ESPE Abstracts

Introduction: The UK 100,000 Genomes Project (100KGP) recently investigated the genetic basis of rare disease using whole genome sequencing. The genetic aetiology of most rare paediatric endocrine disease remains unexplained.

Methods: Children with genetically unexplained rare endocrine disease attending a subspecialist paediatric endocrinology clinic underwent whole genome sequencing as part of the 100KGP. Parental DNA was obtained where possible. Virtual gene panels were applied and bioinformatic analysis used to filter and prioritise variants. Variant pathogenicity was classified using ACMG guidelines, and relevance to clinical phenotype assessed at multidisciplinary (endocrine and genetic) meetings.

Results: A total of 177 children were recruited (58.8% male (n=104); 66.7% trios (n=30), 17.8% duos (n=8), 15.5% individuals (n=7)). Diagnoses included septo-optic dysplasia (32.2%, n=57), congenital hypopituitarism (26.5%, n=47), short stature (11.9%, n=21), isolated growth hormone deficiency (16.4%, n=29), hypogonadotropic hypogonadism (4.0%, n=7) and other rare endocrine conditions (9.0%, n=16). Multiple pituitary hormone deficiencies were present in 50.8% (n=90). Of the 82.2% (n=149) children with pituitary imaging, most had structurally abnormal pituitary glands (85.9%, n=128). A genetic diagnosis was obtained in 25.6% (n=45) of children. Within this group, heterozygote variants were detected in 66.6% (n=30) in several genes (ACTB, ACAN, ARID1B, EP300, PTPN11, SIX3, TBL1X41, ADNP, KRAS, PTCHD1, GRIN2A, SMC3, DEPDC5, GLI2, IGF1R, NPR2, NF1, N2RF1, CLCN7, DPF2, EFNB1, FGFR1, FGFR3, TGIF1, ZNF148). These were confirmed de novo in 23.3% (n=7). Homozygous or compound heterozygote variants were found in 31.1% (n=14) within AIRE, PKHD1, TYR, CHD7, DHTKD1, CEP57, BBS1, CPS1, GHRHR, TBC1D32, and CLPP. One patient had variants detected in both GLI2 and LHX4. Diagnoses were associated with extra-endocrine features in 44.4% (n=20). There were fewer genetic diagnoses in children with septo-optic dysplasia compared to those with other pituitary conditions (15.8% vs 30.3%, P=0.042). There were more genetic diagnoses in children with developmental delay (35.9% vs 19.5%, P=0.016) and other extra-endocrine features (34.8% vs 8.1%, P=<0.001) compared to those without. There were no significant associations between obtaining a genetic diagnosis and patient gender, pituitary gland structure, or number of pituitary hormone abnormalities.

Conclusion: A genetic diagnosis was achieved in a significant proportion of children recruited to the 100KGP. This knowledge empowers families and demonstrates the value of integrating next generation sequencing approaches into standard clinical care. Several genetic diagnoses identified influenced clinical management. Expanding this analysis to include other coding and non-coding regions may yield further diagnoses.