SFEBES2014 Poster Presentations Growth and development (9 abstracts)
Altered frequency of sequence variants in growth-related genes in children with short stature
Philip Murray 1, , Adam Stevens 1 , Daniel Hanson 1 , Andrew Whatmore 1 , Mireille Bonnemarie 3 , Laurent Naudin 3 , Pascale Dutailly 3 , Patrice Denefle 3 & Peter Clayton 1,
1University of Manchester, Manchester, UK; 2Royal Manchester Children’s Hospital, Manchester, UK; 3IPSEN Pharma SAS, Boulogne-Billancourt, France.
Background: Many children with short stature (defined as height SDS <−2 S.D.) have no identified cause for their growth impairment and are classified as either small for gestational age (SGA) or idiopathic short stature (ISS) depending on birth size. Adult height is a polygenic trait and has been associated with >180 single nucleotide polymorphisms (SNPs) to date. We hypothesized that sequence variants (SNPs or insertion/deletions (indels)) in candidate genes (associated with short stature disorders, growth pathways or adult height) may contribute to the growth impairment in ISS and SGA children.
Study population: 263 children and 263 ethnically matched controls from nine European countries classified as either ISS or SGA and enrolled in the EPIGROW study in whom next generation sequencing of 232 candidate genes had been performed.
Methods: Analysis of the sequencing data to determine genes with a different frequency of SNPs or indels between the patient and control cohorts. SNP/indel frequency was considered to be different where a Benjamini–Hochberg adjusted P value from a χ2 test was <0.05. SNP/indel frequency was assessed for both carriage of SNP/indel (homozygous+heterozygous vs normal) and carriage of homozygous SNP/indel (homozygous vs heterozygous+normal).
Results: 30 genes were identified where SNP carriage frequency (homozygous+heterozygous) was significantly different. In patients SNP frequency was increased for 12 genes and decreased for 18 genes. These included IGFALS (↓), HRAS (↑), STAT5b (↓) and FANCA (↓) which are associated with short stature conditions, MAP2K1 (↑) and SOCS1 (↑) associated with growth pathways and SDR16A5 (↑) associated with adult height. No genes were identified in which the frequency of carriage (homozygous+heterozygous) of an indel significantly differed. For one gene RPS6KA6 (a protein kinase involved in growth factor signalling), carriage of homozygous indels were more common in patients (P=0.001).
Conclusions: There are growth-related genes in which sequence variant frequency were significantly different between children with short stature and controls. Combinations of functional variants in these genes may contribute to growth impairment.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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