Endocrine Abstracts

Introduction: The UK 100,000 Genomes Project (100KGP) investigated the genetic basis of rare disease. The molecular drivers of most paediatric pituitary disease remains unknown.

Methods: Children with genetically unexplained pituitary disorders attending a tertiary paediatric endocrinology centre were recruited to the 100KGP and underwent whole genome sequencing. Parental DNA was obtained where feasible. Virtual gene panels were applied and bioinformatic pipelines used for variant filtering. A variant was considered a finding if it met ACMG pathogenicity criteria and if it was relevant to the phenotype as assessed by a multidisciplinary endocrine and genetic team.

Results: A total of 140 children were recruited (61.8% male (n=89)). Diagnoses included septo-optic dysplasia (39.6%, n=57), congenital hypopituitarism (32.6%, n=47), isolated growth hormone deficiency (17.9%, n=25), growth hormone neurosecretory dysfunction (2.8%, n=4), hypogonadotropic hypogonadism (4.9%, n=7) and holoprosencephaly (2.8%, n=4). Multiple pituitary hormone deficiencies were present in 62.5% (n=90). Most children had structurally abnormal pituitary glands (87.5%, n=126). A genetic diagnosis was obtained in 20.1% (n=29) of children (65.6% trios (n=19); 34.5% duos/individuals (n=10)). Heterozygote variants were detected in 72.4% (n=21) in N2RF1, ACTB, TGIF1, PTPN11, KRAS, DPF2, SMC3, ZNF148, FGFR1, FGFR3, SIX3, GRIN2A, GLI2, CLCN7, EP300, TBL1XR1, and GHRHR; de novo in 23.8% (n=5). Homozygous or compound heterozygote variants were found in 27.6% (n=8) within GLI2, PKHD1, CHD7, DHTKD1, GHRHR, and TBC1D32. One child carried variants in both GLI2 and LHX4. Children with extra-endocrine features were more likely to have a genetic finding identified compared to those with solely endocrine presentations (27.6% vs 8.8%, P=0.006). A finding was confirmed in 15.8% of children with septo-optic dysplasia compared to 23.8% of those with other pituitary conditions and in 28.0% of those with development delay compared to 16.0% of those without. There were no significant associations between obtaining a genetic diagnosis and patient gender, pituitary gland structure, or number of pituitary endocrinopathies.

Conclusion: The 100KGP facilitated a novel approach to diagnosing the molecular basis of paediatric pituitary disease. We demonstrate the importance of using a transparent, process-driven, multidisciplinary approach to variant classification and the value of integrating next generation sequencing approaches into standard clinical care.