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

Abstract

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 months of age with a history of intrauterine growth restriction (IUGR), poor feeding, mild developmental delays, microcephaly, and dysmorphic facial features. Whole exome sequencing revealed a novel c.1464 T>G (p.Cys488Trp) variant in the IGF1R gene, initially classified as a variation of uncertain significance (VUS). We enrolled the patient in 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 IGF1 level consistent with abnormal IGF1 receptor function. Work-up 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 URDC, a multidisciplinary clinical program whose major goal is to end the diagnostic odyssey in patients with rare diseases.

Comprehensive genetic testing approaches as the basis for personalized management of growth disturbances: current status and perspectives

“…1 ) ( 47 ), as the rationale for this procedure has been corroborated by numerous examples (e.g. ( 43 ), Table 1 – case 1 ( 48 )).…”

“…variants of uncertain clinical significance (VUS) and incidental findings. The chance to detect these types of variants increases with the scale of genetic tests ( Table 2 ), as impressively illustrated for genetic testing in hereditary breast cancer ( 42 , 43 ).…”

Undiagnosed rare disease clinic identifies a novel UBE3A variant in two sisters with Angelman syndrome: The end of a diagnostic odyssey

“…Each sister had a negative methylation analysis but was subsequently found to have a maternally inherited UBE3A variant, c.2443C>T p.(Pro815Ser) in the HECT domain (Figure 1B), that was initially classified as a variant of uncertain significance (VUS). To further investigate this variant, the patients were enrolled in Indiana University's Undiagnosed Rare Disease Clinic (URDC), a multidisciplinary program with the aim to provide families affected by rare genetic diseases with diagnoses 12 …”

“…To further investigate this variant, the patients were enrolled in Indiana University's Undiagnosed Rare Disease Clinic (URDC), a multidisciplinary program with the aim to provide families affected by rare genetic diseases with diagnoses. 12 2 | RESULTS…”