Prenatal diagnosis of a fetus with pure partial trisomy 1q32-44 due to a familial balanced rearrangement

We diagnosed a pure partial trisomy of the long arm of chromosome 1 in a fetus with multiple malformations detected prenatally. The father was a carrier of a balanced rearrangement involving 46,XY,inv(1)(qter→p36::q32→qter::p36→q32). The fetus had preaxial polydactyly, low-set ears, macrocephaly, a prominent forehead, a broad and flat nasal bridge, a small mouth, an arched palate, micrognathia and unilateral renal agenesis. The couple had previously an infant with the same phenotypic abnormalities. The aberration was initially detected on amniocentesis with GTG banding and was confirmed by fluorescence in situ hybridization (FISH). Our case and other published pure trisomy 1q32-44 cases showed similarities, which allowed the further delineation of the trisomy 1q syndrome. Copyright © 2002 John Wiley & Sons, Ltd.     

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.     

Early and severe tricuspid valve dysplasia in a fetus with cardiospondylocarpofacial syndrome due to a variant c.616T>G p.(Tyr206Asp) in MAP3K7

Cardiospondylocarpofacial syndrome (CSCF; MIM#157800) is a rare condition caused by monoallelic variants in the MAP3K7 gene. The characteristic features of CSCF include growth retardation, facial dysmorphism, carpal-tarsal fusion, dorsal spine synostosis, deafness, inner ear malformation, cardiac septal defect and valve dysplasia. We present here a 20-week-old fetus with cardiospondylocarpofacial syndrome arising from a de novo variant c.616T>G p.(Tyr206Asp) in the MAP3K7 (NM_145331.3) gene with early and severe tricuspid valve dysplasia as a prenatal manifestation. Fetal echocardiography revealed tricuspid regurgitation with valve prolapse. Fetus had facial dysmorphism and dilated right atrium and right ventricle with tricuspid valve dysplasia on perinatal evaluation. To the best of our knowledge, this is the first report mentioning the prenatal manifestation of cardiospondylocarpofacial syndrome.     

Elevated delta OD 450 due to transient abnormal myelopoiesis in a Down syndrome fetus with hepatosplenomegaly on ultrasound

Transient abnormal myelopoiesis (TAM) is a relatively common finding in children with Down syndrome but has also been diagnosed prenatally, most often presenting with fetal hepatosplenomegaly. We report a case of TAM with hepatosplenomegaly found on ultrasound and associated with an increased amniotic fluid Δ OD 450 value. TAM is most commonly transient but can be associated with fatality and therefore should be considered in the differential diagnosis when fetal hepatosplenomegaly is found on ultrasound. Amniocentesis with chromosomal analysis and a Δ OD 450 may aid in diagnosing TAM and predicting the severity of the liver involvement. © 2013 John Wiley & Sons, Ltd.     

Prenatal diagnosis and post-mortem study of a fetus with mosaic trisomy 14 due to a dic(14)(p11)

Amniocentesis at 17 weeks' gestation revealed a mosaic karyotype—46,XX/46,XX, — 14,+dic(14)(p11). No abnormalities were detected on ultrasound. Growth and placentation were normal. The fetus was examined after termination of pregnancy and micrognathia and pulmonary hyperlobation were the only abnormalities detected. Several tissues were set up for cytogenetics, including fetal skin, kidney, ovary, and placenta. The diagnosis was confirmed by these studies. The level of mosaicism varied between tissues, with the trisomy 14 cell line highest in amniotic fluid.     

Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata,ichthyosis, and Kallmann syndrome due to an Xp deletion

We report the prenatal diagnosis of a male fetus with X-linked recessive chondrodysplasia punctata (CDPX), steroid sulphatase (STS) deficiency, X-linked Kallmann syndrome (KAL), and a chromosome deletion at Xp22.31. Biochemical analysis of bone from this case indicates that CDPX is not a defect of vitamin K metabolism. Immunocytochemical study of the brain suggests that KAL is a defect in neuronal migration.     

All-in-one whole exome sequencing strategy with simultaneous copy number variant,single nucleotide variant and absence-of-heterozygosity analysis in fetuses with structural ultrasound anomalies: A 1-year experience

Objective

We performed a 1-year evaluation of a novel strategy of simultaneously analyzing single nucleotide variants (SNVs), copy number variants (CNVs) and copy-number-neutral Absence-of-Heterozygosity from Whole Exome Sequencing (WES) data for prenatal diagnosis of fetuses with ultrasound (US) anomalies and a non-causative QF-PCR result.

Methods

After invasive diagnostics, whole exome parent-offspring trio-sequencing with exome-wide CNV analysis was performed in pregnancies with fetal US anomalies and a non-causative QF-PCR result (WES-CNV). On request, additional SNV-analysis, restricted to (the) requested gene panel(s) only (with the option of whole exome SNV-analysis afterward) was performed simultaneously (WES-CNV/SNV) or as rapid SNV-re-analysis, following a normal CNV analysis.

Results

In total, 415 prenatal samples were included. Following a non-causative QF-PCR result, WES-CNV analysis was initially requested for 74.3% of the chorionic villus (CV) samples and 45% of the amniotic fluid (AF) samples. In case WES-CNV analysis did not reveal a causative aberration, SNV-re-analysis was requested in 41.7% of the CV samples and 17.5% of the AF samples. All initial analyses could be finished within 2 weeks after sampling. For SNV-re-analysis during pregnancy, turn-around-times (TATs) varied between one and 8 days.

