Abstract
PurposeCongenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms via a candidate gene-based mutational burden analysis.MethodsWe retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis.ResultsIn 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD (NF1 [c.2329T>A, c.7131C>G], GHRHR [c.731G>A], STAT5B [c.1102delC], HRAS [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that POLR3A (p = 0.005), SUFU (p = 0.006), LHX3 (p = 0.021) and CREB3L4 (p = 0.040) represented top genes enriched in GHD patients.ConclusionOur study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.
Highlights
Congenital growth hormone deficiency (GHD) is a rare disease characterized by decreased growth hormone (GH) secretion of the anterior pituitary, which leads to growth impairment and metabolic dysfunction in children [1, 2]
There were no significant differences in sex-distribution and delayed bone age between Group I and II except for age, Z-score of height, peak GH concentration, in GHinsulin like growth factor 1 (IGF1) and growth velocity (Table 1)
Among all the genes related to GH synthesis and secretion, we found that rare variants of uncertain significance (VUS) in 40 genes enriched in our GHD cohort (Table S2)
Summary
Congenital growth hormone deficiency (GHD) is a rare disease characterized by decreased growth hormone (GH) secretion of the anterior pituitary, which leads to growth impairment and metabolic dysfunction in children [1, 2]. The causes of GHD include pituitary dysplasia and pathogenic mutations in GHinsulin like growth factor 1 (IGF1) axis-related genes, such as GH1, GHRHR [3, 4]. Clinical presentation of symptoms including neonatal hypoglycemia, midfacial defects such as cleft lip or palate, history of external head injuries, and vacuolated Sella turcica found in pituitary magnetic resonance imaging (MRI) or pituitary dysplasia can assist in GHD diagnosis [7,8,9]. According to the guidelines set by the GH Research Society (GRS), the clinical diagnosis of GHD needs to be based on growth and development data, and data from various laboratory tests (i.e. decreased peak of GH provocation test with two different agents, serological detection of IGF1 and IGF1BP3, combined gonadal hormone when necessarily, and genetic test), and imaging data (craniocerebral MRI) [10]. There is still a high falsepositive rate in the existing serological diagnosis methods [11,12,13,14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
