ESPEYB21 7. Puberty Clinical Guidance and Studies (8 abstracts)
7.7. Contributions of common genetic variants to constitutional delay of puberty and idiopathic hypogonadotropic hypogonadism
Lippincott MF , Schafer EC , Hindman AA , He W , Brauner R , Delaney A , Grinspon R , Hall JE , Hirschhorn JN , McElreavey K , Palmert MR , Rey R , Seminara SB , Salem RM , Chan YM & Delayed Puberty Genetics Consortium
J Clin Endocrinol Metab. 2024 Mar 13:dgae166. doi: 10.1210/clinem/dgae166. PMID: 38477512. https://pubmed.ncbi.nlm.nih.gov/38477512/
Brief Summary: this case-control study shows that the common genetic variants that influence pubertal timing in the general population also contribute to constitutional delay of puberty (CDP) and less significantly to normosmic idiopathic hypogonadotropic hypogonadism (IHH).
CDP and IHH are two different conditions that are notoriously difficult to distinguish clinically on initial presentation. Because CDP has clear heritability traits1, and half of individuals with IHH have an identified genetic cause2, the authors hypothesized that common genetic variants could help to separate these conditions.
Polygenic scores (PGS) were established for pubertal timing (age at voice-breaking and facial hair for boys and age at menarche for girls) based on genome-wide association studies3,4. 80 individuals with CDP, 301 with normosmic IHH and 348 with Kallmann syndrome (KS) were analysed. DNA was extracted from saliva and blood samples. PGS scores were established and then compared to controls (9222 genotyped on the same platform as the CDP cohort, and 1868 on the same platform as the normosmic IHH and KS cohort).
There was a strong contribution of common genetic variants to CDP, and only a small contribution to IHH, supporting the idea that they are distinct entities that share some pathophysiological pathways. By contrast, the common genetic variants did not appear to contribute to Kallmann syndrome.
References: 1. Sedlmeyer IL, Hirschhorn JN, Palmert MR. Pedigree analysis of constitutional delay of growth and maturation: determination of familial aggregation and inheritance patterns. J Clin Endocrinol Metab. 2002;87(12):5581-5586. 2. Al Sayed Y, Howard SR. Panel testing for the molecular genetic diagnosis of congenital hypogonadotropic hypogonadism—a clinical perspective. Eur J Hum Genet. 2023;31(4):387-394. 3. Day FR, Thompson DJ, Helgason H, et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet. 2017;49(6):834-841. 4. Hollis B, Day FR, Busch AS, et al. Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan. Nat Commun. 2020;11(1):1536.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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