A New De Novo Missense Variant of the TET3 Gene in a Patient with Epilepsy and Macrocephaly.

The etiology of neurodevelopmental disorders and epilepsy is very heterogeneous and partly still unknown, and the research of causative genes related to these diseases is still in progress. In 2020, pathogenic variants of the TET3 gene were associated with Beck-Fahrner syndrome, which is characterized by neurodevelopmental delay, intellectual and learning disabilities of variable degree, growth abnormalities, hypotonia and seizures. Variants of TET3 have been described having both an autosomal dominant with a milder phenotype and an autosomal recessive pattern. To date, in the literature, only 28 patients are reported with pathogenic variants of the TET3 gene, and only 9 of them have epilepsy. We describe a 31-year-old woman with macrocephaly, mild neurodevelopmental delay and a long history of epilepsy. Trio-based exome sequencing identified a de novo heterozygous TET3 variant, c.2867G>A p.(Arg956Gln), never described before, absent in the general population and predicted to be potentially pathogenetic by bioinformatics tools. This report aims to describe the clinical history of our patient, the pharmacological treatment and clinical response, as well as the biological characteristics of this new variant.

A Case Report of a Feto-Placental Mosaicism Involving a Segmental Aneuploidy: A Challenge for Genome Wide Screening by Non-Invasive Prenatal Testing of Cell-Free DNA in Maternal Plasma.

Non-invasive prenatal testing (NIPT) using cell-free DNA can detect fetal chromosomal anomalies with high clinical sensitivity and specificity. In approximately 0.1% of clinical cases, the NIPT result and a subsequent diagnostic karyotype are discordant. Here we report a case of a 32-year-old pregnant patient with a 44.1 Mb duplication on the short arm of chromosome 4 detected by NIPT at 12 weeks' gestation. Amniocentesis was carried out at 18 weeks' gestation, followed by conventional and molecular cytogenetic analysis on cells from the amniotic fluid. SNP array analysis found a de novo deletion of 1.2 Mb at chromosome 4, and this deletion was found to be near the critical region of the Wolf-Hirschhorn syndrome. A normal 46,XY karyotype was identified by G-banding analysis. The patient underwent an elective termination and molecular investigations on tissues from the fetus, and the placenta confirmed the presence of type VI true fetal mosaicism. It is important that a patient receives counselling following a high-risk call on NIPT, with appropriate diagnostic analysis advised before any decisions regarding the pregnancy are taken. This case highlights the importance of genetic counselling following a high-risk call on NIPT, especially in light of the increasing capabilities of NIPT detection of sub-chromosomal deletions and duplications.

Case Report: Two cases of apparent discordance between non-invasive prenatal testing (NIPT) and amniocentesis resulting in feto-placental mosaicism of trisomy 21. Issues in diagnosis, investigation and counselling.

The sequencing of cell-free fetal DNA in the maternal plasma through non-invasive prenatal testing (NIPT) is an accurate genetic screening test to detect the most common fetal aneuploidies during pregnancy. The extensive use of NIPT, as a screening method, has highlighted the limits of the technique, including false positive and negative results. Feto-placental mosaicism is a challenging biological issue and is the most frequent cause of false positive and negative results in NIPT screening, and of discrepancy between NIPT and invasive test results. We are reporting on two cases of feto-placental mosaicism of trisomy 21, both with a low-risk NIPT result, identified by ultrasound signs and a subsequent amniocentesis consistent with a trisomy 21. In both cases, after the pregnancy termination, cytogenetic and/or cytogenomic analyses were performed on the placenta and fetal tissues, showing in the first case a mosaicism of trisomy 21 in both the placenta and the fetus, but a mosaicism in the placenta and a complete trisomy 21 in the fetus in the second case. These cases emphasize the need for accurate and complete pre-test NIPT counselling, as well as to identify situations at risk for a possible false negative NIPT result, which may underestimate a potential pathological condition, such as feto-placental mosaicism or fetal trisomy. Post-mortem molecular autopsy may discriminate between placental, fetal and feto-placental mosaicism, and between complete or mosaic fetal chromosomal anomalies. A multidisciplinary approach in counselling, as well as in the interpretation of biological events, is essential for the clarification of complex cases, such as feto-placental mosaicisms.

Deletion 2p15-16.1 syndrome: case report and review.

We report on a 9-year-old female patient with facial anomalies and developmental delay, heterozygous for three de novo rearrangements: a paracentric inversion of chromosome 7, an apparently balanced translocation between chromosome 1 and 7, involving the same inverted chromosome 7, detected by standard cytogenetic analysis [46,XX, der(7) inv(7)(q21.1q32.1)t(1;7)(q23q32.1)]; and a 2p16.1 deletion, spanning about 3.5 Mb of genomic DNA, shown by SNP-array analysis [arr 2p16.1 (56,706,666-60,234,485)x1 dn]. Clinical features and cytogenetic imbalance in our patient were similar to those reported in five published cases, suggesting that this genomic region is prone to recombination and its hemizygosity results in a distinct although variable spectrum of clinical manifestations.

2q31.2q32.3 deletion syndrome: report of an adult patient.

A 36-year-old patient with a disorder characterized by severe mental retardation, behavioral problems, dysmorphic face, "muscular build," and hand/foot anomalies, is reported. Following a diagnosis of de novo pericentric inversion of chromosome 8 based on standard cytogenetic analysis, a subsequent 75 kb array-CGH investigation disclosed a deletion spanning for about 13.7 Mb in the 2q31.2q32.3 region. Whole painting of chromosome 8 established the intrachromosomal nature of the rearrangement and FISH analysis with locus-specific probes confirmed the deletion on the long arm of chromosome 2. The deleted region, clinical outcome, and medical history in this patient are mainly superimposable to those reported in a published 8-year-old boy, suggesting that this genomic segment is prone to rearrangements and its hemizygosity gives rise to a clinically recognizable syndrome. The role of some genes mapping in the deleted region and related with distinct disorders is discussed. Interestingly, deletion of MSTN gene, a negative regulator of muscle growth, was associated in our patient with a "muscular build," a feature which could be regarded as a handle for clinical recognition of this syndrome.