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.

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2022-03-24 Print Date: 2022-02-01 DOI:10.1101/mcs.a006170
Annalise Jacobs, Catherine Burns, Purva Patel, Kayla Treat, Benjamin M Helm, Erin Conboy, Francesco Vetrini
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引用次数: 1

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 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.

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一个具有可变产前和产后生长迟缓和畸形特征的家庭中IGF1R基因新变异的再分析:IUSM-URDC(未确诊罕见病诊所)计划的益处和可行性
igf1r相关疾病与宫内生长受限(IUGR)、出生后生长衰竭、身材矮小、小头畸形、发育迟缓和面部畸形有关。我们报告一位7月龄时就诊于医学遗传学的患者,有IUGR病史、喂养不良、轻度发育迟缓、小头畸形和面部畸形。全外显子组测序显示,IGF1R基因中存在一种新的c.1464T > G .(Cys488Trp)变异,最初被归类为不确定意义变异(VUS)。我们将患者纳入URDC(未确诊罕见病诊所),并进行了额外的研究,包括深度表型和家族分离分析,结果表明患者的IGF1R VUS存在于表型相似的家庭成员中。此外,生化检测显示血清IGF-1水平升高与IGF-1受体功能异常一致。检查结果表明,患者的变异从VUS升级为可能致病。我们的报告扩展了igf1r相关疾病的变异和表型谱,并通过URDC(一个多学科临床项目,其主要目标是结束罕见疾病患者的诊断过程)通过深度表型、3D建模、额外的生化测试和家族分离研究,阐明了在初始分子诊断之外重新评估VUS的益处和可行性。
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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