ESPEYB21 1. Pituitary and Neuroendocrinology Novel Genes (5 abstracts)
1.9. Exome Sequencing has a high diagnostic rate in sporadic congenital hypopituitarism and reveals novel candidate genes
Martinez-Mayer J , Vishnopolska S , Perticarari C , Garcia LI , Hackbartt M , Martinez M , Zaiat J , Jacome-Alvarado A , Braslavsky D , Keselman A , Bergadá I , Marino R , Ramírez P , Garrido NP , Ciaccio M , Di Palma MI , Belgorosky A , Forclaz MV , Benzrihen G , D’Amato S , Cirigliano ML , Miras M , Nuñez AP , Castro L , Mallea-Gil MS , Ballarino C , Latorre-Villacorta L , Casiello AC , Hernandez C , Figueroa V , Alonso G , Morin A , Guntsche Z , Lee H , Lee E , Song Y , Marti MA & Perez-Millan MI
J Clin Endocrinol Metab. 2024 May 8:dgae320. doi: 10.1210/clinem/dgae320. PubMed: 38717911
Brief Summary: This study significantly advances our understanding of the genetic underpinnings of congenital hypopituitarism (CH) by utilizing whole exome sequencing (WES) in a large cohort of patients from Argentina.
CH is a complex and highly heterogeneous disorder that is associated with highly variable clinical phenotypes that range in severity (1). The aetiology of CH may extend beyond monogenic causes, involving oligogenic, polygenic, or multifactorial factors driven by gene-environment interactions (2). High-throughput analyses offer the opportunity to identify cases of oligogenic disease, in which variants in multiple genes collaborate to produce the clinical features (3). Large cohort studies are required to detect causal variants, which may be rare or common.
This study found a diagnostic yield of 19.1% for known pathogenic (P) variants and an additional 16% for likely pathogenic (LP) variants in novel candidate genes, demonstrating the complexity and heterogeneity of the genetic aetiology of CH.
One key findings was the identification of ROBO1 as the most frequent gene mutation in this cohort, which extends beyond its previously known association with pituitary stalk interruption syndrome (PSIS). The study also introduces new candidate genes, and members of the PTPN family, further broadening the spectrum of potential genetic causes of CH. These discoveries not only enhance our understanding of CH but also emphasize the role of WES in identifying rare and novel genetic variants that might be missed by more targeted approaches.
Moreover, the study highlights the importance of considering syndromic cases and the need for comprehensive genetic analysis, particularly in populations with diverse genetic backgrounds like Argentina. The authors advocate for the inclusion of WES (including CNV analysis) in routine diagnostic workflows for CH, especially in cases with complex or atypical presentations.
In conclusion, this study provides valuable insights into the genetic diversity of CH and reinforces the necessity of advanced genomic techniques in improving diagnostic accuracy.
References: 1. Gregory LC, Cionna C, Cerbone M, Dattani MT. Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders. Genet Med. 2023;25(9):100881.2. Bougnères P. Congenital Hypopituitarism: Current Agnostic Genetics Faces Its Limits. J Clin Endocrinol Metab. 2024.3. Bando H, Urai S, Kanie K, Sasaki Y, Yamamoto M, Fukuoka H, et al. Novel genes and variants associated with congenital pituitary hormone deficiency in the era of next-generation sequencing. Front Endocrinol (Lausanne). 2022;13:1008306.
Volume 21
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ESPE Yearbook of Paediatric Endocrinology
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