Reanalysis of a novel variant in the IGF1R gene in a family with variable prenatal and postnatal growth retardation and dysmorphic features: benefits and feasibility of IUSM-URDC (Undiagnosed Rare Disease Clinic) program

Cold Spring Harb Mol Case Stud. 2022 Mar 24;8(2):a006170. doi: 10.1101/mcs.a006170. Print 2022 Feb.


IGF1R-related disorders are associated with intrauterine growth restriction (IUGR), postnatal growth failure, short stature, microcephaly, developmental delay, and dysmorphic facial features. We report a patient who presented to medical genetics at 7 mo of age with a history of IUGR, poor feeding, mild developmental delays, microcephaly, and dysmorphic facial features. Whole-exome sequencing revealed a novel c.1464T > G p.(Cys488Trp) variant in the IGF1R gene, initially classified as a variation of uncertain significance (VUS). We enrolled the patient in the URDC (Undiagnosed Rare Disease Clinic) and performed additional studies including deep phenotyping and familial segregation analysis, which demonstrated that the patient's IGF1R VUS was present in phenotypically similar family members. Furthermore, biochemical testing revealed an elevated serum IGF-1 level consistent with abnormal IGF-1 receptor function. Workup resulted in the patient's variant being upgraded from a VUS to likely pathogenic. Our report expands the variant and phenotypic spectrum of IGF1R-related disorders and illustrates benefits and feasibility of reassessing a VUS beyond the initial molecular diagnosis by deep phenotyping, 3D modeling, additional biochemical testing, and familial segregation studies through the URDC, a multidisciplinary clinical program whose major goal is to end the diagnostic odyssey in patients with rare diseases.

Keywords: downslanted palpebral fissures; high forehead; long philtrum; low hanging columella; microcephaly; mild global developmental delay; moderate intrauterine growth retardation; moderate postnatal growth retardation; tented upper lip vermilion.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple
  • Feasibility Studies
  • Female
  • Fetal Growth Retardation / genetics
  • Growth Disorders / genetics
  • Heterozygote
  • Humans
  • Microcephaly* / genetics
  • Pregnancy
  • Rare Diseases*
  • Receptor, IGF Type 1 / genetics


  • IGF1R protein, human
  • Receptor, IGF Type 1

Supplementary concepts

  • Insulin-Like Growth Factor I, Resistance To