SFEBES2014 Poster Presentations Growth and development (9 abstracts)
A novel gene affecting the timing of puberty
Sasha Howard 1 , Leo Guasti 1 , Helen Storr 1 , Lou Metherell 1 , Anna Cariboni 3 , Michael Barnes 1 , Claudia Cabrera 1 , Karoliina Wehkalampi 2 & Leo Dunkel 1
1Queen Mary, University of London, London, UK; 2Children’s Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland; 3University College London, London, UK.
Background: Disturbances of pubertal timing affect >4% of the population and are associated with adverse health outcomes. Studies estimate 60–80% of variation in pubertal onset is genetically determined, but few genetic factors are known. We hypothesise that causal variants will be low-frequency, intermediate-impact variants and will be enriched in populations at the extremes of normal pubertal timing. Families with constitutional delay in growth and puberty (CDGP) have pubertal onset delayed by >2 S.D., often with an apparent autosomal dominant inheritance pattern.
Methods: Seven highly informative families from our large, accurately phenotyped CDGP cohort were selected for whole exome sequencing. Annotation and filtering of variants produced an extensive list of potential causative mutations that segregate with trait. Variants were ranked on the basis of presence in greater than one family, minor allele frequency <5% or novel, predicted effect on the protein and conservation. Pathway analysis was performed to identify genes with action within the hypothalamic–pituitary–gonadal axis or in linkage disequilibrium (D’>0.8) with loci identified by genome-wide association studies (GWAS) of age-at-menarche.
Results: The 15 top-ranking genes identified all contained non-synonymous missense variants segregating an autosomal dominant pattern. Validation of these 15 genes through targeted re-sequencing in a further 288 CDGP individuals has identified a novel candidate gene, with variants in nine families. This gene has a predicted role in neural outgrowth and is expressed in nasal placode mesenchyme during embryogenesis, suggesting a possible function in GnRH neuronal development. Minimal overlap with GWAS loci was identified. Functional studies of these novel variants are in progress.
Discussion: We describe our strategy for identification of novel causal gene variants from next-generation sequencing data in this common condition. In addition to the exciting finding of a novel gene implicated in the timing of puberty, our results highlight the significant genetic heterogeneity seen in CDGP.
Volume 34
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more