ESPE Abstracts

Background: Primary IGF1 deficiency (PIGFD) is a rare disease defined by low IGF1 levels, GH sufficiency and absence of secondary causes of growth failure. Whereas some members of the GH–IGF axis have been shown to be implicated in the severe syndromic forms of PIGFD due to GH insensitivity, genetic causes of less severely affected patients are mostly unknown.

Objective and hypotheses: The aim of the present study was to systematically investigate frequencies of mutations/deletions in selected growth-relevant genes (GHR, PTPN-11, STAT5B, IGFALS, IGF1, IGF2, IGFBP1–4, CUL-7, IRS1, IRS2, AKT1–3, SOCS2/3, JAK2, SHP2, SH2-B, SHOX1, and SHOX2) in patients with PIGFD.

Method: We performed whole-exome sequencing (WES) in three complete case-parent-trios and eight single patients with PIGFD.

Results: We identified six novel missense mutations with a frequency below 1% in the general population in four different patients. Of these two different missense mutations were identified in SHOX2 (one de novo and one homozygous respectively), two different missense mutations were identified in IRS1 in two different patients, two missense mutations were identified in IGFBP4 and SOCS3. Furthermore we identified one known missense mutation in GHR. The mutation in GHR was transmitted from an affected mother; the mutation in SOCS3-3 was transmitted from an affected father.

Conclusion: Preliminary WES analysis in our patient cohort with PIGFD identified putative disease causing mutations in three patients (twice transmitted from an affected parent, once de novo). The identification of four additional novel missense mutations warrants segregation analysis in the parents as soon as DNA will be available. WES provides an efficient method to identify putative disease causing mutations in growth-relevant genes in subjects with PIGFD.