Expanding Genetic and Functional Diagnoses of IGF1R Haploinsufficiencies

Paula Ocaranza, Marjorie C. Golekoh, Shayne F. Andrew, Michael H. Guo, Paul Kaplowitz, Howard Saal, Ronald (Ron) Rosenfeld, Andrew Dauber, Fernando Cassorla, Philippe F. Backeljauw, Vivian Hwa

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: The growth-promoting effects of IGF-I is mediated through the IGF-I receptor (IGF1R), a widely expressed cell-surface tyrosine kinase receptor. IGF1R copy number variants (CNV) can cause pre- and postnatal growth restriction or overgrowth. Methods: Whole exome sequence (WES), chromosomal microarray, and targeted IGF1R gene analyses were performed on 3 unrelated children who share features of small for gestational age, short stature, and elevated serum IGF-I, but otherwise had clinical heterogeneity. Fluorescence-activated cell sorting (FACS) analysis of cell-surface IGF1R was performed on live primary cells derived from the patients. Results: Two novel IGF1R CNV and a heterozygous IGF1R nonsense variant were identified in the 3 patients. One CNV (4.492 Mb) was successfully called from WES, utilizing eXome-Hidden Markov Model (XHMM) analysis. FACS analysis of cell-surface IGF1R on live primary cells derived from the patients demonstrated a ∼50% reduction in IGF1R availability associated with the haploinsufficiency state. Conclusion: In addition to conventional methods, IGF1R CNV can be identified from WES data. FACS analysis of live primary cells is a promising method for efficiently evaluating and screening for IGF1R haploinsufficiency. Further investigations are necessary to delineate how comparable IGF1R availability leads to the wide spectrum of clinical phenotypes and variable responsiveness to rhGH therapy.

Original languageEnglish (US)
JournalHormone Research in Paediatrics
DOIs
StateAccepted/In press - Apr 10 2017

Fingerprint

Haploinsufficiency
Exome
Flow Cytometry
Insulin-Like Growth Factor I
IGF Type 1 Receptor
Receptor Protein-Tyrosine Kinases
Growth
Gestational Age
Phenotype
Serum
Genes

Keywords

  • FACS analysis
  • IGF1R copy number variants
  • Short stature
  • Whole exome sequencing

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Ocaranza, P., Golekoh, M. C., Andrew, S. F., Guo, M. H., Kaplowitz, P., Saal, H., ... Hwa, V. (Accepted/In press). Expanding Genetic and Functional Diagnoses of IGF1R Haploinsufficiencies. Hormone Research in Paediatrics. https://doi.org/10.1159/000464143

Expanding Genetic and Functional Diagnoses of IGF1R Haploinsufficiencies. / Ocaranza, Paula; Golekoh, Marjorie C.; Andrew, Shayne F.; Guo, Michael H.; Kaplowitz, Paul; Saal, Howard; Rosenfeld, Ronald (Ron); Dauber, Andrew; Cassorla, Fernando; Backeljauw, Philippe F.; Hwa, Vivian.

In: Hormone Research in Paediatrics, 10.04.2017.

Research output: Contribution to journalArticle

Ocaranza, P, Golekoh, MC, Andrew, SF, Guo, MH, Kaplowitz, P, Saal, H, Rosenfeld, RR, Dauber, A, Cassorla, F, Backeljauw, PF & Hwa, V 2017, 'Expanding Genetic and Functional Diagnoses of IGF1R Haploinsufficiencies', Hormone Research in Paediatrics. https://doi.org/10.1159/000464143
Ocaranza, Paula ; Golekoh, Marjorie C. ; Andrew, Shayne F. ; Guo, Michael H. ; Kaplowitz, Paul ; Saal, Howard ; Rosenfeld, Ronald (Ron) ; Dauber, Andrew ; Cassorla, Fernando ; Backeljauw, Philippe F. ; Hwa, Vivian. / Expanding Genetic and Functional Diagnoses of IGF1R Haploinsufficiencies. In: Hormone Research in Paediatrics. 2017.
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