Conclusion

We show a highly efficient all-in-one WES-based strategy, with short TATs, and the option of rapid SNV-re-analysis after a normal CNV result.     

Prenatal diagnosis of Myhre syndrome with a heterozygous pathogenic variant in SMAD4 gene presented with thick nuchal translucency and cardiac abnormalities

Prenatal testing was performed in a 39-year-old Chinese pregnant woman referred for increased nuchal translucency measuring 5.7 mm. Non-invasive prenatal testing and SNP array study on amniotic fluid samples were normal. Whole exome sequencing (WES) was initiated further as the fetus had pericardial effusion of 1.2 mm, thickened myocardium over the right ventricular lateral wall and aberrant right subclavian artery. A detailed fetal echocardiogram also revealed persistent left superior vena cava and dilated coronary sinus at 20 weeks. From whole exome sequencing of the trio, a de novo heterozygous variant NM_005359.5(SMAD4): c.1499T>C (p.Ile500Thr) was detected. This pathogenic variant has been reported in the postnatal case cohort of Myhre syndrome. This condition is characterized by facial dysmorphism, intellectual disability, hearing loss, skeletal abnormalities and potential life threatening respiratory or cardiovascular manifestations. Termination of pregnancy was performed at 23 weeks. Small chins, pre-axial polydactyly, brachydactyly and clinodactyly were noted in the abortus. Ultrasound findings of increased nuchal translucency, thickened myocardium and pericardial effusion prompted further genetic evaluation for the prenatal diagnosis of Myhre syndrome by whole exome sequencing.     

Maternally inherited autosomal dominant PLAG-1 related Silver Russell syndrome in a fetus with intra-uterine growth restriction

We report a case of maternally inherited autosomal dominant PLAG-1 related Silver Russell syndrome (SRS) in a fetus with IUGR and a mother who had growth and feeding problems in early life, dextrocardia and an atrio-ventricular septal defect. Amniocentesis was performed due to marked intra-uterine growth restriction (IUGR). The array was normal. Whole exome sequencing (WES) revealed a maternally inherited heterozygous likely pathogenic variant in PLAG1 (NM_002655.3): c.402delT p.(Gly135Aspfs*94). This variant has not been reported previously. PLAG1 pathogenic variants are associated with autosomal dominant Silver Russell syndrome, which fits with the clinical phenotypes of both fetus and mother. PLAG1 variants have previously been reported post-natally in Silver Russell syndrome, but the phenotype tends to be milder than in 11p15.5 methylation-related cases with fewer physical features. Although cardiac anomalies are uncommon in SRS, they have been previously reported. To our knowledge, dextrocardia has not been previously associated with SRS and there were no other potential causative genetic variants found. This report aims to highlight this rare type of SRS as a cause of IUGR.     

Prenatal diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in a family with a previous fatal case of sudden unexpected death in childhood

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a potentially fatal inherited disease with a carrier frequency of approximately 1:100 in most Caucasian populations. The disease is implicated in sudden unexpected death in childhood. A prevalent disease-causing point mutation (A985G) in the MCAD gene has been characterized, thus rendering diagnosis easy in the majority of cases. Since the clinical spectrum of MCAD deficiency ranges from death in the first days of life to an asymptomatic life, there are probably other genetic factors—in addition to MCAD mutations—involved in the expression of the disease. Thus, families who have experienced the death of a child from MCAD deficiency might have an increased risk of a seriously affected subsequent child. In such a family we have therefore performed a prenatal diagnosis on a chorionic villus sample by a highly specific and sensitive polymerase chain reaction (PCR) assay for the G985 mutation. The analysis was positive and resulted in abortion. We verified the diagnosis by direct analysis on blood spots and other tissue material from the aborted fetus and from family members.     

Current controversies in prenatal diagnosis 1: NIPT for chromosome abnormalities should be offered to women with low a priori risk

In its successful annual cycle of controversies and debates, the International Society of Prenatal Diagnosis and Therapy once again addressed non-invasive prenatal testing (NIPT) by following up on the 2013 controversy, ‘Should non-invasive DNA testing be the standard screening test for Down syndrome in all pregnant women’? with the proposition, ‘NIPT for chromosomel abnormalities should be offered to women with low a priori risk’. © 2014 John Wiley & Sons, Ltd.     

Molecular diagnosis of a novel heterozygous 268C→T (R90C) mutation in TGIF gene in a fetus with holoprosencephaly and premaxillary agenesis

We report the sonographic diagnosis and molecular analysis of holoprosencephaly (HPE) and premaxillary agenesis in a second-trimester fetus with a 46,XY karyotype. Mutational sequence analyses for the entire coding region and exon–intron boundaries of SHH, ZIC2, SIX3 and TGIF genes identified a novel heterozygous missense TGIF mutation 268C→T (CGC→TGC change) that predicts an Arg90Cys substitution in the homeodomain region of TGIF. The proband's parents did not carry the mutation. The present case is an example of the heterogeneous entity of the HPE spectrum and demonstrates that adjunctive molecular analyses of distinct human genes for HPE can reassure genetic counselling by elucidating the genetic pathogenesis, especially in cytogenetically normal fetuses affected with HPE. Copyright © 2002 John Wiley & Sons, Ltd.