Diagnostic yield of chromosomal microarray analysis in fetuses with isolated increased nuchal translucency: a French multicenter study.

OBJECTIVE: To determine the frequency and nature of copy number variants (CNVs) identified by chromosomal microarray analysis (CMA) in a large cohort of fetuses with isolated increased nuchal translucency thickness (NT) ≥ 3.5 mm. METHODS: This was a retrospective, multicenter study, including 11 French hospitals, of data from the period between April 2012 and December 2015. In total, 720 fetuses were analyzed by rapid aneuploidy test and the fetuses identified as euploid underwent CMA. CNVs detected were evaluated for clinical significance and classified into five groups: pathogenic CNVs; benign CNVs; CNVs predisposing to neurodevelopmental disorders; variants of uncertain significance (VOUS); and CNVs not related to the phenotype (i.e. incidental findings). RESULTS: In 121 (16.8%) fetuses, an aneuploidy involving chromosome 13, 18 or 21 was detected by rapid aneuploidy test and the remaining 599 fetuses were euploid. Among these, 53 (8.8%) had a CNV detected by CMA: 16/599 (2.7%) were considered to be pathogenic, including 11/599 (1.8%) that were cryptic (not visible by karyotyping); 7/599 (1.2%) were CNVs predisposing to neurodevelopmental disorders; and 8/599 (1.3%) were VOUS. Additionally, there was one (0.2%) CNV that was unrelated to the reason for referral diagnosis (i.e. an incidental finding) and the remaining 21 were benign CNVs, without clinical consequence. Interestingly, we identified five genomic imbalances of the 1q21.1 or 15q11.2 regions known to be associated with congenital heart defects. CONCLUSION: Our study demonstrates the benefit of CMA in the etiological diagnosis of fetuses with isolated increased NT. It is worth noting that most (69%) of the detected pathogenic CNVs were cryptic. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Marfan syndrome and fibrillin disorders.

Marfan syndrome is the second most common inherited connective tissue disorder after osteogenesis imperfecta. Musculoskeletal abnormalities are at the forefront of the clinical picture and count among the major diagnostic criteria for Marfan syndrome, together with cardiovascular and ocular system involvement. Early diagnosis is of the utmost importance since preventive measures significantly increase life expectancy and prevent the occurrence of impairments and disabilities. Marfan syndrome is due to mutations within the fibrillin-1 gene, which is the main protein of the microfibril network. Microfibrils play a crucial role in the trophicity and function of elastic tissue. Multidisciplinary management of the patients and their families is vital.

[Aortic aneurysms excluding Marfan's syndrome]. / Anévrismes aortiques en dehors du Marfan.

The causal factors of aneurysm are not the same in the ascending and abdominal aorta. Atheroma is the dominant lesion in the abdominal aorta and genetic abnormalities predisposing to "mediacystic necrosis" are more frequently observed in ascending aortic aneurysms. The causal genetic abnormalities are multiple: abnormalities of fibrillin type I in Marfan's syndrome, collagen abnormalities in the Ehlers-Danlos syndrome, abnormalities of microfibrils, possible metallo-proteases, with many gene candidates. Finally, some ascending aortic aneurysms are associated with bicuspid aortic valves, some of which are familial. Familial factors are less evident in abdominal aortic aneurysms: genes favoring atheroma may be responsible but the factors which predispose to dilatation and non stenosis are not well known: they would seem to be general factors because the tendency to arterial dilatation is diffuse. In all cases, because of the high risk of disease in a close relative, a familial enquiry would seem to be justified with echocardiography for close relatives of affected subjects, especially when young and female.

[Prenatal diagnosis of a probable human chimera after fertilization in vitro]. / Diagnostic prénatal d'une probable chimère humaine après fécondation in vitro.

Chimerism is the coexistence of more than one cell line in an individual, due to the fusion of originally separate zygotes. It has been very rarely described in humans. A 36-year-old woman referred for in vitro fertilization (IVF) had three embryos transferred leading to a monofetal pregnancy. Ultrasound examination at 17 weeks showed severe intrauterine growth retardation. Amniocentesis revealed a mixture of 46,XY and 46,XX clones. Histopathologic examination showed a dysmorphic fetus with female phenotype and severe growth retardation. Fusion of two of the three embryos (one male and one female) seems to be the most probable mechanism that could explain both cytogenetic and histopathologic observations.

Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.

Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

Unbalanced karyotype due to adjacent 1 segregation of t(11;22)(q23.3;q13.2).

The 11q;22q translocations, whatever the breakpoints may be, are of particular interest because of their propensity to 3:1 segregation of the chromosomes at meiosis I. Until now, no unbalanced karyotype resulting from 2:2 adjacent segregation was published among offspring of 11q;22q translocation carriers. The authors report the case of an unbalanced karyotype due to adjacent 1 segregation of a maternal translocation (11;22)(q23.3;q13.2). The proband's karyotype was 46,XX,-22,+der(22)(11;22)(q23.3;q13.2)mat. This finding demonstrates that adjacent 1 segregation is possible in t(11;22) with breakpoints at 11q23 and 22q13, and can lead to birth of viable infants.

Possible human chimera detected prenatally after in vitro fertilization: a case report.

BACKGROUND: Chimerism is the coexistence of more than one cell line in an individual, due to the fusion of originally separate zygotes. It has been very rarely described in humans. METHODS: A 36-year-old woman who was referred for in vitro fertilization (IVF) for unexplained infertility had three embryos transferred. RESULTS: Four weeks and five days after the transfer, ultrasound examination detected a single fetus in the uterus. Ultrasound examination at 17 weeks for metrorrhagia showed severe intrauterine growth retardation. Amniocentesis revealed a mixture of 46,XY and 46,XX clones. Histopathologic examination showed a dysmorphic fetus with female phenotype and severe growth retardation. CONCLUSIONS: Although demonstration by fingerprinting has not been possible, fusion of two of the three transferred embryos (one male and one female) seems to be the most probable mechanism that could explain both cytogenetic and histopathologic observations. No chimera has yet been described after IVF. It would be interesting to collect any such observations from other IVF centers.

Loss of heterozygosity on 10q and mutational status of PTEN and BMPR1A in colorectal primary tumours and metastases.

We investigated the possible role of chromosome 10q losses in colorectal cancer metastasis by carrying out an allelic imbalance study on a series of microsatellite instability-negative (MSI-) primary tumours (n=32) and metastases (n=36) from 49 patients. Our results demonstrate that 10q allelic losses are associated with a significant proportion (25%) of MSI- colorectal tumours, but are not involved in the metastatic process. PTEN and BMPR1A, two genes located in the common deleted region, were screened for mutations in samples with loss of heterozygosity. The absence or low frequency of mutations indicates that the inactivation of these genes by deletion of one allele and mutation of the other one plays only a minor role in MSI- tumours.