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Prevalence and associated phenotypes of PLXNA1 variants in normosmic and anosmic idiopathic hypogonadotropic hypogonadism
Author(s) -
Kotan Leman D.,
Isik Emregul,
Turan Ihsan,
Mengen Eda,
Akkus Gamze,
Tastan Mehmet,
Gurbuz Fatih,
Yuksel Bilgin,
Topaloglu A. Kemal
Publication year - 2019
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13482
Subject(s) - kallmann syndrome , hypogonadotropic hypogonadism , missense mutation , anosmia , genetics , medicine , phenotype , exome sequencing , endocrinology , etiology , pedigree chart , biology , gene , disease , hormone , covid-19 , infectious disease (medical specialty)
Idiopathic hypogonadotropic hypogonadism (IHH) can be divided into two major forms, normosmic IHH and Kallmann syndrome (KS). Genetic mutations are responsible for the majority of IHH. PLXNA1 has recently been implicated in the GnRH neuron migration and the etiology of KS. We aimed to investigate the prevalence and associated phenotypes of PLXNA1 variants in a large cohort of IHH patients. We screened the whole exome data of 215 IHH patients in a single center for causative PLXNA1 variants. Our studies showed eight novel (p.Arg836His, p.Lys1451Arg, p.Val287Met, p.Val536Ile, p.Ser1850Arg, p.Ile1701Val, p.Arg319Trp, and p.Pro485Leu) and two previously described (p.Arg528Trp and p.Gly720Glu) heterozygous PLXNA1 variants in nine affected individuals from seven unrelated families. Only three of nine patients were anosmic (KS) while the remaining patients showed normal olfactory function (nIHH). Seven of nine patients (77.7%) harbored additional one or two variants in other nIHH/KS‐associated genes, including PROKR2 , IGSF10 , HS6ST1 , SEMA3E , CCDC141 , FGFR1 , NRP1 , POLR3A , and SRA1 . Our findings indicate that PLXNA1 variants cause not only anosmic but also normosmic IHH with a relatively high prevalence (3.9%). Heterozygous missense PLXNA1 variants appear to be involved together with other IHH gene variants in bringing about the IHH disease phenotype.