Risk estimation of uniparental disomy of chromosome 14 or 15 in a fetus with a parent carrying a non-homologous Robertsonian translocation. Should we still perform prenatal diagnosis?

OBJECTIVE: Uniparental disomy (UPD) testing is currently recommended during pregnancy in fetuses carrying a balanced Robertsonian translocation (ROB) involving chromosome 14 or 15, both chromosomes containing imprinted genes. The overall risk that such a fetus presents a UPD has been previously estimated to be around ~0.6-0.8%. However, because UPD are rare events and this estimate has been calculated from a number of studies of limited size, we have reevaluated the risk of UPD in fetuses for whom one of the parents was known to carry a nonhomologous ROB (NHROB). METHOD: We focused our multicentric study on NHROB involving chromosome 14 and/or 15. A total of 1747 UPD testing were performed in fetuses during pregnancy for the presence of UPD(14) and/or UPD(15). RESULT: All fetuses were negative except one with a UPD(14) associated with a maternally inherited rob(13;14). CONCLUSION: Considering these data, the risk of UPD following prenatal diagnosis of an inherited ROB involving chromosome 14 and/or 15 could be estimated to be around 0.06%, far less than the previous estimation. Importantly, the risk of miscarriage following an invasive prenatal sampling is higher than the risk of UPD. Therefore, we do not recommend prenatal testing for UPD for these pregnancies and parents should be reassured.

The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy.

BACKGROUND: DYRK1A plays different functions during development, with an important role in controlling brain growth through neuronal proliferation and neurogenesis. It is expressed in a gene dosage dependent manner since dyrk1a haploinsufficiency induces a reduced brain size in mice, and DYRK1A overexpression is the candidate gene for intellectual disability (ID) and microcephaly in Down syndrome. We have identified a 69 kb deletion including the 5' region of the DYRK1A gene in a patient with growth retardation, primary microcephaly, facial dysmorphism, seizures, ataxic gait, absent speech and ID. Because four patients previously reported with intragenic DYRK1A rearrangements or 21q22 microdeletions including only DYRK1A presented with overlapping phenotypes, we hypothesised that DYRK1A mutations could be responsible for syndromic ID with severe microcephaly and epilepsy. METHODS: The DYRK1A gene was studied by direct sequencing and quantitative PCR in a cohort of 105 patients with ID and at least two symptoms from the Angelman syndrome spectrum (microcephaly < -2.5 SD, ataxic gait, seizures and speech delay). RESULTS: We identified a de novo frameshift mutation (c.290_291delCT; p.Ser97Cysfs*98) in a patient with growth retardation, primary severe microcephaly, delayed language, ID, and seizures. CONCLUSION: The identification of a truncating mutation in a patient with ID, severe microcephaly, epilepsy, and growth retardation, combined with its dual function in regulating the neural proliferation/neuronal differentiation, adds DYRK1A to the list of genes responsible for such a phenotype. ID, microcephaly, epilepsy, and language delay are the more specific features associated with DYRK1A abnormalities. DYRK1A studies should be discussed in patients presenting such a phenotype.

Case report of apoptosis in testis of four AZFc-deleted patients: increased DNA fragmentation during meiosis, but decreased apoptotic markers in post-meiotic germ cells.

AZFc deletions of the Y chromosome are the major known genetic cause of spermatogenetic failure. Meiotic studies have shown a prevalence of synaptonemal complex fragmentation and an excess of early-stage sperm cells, suggesting that the maturation block could involve apoptosis. We present a prospective and observational study of apoptotic markers in the sperm of four AZFc-deleted patients and two non-obstructive azoospermic controls without an AZFc deletion. Polycaspases assays and terminal deoxynucleotidyl transferase dUDP nick-end labelling (TUNEL) assays were combined to evaluate the incidence of apoptosis in pre-meiotic, meiotic and post-meiotic germs cells identified, respectively, using anti-melanoma-associated antigen A4 (MAGE-A4), anti-synaptonemal complex protein 3 (SCP3) and anti-sperm acrosome membrane-associated protein 1 (SPACA1) antibodies. We detected apoptosis at all stages of AZFc-deletion spermatogenesis. Using the caspase assay, the incidence of positive cells was found to be heterogeneous for pre-meiotic (from 4.8 to 84.5%) and meiotic stages (from 7.9 to 57.6%), while for post-meiotic cells, the mean incidence was 6% in AZFc-deleted patients compared with 26.5% in controls (P < 0.05). Using the TUNEL assay, the mean percentage with DNA fragmentation for meiotic cells was 54.0% in AZFc-deleted patients compared with 20.3% in controls (P < 0.05), while the percentage of TUNEL-positive post-meiotic cells ranged from 5.3 to 44.7%. Spermatocyte loss in AZFc-deleted patients occurs via the apoptotic pathway. In post-meiotic cells, the lower incidence of apoptosis in testis from three of the four AZFc-deleted patients, compared with controls, is consistent with AZFc deletions having little negative impact on sperm quality.

Prenatal detection of the 17p11.2 duplication in Charcot-Marie-Tooth disease type 1A: necessity of a multidisciplinary approach for heterogeneous disorders.

Charcot-Marie-Tooth (CMT) disease is a typical example of a clinically and genetically heterogeneous disorder and, in most cases, is dominantly inherited and caused by a 1.5 megabase duplication on chromosome 17p11.2 containing the PMP22 gene. This is a non-lethal disease with a wide spectrum of severity, from asymptomatism to severe motor and sensory disability. Unpredictable degree of disability is usually the reason why prenatal diagnosis is required and must be addressed. Molecular procedures such as the use of polymorphic non microsatellite STRs, allowing very fast and reliable results even when requiring a gene dosage interpretation are now available and have been recently validated in post-natal diagnosis. Our results indicate that this approach is also the best-adapted method in case of prenatal diagnosis. Nevertheless, ethical considerations raised by prenatal diagnosis in CMT and more generally in non-lethal disorders remain to be actively considered. Here, we present our experience in genetic counselling, and address the psychological issues for 7 CMT at risk pregnancies. In five cases, a CMT1A duplication was evidenced; pregnancy was terminated in four of these cases and the parents from one affected foetus decided to pursue the pregnancy.