SUN-034 Genetic Diagnosis of Congenital Isolated or Combined Growth Hormone Deficiency by Massive Parallel Sequencing Using a Target Gene Panel

Background: Congenital GH deficiency (GHD) can be isolated (IGHD) or combined with other pituitary hormone deficiencies (CPHD). The identification of mutations has clinical implications for the management of patients and genetic counseling. Objective: to conduct a prospective molecular-genetic analysis in genes associated with IGHD or CPHD. Method: 119 patients (65 males) with IGHD (n= 27) or CPHD (n= 92) were studied using target gene approach. Targeted regions (involving 26 genes associated with GHD) were captured using Agilent Sure Select technology. Sequencing was performed with Illumina NextSeq. All variants were absent or extremely rare in public databases and were classified according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP). Results: Eight patients (6.7%) had variants classified as pathogenic (n = 7) or likely pathogenic (n = 4). Two loss of function mutations were found in homozygous state in GHRHR receptor [c.57+1G>A];[c.57+1G>A] and [c.820_821insC];[c.820_821insC]. Two nonsense variants were in heterozygous state in GLI2 [c.1681G>T] and OTX2 [c.319C>T] and two heterozygous missense variants were identified in TGIF1 [c.260A>T] and GHSR [c.545T>C] - the last variant was present in two different individuals. A compound heterozygous variant in PROP1 [c.301_302del];[ c.109+1G>A] was previously published with a cohort of PROP1 Brazilian patients. Conclusion: The panel established the diagnosis of 8 patients and the patients with negative results are candidates for whole exome sequencing.