Genetic disruption of the oncogenic HMGA2–PLAG1–IGF2 pathway causes fetal growth restriction

Abstract

PurposeFetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver–Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2.MethodsWhole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway.ResultsWe report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.ConclusionGenetic defects of the HMGA2–PLAG1–IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.

Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing

“…All seven variants were detected by the initial WGS experiments but not recognized as pathogenic. At the time of the first data annotation in 2014, five of the seven genes (AP3B2, HMGA2, KCNB1, SON, and WAC) were not recognized in OMIM to cause human disease [17][18][19][20][21][22]. In one case (SMAD6), the phenotypes of the individuals reported in the literature did not overlap the clinical presentation of our patient.…”

“…Currently, a main advantage is the ability to immediately capitalize on the discovery of new disease genes. For example, since 2015 the first three probands have been reported in the literature with HMGA2 sequence variants and a phenotype resembling Silver-Russell syndrome [17,18]. The phenotype of Case 1096 was notable for intrauterine growth restriction, short stature, and other features (Supplemental file).…”

Structural and sequence variants in patients with Silver-Russell syndrome or similar features-Curation of a disease database

“…The full data can be found in ; and Table shows a subset of this data. Furthermore, 10 unrelated patients/families (a total of 20 affected individuals) had sequence variants of CDKN1C, HMGA2, IGF2 or PLAG1 (Table ; Abi Habib et al., ;Begemann et al., ; Brioude et al., ; De Crescenzo et al., ; Yamoto et al., ). However, it should be noted that some patients with (even typical) SRS phenotype and a structural variant may be overlooked, either because the term “SRS” was not included in the title or as keyword of the publication, or because they belonged to a large study cohort and were not specified in the general dataset.…”

“…On the other hand, loss‐of‐function sequence variants of CDKN1C cause the overgrowth disorder Beckwith‐Wiedemann syndrome (MIM# 130650). Sequence variants of the paternally methylated IGF2 were found de novo in three unrelated patients (Abi Habib et al., ; Yamoto et al., ) and a family with four affected members causing a phenotype only in case of paternal inheritance (Begemann et al., ). NH‐CSS suggested clinical SRS in all the individuals when applicable.…”

A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation

“…Begemann et al reported the first heterozygous IGF2 variation (NM_001127598: c.191C→A, p.Ser64Ter) in a multigenerational family with a severe growth retardation (9). Habib ), which might influence IGF2/IGF1R interaction (10,12). All mutations are located on the paternal allele.…”