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Lookup NU author(s): Dr Richard Quinton
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© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. A genetic basis of congenital isolated hypogonadotropic hypogonadism (CHH) can be defined in almost 50% of cases, albeit not necessarily the complete genetic basis. Next-generation sequencing (NGS) techniques have led to the discovery of a great number of loci, each of which has illuminated our understanding of human gonadotropin-releasing hormone (GnRH) neurons, either in respect of their embryonic development or their neuroendocrine regulation as the “pilot light” of human reproduction. However, because each new gene linked to CHH only seems to underpin another small percentage of total patient cases, we are still far from achieving a comprehensive understanding of the genetic basis of CHH. Patients have generally not benefited from advances in genetics in respect of novel therapies. In most cases, even genetic counselling is limited by issues of apparent variability in expressivity and penetrance that are likely underpinned by oligogenicity in respect of known and unknown genes. Robust genotype–phenotype relationships can generally only be established for individuals who are homozygous, hemizygous or compound heterozygotes for the same gene of variant alleles that are predicted to be deleterious. While certain genes are purely associated with normosmic CHH (nCHH) some purely with the anosmic form (Kallmann syndrome—KS), other genes can be associated with both nCHH and KS—sometimes even within the same kindred. Even though the anticipated genetic overlap between CHH and constitutional delay in growth and puberty (CDGP) has not materialised, previously unanticipated genetic relationships have emerged, comprising conditions of combined (or multiple) pituitary hormone deficiency (CPHD), hypothalamic amenorrhea (HA) and CHARGE syndrome. In this review, we report the current evidence in relation to phenotype and genetic peculiarities regarding 60 genes whose loss-of-function variants can disrupt the central regulation of reproduction at many levels: impairing GnRH neurons migration, differentiation or activation; disrupting neuroendocrine control of GnRH secretion; preventing GnRH neuron migration or function and/or gonadotropin secretion and action.
Author(s): Cangiano B, Swee DS, Quinton R, Bonomi M
Publication type: Review
Publication status: Published
Journal: Human Genetics
Year: 2021
Volume: 140
Pages: 77-111
Print publication date: 01/01/2021
Online publication date: 21/03/2020
Acceptance date: 04/03/2020
ISSN (print): 0340-6717
ISSN (electronic): 1432-1203
Publisher: Springer
URL: https://doi.org/10.1007/s00439-020-02147-1
DOI: 10.1007/s00439-020-02147-1
PubMed id: 32200437
