Fetal de novo heterozygous variant in the isocitrate dehydrogenase 1 gene associated with growth restriction, skeletal, cerebral and vascular anomalies

Germline pathogenic variants in isocitrate dehydrogenase 1 (IDH1) can lead to a rare neurodevelopmental disorder called metaphyseal chondromatosis with D‐2‐hydroxyglutaric aciduria, including severe skeletal and cerebral anomalies. To the best of our knowledge, no prenatal case of an IDH1 pathogenic variant has been reported in literature. Somatic sequence variants in IDH1/2 genes are described in distinct cancers, premalignant diseases and rare inherited metabolic disorders. Amniocentesis and further genetic testing including trio exome sequencing were performed due to suspicious findings on a second trimester routine prenatal ultrasound examination. The fetus was found to have growth restriction, cerebral abnormalities (ex vacuo hydrocephalus, cerebellar and vermian hypoplasia, corpus callosum dysgenesis), brachycephaly, narrow chest, persistent left superior vena cava, liver calcifications, hyperechogenic bowel, short tubular bones and joint contractures. A de novo heterozygous variant in the IDH1 gene was detected via trio exome sequencing. The prenatal diagnosis of a de novo pathogenic variant in IDH1 in a fetus with the described phenotype, obtained through trio exome sequencing, helped parents and providers with an informed decision making about pregnancy management.

� This information can help parents and healthcare providers with an informed decision making regarding affected pregnancies.

| FETAL PHENOTYPE
The examination of a 27-year-old woman (Gravida I, Para 0) at 21 þ 1 gestational weeks revealed a female fetus with an estimated weight below the fourth percentile, brachycephaly, retrognathia, hydrocephalus internus, cerebellar and vermian hypoplasia, corpus callosum dysgenesis, narrow chest, left persistent superior vena cava, hypoechogenic liver with calcifications and hyperechogenic bowel, as well as shortening of the tubular bones and joint contractures with radial deviation of the hands and clinodactyly (Figure 1).Fetal movements were sparse.The placenta was thickened and had a jellylike consistency.Fetal and maternal Doppler indices were normal.
The parents opted for further diagnosis and an amniocentesis was performed (Table 1).instructions.Paired-end sequencing was performed using the Novaseq6000 system (Illumina, San Diego, CA, USA).Data analysis for sequence variants and deletions/duplications was performed using the Illumina DRAGEN Bio-IT platform.For data evaluation, VarSeq (GoldenHelix) was utilized.

| DIAGNOSTIC RESULTS AND INTERPRETATION
Cytogenetic testing revealed a normal karyotype.Chromosomal microarray analysis was not performed.Trio exome sequencing detected a de novo heterozygous IDH1 pathogenic variant c.395 G > A (p.Arg132His) in exon 4 of transcript NM_005896.4.
Because of the genetic findings and the fetal phenotype, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria was suspected (Table 2).However, no postpartum X-ray was performed, so the suspicion was not confirmed.
The anomalies and an increased risk of tumorigenesis.

| PREGNANCY OUTCOME
The parents opted to terminate the pregnancy at 26 gestational weeks.The prenatal findings of retrognathia, radial deviation of the hands, clinodactyly and small size for the gestational age were confirmed postnatally (Figure 1).The parents decided against a postmortem examination of the fetus.

| DISCUSSION
Trio exome sequencing was performed using fetal DNA (from amniotic cells) as well as maternal and paternal DNA (from blood).The enrichment of the coding DNA sections was realized using the Twist Human Core þ Reference Sequence database exome (Twist Bioscience, San Francisco, CA, USA).Preparation and capture of all samples were carried out according to the respective manufacturer's F I G U R E 1 Fetal phenotype: B-mode images at 22 þ 3 gestational weeks (a, b, d, e), 3D images (c, f), and the image of fetus after delivery (g).(a) Cerebellar cleft due to vermian hypoplasia (*) (b) Hydrocephalus internus with mildly dilated lateral (**) and third (*) ventricles (c) Fetal profile with retrognathia (d) Abdominal circumference, short ribs, the liver appears hypoechogenic with multiple intrahepatic calcifications (arrows) (e) Narrow chest and short ribs (arrow) when comparing to the abdomen (f) Bilateral contracted and radially deviated hands (g) Image of fetus after delivery.[Colour figure can be viewed at wileyonlinelibrary.com]T A B L E 1 Clinical data.HP:0001321: Cerebellar hypoplasia HP:0001320: Cerebellar vermis hypoplasia HP:0006989: Dysplastic corpus callosum HP:0040019: Finger clinodactyly HP:0001188: Hand clenching HP:0000238: Hydrocephalus HP:0000774: Narrow chest HP:0005301: Persistent left superior vena cava HP: 0000773: Short ribs HP: IDH family of enzymes includes three proteins located in the cytosol, peroxisomes (IDH1) and mitochondria (IDH2 and IDH3).IDH enzymes are involved in many cellular processes, including regulation of cellular redox status, mitochondrial oxidative phosphorylation, lipid metabolism and glucose sensing.IDH1 catalyzes the reversible NADP þ -dependent decarboxylation of isocitrate to α-ketoglutarate (αKG).NADPH is a key reducing agent of the cell protecting against the toxicity of reactive oxygen species.Pathogenic variants in IDH1 result in altered enzyme activity, converting αKG and NADPH to D-2-hydroxyglutarate (D-2HG) and NADPþ.The excess of D-2HG leads to abnormal cellular proliferation, increased DNA and histone methylation, and altered cell/cancer cell differentiation. 1 D-2HG turned to D-2-hydroxyglutaric acid is eliminated through the urine.Dysfunction of IDH1 may therefore lead to proliferation defects of the developing fetal brain as well as skeletal and organ