.[2]
All are inherited in an autosomal recessive manner and are associated with severe central hypothyroidism. (The nomenclature of mutations in this paper follows the most recent HGNC guidelines to include the 20-amino acid signal peptide of TSHb, such that codon numbering may differ from that cited in the previously published articles)
Despite paternal heterozygosity for this mutation, but wild-type maternal TSHB sequence (Fig. 1a), Patient 2 (P2) was apparently homozygous for the same mutation (p.C125Vfs*10)

Summary

Introduction

Isolated congenital central hypothyroidism is rare (incidence 1 in 65 000),[1] with genetic causes comprising mutations in the TSH beta subunit (TSHB), the immunoglobulin superfamily member 1 (IGSF1) or, less frequently, the TRH receptor (TRHR) genes.[2]. The human TSHb subunit gene is organized into 3 exons: exon 1 is untranslated, and exons 2 and 3 encode a 138-amino The twenty N-terminal amino acids encode a signal peptide that is cleaved to yield a 118-amino acid mature protein detectable in serum.[4,5] The most frequently described TSHB mutation is a single-nucleotide deletion (c373delT), resulting in a cysteine 125 to valine conversion (C125V) and disruption of the Cys-Cys 39–125 disulphide bridge, with a subsequent shift in reading frame and premature stop codon at position 134.6 Eight additional mutations have been described, including missense (p.C108Y, p.C105R, p.G49R) and nonsense or frameshift mutations (p.E32*, p.Q69*, p.F77Sfs*6).[3,7,8,9,10,11] Two splice site mutations (c162G>A, IVS2 + 5 G>A),[3,12] and more recently a homozygous TSHB deletion, have been reported.[13] All are inherited in an autosomal recessive manner and are associated with severe central hypothyroidism. All are inherited in an autosomal recessive manner and are associated with severe central hypothyroidism. (The nomenclature of mutations in this paper follows the most recent HGNC guidelines to include the 20-amino acid signal peptide of TSHb, such that codon numbering may differ from that cited in the previously published articles)

Methods

Results

Conclusion