A novel IGF1R variant in a patient with short stature in qatar

Mohammed Fathima Koolikkad; Zainab Jan; Umlai Umm-Kulthum Ismail; Dinesh Velayutham; Noor Hamed; Hajar Dauleh; Khalid Hussain; Jithesh Puthen Veettil

doi:10.1530/endoabs.110.EP831

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Endocrine Abstracts (2025) 110 EP831 | DOI: 10.1530/endoabs.110.EP831

ECEESPE2025 ePoster Presentations Growth Axis and Syndromes (132 abstracts)

A novel IGF1R variant in a patient with short stature in qatar

Fathima Koolikkad Mohammed ^1,2 , Zainab Jan ¹ , Umm-Kulthum Ismail Umlai ¹ , Dinesh Velayutham ³ , Noor Hamed ⁴ , Hajar Dauleh ⁵ , Khalid Hussain ^5,6 & Puthen Veettil Jithesh ¹

Author affiliations

¹College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar; ²Communicable Disease Center, Hamad Medical Corporation, Doha, Qatar; ³Qatar Precision Health Institute, Doha, Qatar; ⁴Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar; ⁵Division of Endocrinology, Department of Pediatrics, Sidra Medicine, Doha, Qatar; ⁶Division of Endocrinology, Department of Pediatric Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar

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Introduction: Short stature (SS) is a common cause of referral to pediatric endocrinology clinics and can arise from a range of underlying causes. Among the endocrine disorders leading to SS are growth hormone and Insulin Growth Factor-1 (IGF-1) signaling defects. Genetic testing plays a crucial role in uncovering variants in genes, such as type 1- insulin-like growth factor receptor gene (IGF1R), associated with SS to tailor personalized treatment options. Here we report a novel missense variant in IGF1R in a SS patient in Qatar.

Case Presentation: A female patient presented with failure to thrive, SS, and microcephaly at 10 years of age. She was born SGA with birth weight of 2.3kg at term. At evaluation, her height was 121.2cm (-2.89 SD) and weight was 19.15kg (-3.89 SD). Her serum IGF-1 level was 47.7 nmol/L (Normal range: 9.9-71.8) and the growth hormone stimulation test was normal. She has a family history of SS on the paternal side. Whole genome sequencing (WGS) and bioinformatics analysis identified a novel missense heterozygous variant c.2240A>G (p.Asn747Ser) in IGF1R. This variant segregated in an autosomal dominant manner, has a Combined Annotation-Dependent Depletion (CADD) score of 22.4, and was predicted to be ‘disease-causing’ by Mutation Taster. Protein-protein docking of the mutated and wild-type IGF1R with interactor proteins using HADDOCK found that mutant IGF1R showed decreased affinity for IGF1 and higher binding for IGF2 compared to the wild type, thus disrupting the normal IGF1 signaling and leading to IGF1 resistance.

Conclusion: We identified a novel c.2240A>G missense variant in IGF1R in SS patient. Her phenotype is consistent with those findings reported in the literature for IGF1R mutations. This emphasizes the importance of WGS in SS patients and examining IGF1R variants in patients with impaired growth, especially those with elevated or normal levels of circulating IGF-1 in the bloodstream.