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Phenotype-Genotype correlation in a familial IGF1R microdeletion case
  1. D C M Veenma1,
  2. H J Eussen2,
  3. L C P Govaerts2,
  4. S W K de Kort3,
  5. R J Odink4,
  6. C H Wouters2,
  7. A C S Hokken-Koelega5,
  8. A de klein2,*
  1. 1 Department of Paediatrics and Clinical Genetics, Erasmus MC, Rotterdam, Netherlands;
  2. 2 Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands;
  3. 3 Department of Paediatrics, Erasmus MC-Sophia, Rotterdam, Netherlands;
  4. 4 Department of paediatrics, Catharina Hospital, Eindhoven, Netherlands;
  5. 5 Department of paediatrics and endocrinology, Erasmus MC, Sophia, Rotterdam, Netherlands
  1. Correspondence to: Annelies de Klein, Clinical Genetics, Erasmus MC, P.O.Box 2040, Rotterdam, 3000 CA, Netherlands; a.deklein{at}


Background: IGF1R (Insulin-Like Growth Factor 1 Receptor) haploinsufficiency is a rare event causing difficulties in defining clear genotype-phenotype correlations, although short stature is its’ well-established hallmark. Several pure 15q26 monosomies (n = 22) have been described in literature, including those with breakpoints proximal of the IGF1R gene. Clinical heterogeneity is characteristic for these mainly de novo telomeric deletions and is illustrated by the involvement of several different organ systems such as heart, diaphragm, lungs, kidneys and limbs, besides growth failure in the patient’s phenotype. The clinical variability in these patients could be explained by the haploinsufficiency of multiple genes besides the IGF1R gene. In comparison, the six different IGF1R mutations revealed to date exhibit some variance in their clinical features as well, probably because different parts of the downstream IGF1R signalling cascade were affected.

Methods and results: Using the recently developed technique Multiplex Ligation-dependant Probe Amplification (MLPA) we identified in a Dutch family a chromosome 15q26.3 microdeletion harbouring part of the IGF1R gene. This deletion segregated with short height in seven out of fourteen relatives across three generations. Metaphase Fluorescence In Situ Hybridisation (FISH) and Affymetrix 250k SNP-microarray were used to characterise the deletion into more detail and showed that exons 11-21 of the IGF1R and a small hypothetical protein (LOC 145814) were deleted.

Conclusion: Clinical work-up of this newly identified family which constitutes the smallest (0.095 Mb) pure 15q26.3 interstitial deletion to date, confirms that disruption of the IGF1R gene does not induce major organ malformation or severe mental retardation.

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