TY - JOUR
T1 - Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures
AU - Cassatella, Daniele
AU - Howard, Sasha R.
AU - Acierno, James S.
AU - Xu, Cheng
AU - Papadakis, Georgios E.
AU - Santoni, Federico A.
AU - Dwyer, Andrew A.
AU - Santini, Sara
AU - Sykiotis, Gerasimos P.
AU - Chambion, Caroline
AU - Meylan, Jenny
AU - Marino, Laura
AU - Favre, Lucie
AU - Li, Jiankang
AU - Liu, Xuanzhu
AU - Zhang, Jianguo
AU - Bouloux, Pierre Marc
AU - De Geyter, Christian
AU - De Paepe, Anne
AU - Dhillo, Waljit S.
AU - Ferrara, Jean Marc
AU - Hauschild, Michael
AU - Lang-Muritano, Mariarosaria
AU - Lemke, Johannes R.
AU - Flück, Christa
AU - Nemeth, Attila
AU - Phan-Hug, Franziska
AU - Pignatelli, Duarte
AU - Popovic, Vera
AU - Pekic, Sandra
AU - Quinton, Richard
AU - Szinnai, Gabor
AU - L'Allemand, Dagmar
AU - Konrad, Daniel
AU - Sharif, Saba
AU - Iyidir, Özlem Turhan
AU - Stevenson, Brian J.
AU - Yang, Huanming
AU - Dunkel, Leo
AU - Pitteloud, Nelly
N1 - Publisher Copyright:
© 2018 The authors.
PY - 2018/4
Y1 - 2018/4
N2 - Objective: Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. Design: We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. Methods: Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). Results: Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10-11) or controls (18%, P = 5.5 × 10-12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10-7). Conclusions: Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.
AB - Objective: Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. Design: We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. Methods: Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). Results: Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10-11) or controls (18%, P = 5.5 × 10-12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10-7). Conclusions: Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.
UR - https://www.scopus.com/pages/publications/85044761932
U2 - 10.1530/EJE-17-0568
DO - 10.1530/EJE-17-0568
M3 - 文章
C2 - 29419413
AN - SCOPUS:85044761932
SN - 0804-4643
VL - 178
SP - 377
EP - 388
JO - European Journal of Endocrinology
JF - European Journal of Endocrinology
IS - 4
ER -
