High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is characterized by lack of normal pubertal development due to deficient gonadotropin-releasing hormone (GnRH) secretion or action, and is caused by genetic defects in several genes. Mutations in the CHD7 gene cause CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital hypoplasia and Ear abnormalities), but have also been found in patients with isolated CHH. The aim of this study was to identify CHD7 mutations in patients with CHH. Fifty Portuguese patients with CHH were screened for mutations in the CHD7 gene by DNA sequencing. Eight (16%) patients had CHD7 rare sequence variants that consisted of six missense (p.Gly388Glu, p.His903Pro, p.Thr1082Ile, p.Val1452Leu, p.Asp1854Gly, and p.Arg2065His) and two synonymous (p.Ser559Ser, and p.Ala2785Ala) mutations. Five of these mutations have never been reported before. Three CHD7 mutations occurred in patients that had mutations in additional CHH-genes. This study uncovered novel genetic variants that expand the known spectrum of mutations associated with CHH. The frequency of CHD7 mutations in this cohort was higher than that of other major CHH-genes and confirms the importance of including CHD7 in the genetic testing of CHH, even in the absence of additional CHARGE features.This work was supported by the Portuguese Foundation for Science and Technology (PTDC/SAU-GMG/098419/2008) and by “Programa Operacional do Centro, Centro 2020” through the funding of the ICON project (Interdisciplinary Challenges On Neurodegeneration; CENTRO-01-0145-FEDER-000013)”. The authors are grateful to the following clinicians who contributed with patient samples and data: Ana Saavedra (Porto), Ana Varela (Porto), António Garrão (Lisboa), Carla Baptista (Coimbra), Carla Meireles (Guimarães), Carolina Moreno (Coimbra), Catarina Limbert (Lisboa) Cíntia Correia (Porto), Cláudia Nogueira (Porto), Duarte Pignatelli (Porto), Eduardo Vinha (Porto), Filipe Cunha (Porto), Francisco Carrilho (Coimbra), Luísa Barros (Coimbra), Luísa Cortez (Lisboa), Margarida Bastos (Coimbra), Maria João Oliveira (Porto), Mariana Martinho (Penafiel), Miguel Melo (Coimbra), Nuno Vicente (Coimbra), Patrícia Oliveira (Coimbra), Paula Freitas (Porto), Raquel Martins (Porto), Selma Souto (Porto), Susana Gama (Famalicão), and Teresa Martins (Coimbra)