Genetic IGF1R defects: new cases expand the spectrum of clinical features

Gönç, E. Nazlı; Özön, Z. Alev; Oğuz, Sümeyra; Kabacam, Serkan; Taşkıran, Ekim Z.; Kiper, Pelin Özlem Şimşek; Ütine, Gülen Eda; Alikaşifoğlu, Ayfer; Kandemir, Nurgün; Boduroğlu, Osman Koray

doi:10.1007/s40618-020-01264-y

Cited by 5 publications

(9 citation statements)

References 32 publications

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“…Finally, the siblings with mutations in LIG4 gene were previously investigated for short stature and microcephaly and reported in a cohort of patients with IGF1R mutations (Gonc et al . 2020).…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic yield of whole‐exome sequencing in non‐syndromic intellectual disability

Taşkıran

Karaosmanoğlu

Koşukçu

et al. 2021

J intellect Disabil Res

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Background Aetiological diagnosis in non‐syndromic intellectual disability (NSID) still poses a diagnostic challenge to clinicians. Methods Screening is currently achieved by chromosomal microarrays followed by whole‐exome sequencing (WES). In search for the aetiological yield of WES in patients with NSID, 59 unrelated patients were studied. Results Among the 59 patients, 44 (74.6%) were from consanguineous unions. Epilepsy was present in 11 (37.9%), behavioural problems in 12 (41.4%) and autistic features in 14 (48.3%). WES analysis resulted in molecular diagnosis in 29 patients (49.2%). Some of the genes were specific for nervous system functioning, like HERC1, TBC1D7, LINS, HECW2, DEAF1, HNMT, DLG3, NRXN1 and HUWE1. Others were ubiquitously expressed genes involved in fundamental cellular processes, like IARS, UBE3A, COQ4, TAF1, SETBP1, ARV1, ZC4H2, KAT6A, ASXL3, THOC6, HNRNPH2, TUBA8 and KIF1A. Twenty‐two (75.8%) were consanguineously married; however, only 12 (41.4%) of the detected genes caused autosomal recessive phenotypes. Conclusions This cohort suggests that recessive genes probably represent an actually smaller subgroup of NSID, even among families with consanguinity. Although in societies with high consanguinity rates, considering the recessive inheritance first seems to be an advantageous strategy, de novo mutations in autosomal dominantly expressed genes represent the major aetiological group in patients with NSID, even among those patients from consanguineous families.

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Section: Discussionmentioning

confidence: 99%

“…The present siblings with KDM5C mutations had autistic features not reported in previous patients. Finally, the siblings with mutations in LIG4 gene were previously investigated for short stature and microcephaly and reported in a cohort of patients with IGF1R mutations (Gonc et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Diagnostic yield of whole‐exome sequencing in non‐syndromic intellectual disability

Taşkıran

Karaosmanoğlu

Koşukçu

et al. 2021

J intellect Disabil Res

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“…Heterozygous mutations in the IGF1R gene, causing partial resistance to IGF1, are associated with several metabolic and endocrine alterations such as hypo/hyperlipidemia, hypothyroidism, diabetes/insulin resistance or even hypoglycaemia (7)(8)(9). These metabolic disorders associated with deletion of the IGF1R pathway revealed that IGF1/IGF1R signaling plays an important role in energy metabolism, muscle glucose uptake and also coordinates the responses to nutrient intake and the appropriate metabolic changes that enable cells to tolerate a variety of stressful stimuli (10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

IGF1R is a mediator of sex-specific metabolism in mice: Effects of age and high-fat diet

Pérez-Matute

López²,

Íñiguez³

et al. 2022

Front. Endocrinol.

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ObjectiveWe aimed to investigate the short and long-term metabolic consequences of IGF1R systemic gene deficiency in mice.MethodsUBC-CreERT2, Igf1rfl/fl mutant mice were used to suppress IGF1R signaling in adult tissues by inducing postnatal generalized Igf1r deletion with tamoxifen. Animals were analyzed at two different ages: i) 13-weeks old young mice, and ii) 12-months old middle-aged mice. In addition, the effects of 10 weeks-long high-fat diet (HFD) were investigated in middle-aged mice.ResultsYoung IGF1R-deficient mice were insulin-resistant, with high IGF1, growth hormone (GH) and IGFBP3, as well as low IGFBP2 circulating levels. Males also presented increased triglycerides in liver. In contrast, middle-aged mice did not clearly show all of these alterations, suggesting possible compensatory effects. Middle-aged IGF1R-deficient male mice were able to counteract the negative effects induced by aging and HFD in adiposity, inflammation and glucose metabolism. A metabolic sexual dimorphism dependent on IGF1R was observed, especially in middle-aged mice.ConclusionsThese results demonstrate that IGF1R is involved in metabolic homeostasis, with effects modulated by diet-induced obesity and aging in a sex dependent manner. Thus, IGF1R deficiency in mice is proposed as a useful tool to understand metabolic alterations observed in patients with IGF1R gene deletions.

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“…Similarly, several patients with pathogenic variants of IGF1R, mainly in the heterozygous state and rarely in the compound heterozygous state, have also been reported to exhibit growth retardation before and after birth [7,8]. Short children born smallfor-gestational age (SGA) have been reported to possibly include patients with IGF1R pathogenic variants [9].…”

Section: Introductionmentioning

confidence: 99%

Diagnosis of Chromosome 15q-Terminal Deletion Syndrome through Elevated Fasting Serum Growth Hormone Levels

et al. 2022

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Chromosome 15q26-qter deletion syndrome is a rare disease that causes prenatal and postnatal growth retardation, microcephaly, developmental delay, and congenital heart diseases, mainly due to haploinsufficiency of IGF1R. In addition, patients with pathogenic variants of the IGF1R show similar symptoms. We report the case of a 5-month-old girl with prenatal and postnatal growth retardation, microcephaly, and congenital heart disease. At 5 months of age, her length was 54.7 cm (−4.3 SD), her weight was 4.4 kg (−3.1 SD), and her head circumference was 37.4 cm (−2.8 SD), thus presenting severe growth retardation. Repeated pre-feeding serum GH levels were abnormally high (26.1–85.5 ng/mL), and IGF-1 levels (+0.16 to +1.2 SD) were relatively high. The 15q sub-telomere fluorescence in situ hybridization analysis revealed a heterozygous deletion in the 15q terminal region. Whole-genome single nucleotide polymorphism microarray analysis showed a terminal deletion of 6.4 Mb on 15q26.2q26.3. This is the first report showing that fasting GH levels are high in early infancy in patients with IGF1R abnormalities. In addition to relatively high IGF-1 levels, elevated fasting GH levels in early infancy may contribute to the diagnosis of IGF1R abnormalities.

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Genetic IGF1R defects: new cases expand the spectrum of clinical features

Cited by 5 publications

References 32 publications

Diagnostic yield of whole‐exome sequencing in non‐syndromic intellectual disability

Diagnostic yield of whole‐exome sequencing in non‐syndromic intellectual disability

IGF1R is a mediator of sex-specific metabolism in mice: Effects of age and high-fat diet

Diagnosis of Chromosome 15q-Terminal Deletion Syndrome through Elevated Fasting Serum Growth Hormone Levels

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