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A novel IGSF 1 mutation in a large Irish kindred highlights the need for familial screening in the IGSF 1 deficiency syndrome
Author(s) -
Roche Edna F.,
McGowan Anne,
Koulouri Olympia,
Turgeon MarcOlivier,
Nicholas Adeline K.,
Heffernan Emmeline,
ElKhairi Ranna,
Abid Noina,
Lyons Greta,
Halsall David,
Bonomi Marco,
Persani Luca,
Dattani Mehul T.,
Gurnell Mark,
Bernard Daniel J.,
Schoenmakers Nadia
Publication year - 2018
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/cen.13827
Subject(s) - penetrance , phenotype , mutation , biology , endocrinology , medicine , genetics , gene
Summary Objective Loss‐of‐function mutations in IGSF 1 result in X‐linked central congenital hypothyroidism (Ce CH ), occurring in isolation or associated with additional pituitary hormone deficits. Intrafamilial penetrance is highly variable and a minority of heterozygous females are also affected. We identified and characterized a novel IGSF 1 mutation and investigated its associated phenotypes in a large Irish kindred. Design, Patients and Measurements A novel hemizygous IGSF 1 mutation was identified by direct sequencing in two brothers with Ce CH , and its functional consequences were characterized in vitro. Genotype‐phenotype correlations were investigated in the wider kindred. Results The mutant IGSF 1 protein (c.2318T > C, p.L773P) exhibited decreased plasma membrane expression in vitro due to impaired trafficking from the endoplasmic reticulum. Ten hemizygous males and 11 heterozygous females exhibited characteristic endocrine deficits. Ireland operates a TSH ‐based CH screening programme, which does not detect Ce CH ; therefore, genetic ascertainment preceded biochemical diagnosis of moderate CH in five of seven boys as well as their 75‐year‐old grandfather. Clinical features potentially attributable to hypothyroidism were variable; normal free T3 ( FT 3) and low/low normal reverse T3 ( rT 3) concentrations suggested that preferential deiodination of FT 4 to FT 3 may help maintain tissue euthyroidism in some individuals. However, neonatal jaundice, delayed speech or growth, and obesity were observed in seven subjects in whom diagnosis was delayed. Conclusions As observed with other IGSF 1 mutations, p.L773P results in variably penetrant IGSF 1 deficiency syndrome. Our observations emphasize the need for multi‐generation genetic ascertainment in affected families, especially where TSH ‐based CH screening programmes may fail to detect Ce CH at birth.