Les objectifs qui seront abordés concernent:
1) Le développement d’un diagnostic précoce du CHH utilisant une approche basée sur l’intelligence artificielle et permettant de distinguer les cas de CDGP par rapport au CHH.
2) Le développement d’une médecine personnalisée impliquant l’approche génétique dans la conduite du diagnostic clinique. La classification traditionnelle des différents syndromes basée sur une constellation de phénotypes sera ainsi réadaptée.
3) L’analyse du rôle des facteurs environnementaux impliqués dans le reversal du CHH permettra d’améliorer le management clinique du CHH.
4) Une approche combinant séquençage de génome entier et transcriptomique va permettre de découvrir de nouveaux variantes liés au CHH qui n’auraient pas pu être mis en évidence par le séquençage d’exomes. Ces nouveaux gènes permettront de définir l’ontogénie des neurones à GNRH ainsi que leur mode de régulation.
5) Enfin, les cellules de patients CHH permettront d’obtenir des cellules pluripotentes induites afin d’identifier de manière fonctionnelle le rôle du fonds génétique sur la biologie du développement des neurones à GNRH. Cette stratégie permettra également d’identifier des traitements individuels du CHH.
Ce projet a pour but de répondre aux problématiques les plus importantes concernant la clinique et la génétique du CHH (nouvelles découvertes, traitement individualisé), et permettra d’approfondir les connaissances des mécanismes biologiques sous-jacents au contrôle neuroendocrinien de la reproduction humaine.
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by absent puberty and infertility caused by GnRH deficiency. The clinical overlap with constitutional delay of growth and puberty (CDGP), a common and transient form of GnRH deficiency, makes it virtually impossible to differentiate these two entities in patients prior to age 16, leading to delay in treatment and psychological burden for patients and family. Clinical heterogeneity occurs not only for the reproductive phenotype, but also for the CHH-associated non-reproductive phenotypes (i.e. cleft lip/palate, sensorineural hearing loss, etc.). Genetic heterogeneity also prevails in CHH, with over 40 loci known to underlie the disease either alone or in combination. Further, variable expressivity and incomplete penetrance illustrate the complexity of the phenotype-genotype correlation. This project will focus on clinical, genetic and basic aspect of GnRH neuron biology, employing a multidisciplinary and translational approach to address the current challenges in the field: (1) A more timely and accurate diagnosis of CHH can provide significant relief of psychosocial burden for both patients and families. We therefore propose to improve the early diagnosis of CHH by validating machine learning to distinguish CDGP from CHH. (2) The clinical heterogeneity in CHH with variable frequency of associated phenotypes make it difficult to conduct an efficient clinical evaluation for each patient. We aim to promote personalized medicine by demonstrating the role of genetics in guiding clinical assessment. The present work will challenge our traditional view of the classification of syndromes based on constellation of phenotypes. (3) The dogma that a congenital disorder such as CHH is permanent has been challenged by the discovery of HH reversal in adulthood, suggesting the implication of GnRH neuron plasticity. We will investigate the contribution of environmental factors in CHH reversal to improve clinical management of CHH. (4) Despite the advent of next generation sequencing, the majority of patients remain without molecular diagnosis. Recently, the increasing affordability of whole genome sequencing (WGS) allows to screen large CHH cohorts for variants in regulatory non-coding regions, previously not accessible by whole exome sequencing. Yet, interpretation of identified rare variants remains challenging. We propose to combine WGS with transcriptomics to increase the yield of molecular diagnosis and translate these findings in clinical genetics. The discovery of novel genes in CHH will also shed light into the ontogeny of GnRH neurons and their regulation. (5) Finally, we will use the CHH patients-derived iPSC and genome editing technologies to functionally validate the genetic makeup of each patient, along the evaluation of potential individualized treatments.
Last updated:18.06.2022
