RT Journal Article SR Electronic T1 Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 19 OP 25 DO 10.1136/jmedgenet-2016-104064 VO 54 IS 1 A1 Mary R Richards A1 Lacey Plummer A1 Yee-Ming Chan A1 Margaret F Lippincott A1 Richard Quinton A1 Philip Kumanov A1 Stephanie B Seminara YR 2017 UL http://jmg.bmj.com/content/54/1/19.abstract AB Background A constellation of neurodegenerative disorders exists (Gordon Holmes syndrome, 4H leucodystrophy, Boucher-Neuhauser syndrome) in which patients suffer from both neurological disease (typically manifested by ataxia) and reproductive failure (idiopathic hypogonadotropic hypogonadism (IHH)). POLR3B, which encodes the second largest subunit of RNA polymerase III (pol III), and POLR3A, which forms the pol III catalytic centre, are associated with 4H leucodystrophy.Methods Whole exome sequencing was performed on a large cohort of subjects with IHH (n=565). Detailed neuroendocrine studies were performed in some individuals within this cohort.Results Four individuals (two of them siblings) were identified with two rare nucleotide variants in POLR3B. On initial evaluation, all subjects were free of neurological disease. One patient underwent treatment with exogenous pulsatile gonadotropin-releasing hormone for 8 weeks which failed to result in normalisation of his sex steroid milieu due to pituitary resistance.Conclusions These findings suggest that the spectrum of phenotypes resulting from POLR3B mutations is wider than previously believed and that POLR3B can be associated exclusively with disorders characterised by abnormal gonadotropin secretion.