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.

[22q11.2 microdeletion syndrome: Analysis of the care pathway before the genetic diagnosis]. / Syndrome de microdélétion 22q11.2 : analyse du parcours patient avant le diagnostic génétique.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is a very broad phenotypic spectrum disorder. It can affect many organs or systems. 22q11.2DS is the most common microdeletion syndrome in humans, with a prevalence ranging from one in every 2000 to one in 4000 newborns. It seems to be more prevalent than reported and under-recognized or undiagnosed because of its inherent clinical variability and heterogeneity. In France, 15,000 patients may be affected by this disease, more than half without knowing it. The aim of this study was to analyze the care pathway before the genetic diagnosis of 22q11.2DS. METHODS: We conducted a single-center, retrospective analysis of postnatally diagnosed patients recruited by the cytogenetic laboratory of Nancy (France) from January 2000 to December 2015. Clinical data were first collected by consulting the medical files of patients and then by calling them directly. Written informed consent was obtained and the study was approved by local research ethics boards. Data concerned only clinical features before the diagnosis. RESULTS: The cohort consisted of 32 individuals with 22q11.2DS. The average age at diagnosis was 9 years and 2 months and the median age was 2 years and 11 months. Fetal echography was abnormal in 15 pregnancies. During the neonatal period, the most important features were eating difficulties and congenital malformations (n=20), with a majority of complex heart diseases (n=16), dominated by conotruncal malformations (n=6). In case of malformation, the average age at diagnosis decreased to 2 years and 6 months. A congenital heart disease brought the average age of diagnosis down to 2 years and 6 months. Hypocalcemia and dysmorphism were also classical features (n=14). Before the age of 3 years, speech delay occurred in nine patients. After 3 years of age, rhinolalia was predominant (n=11). Academic disabilities were present in all subjects. At least 14 patients had a de novo deletion. Five patients were diagnosed within genetic counseling, with the deletion was inherited from the mother in three out of four cases. One was the monozygotic twin of a patient. Seven patients were diagnosed as adults. Four of them were diagnosed only because of the clinical presentation of their children or fetuses. Retrospectively, all adult patients had clinical signs suggesting the 22q11.2DS diagnosis. Relational disorders affected eight patients. None of them had been referred to the geneticist for this reason. In most cases, the pediatric cardiologist referred patients to the geneticist (n=9). Physiotherapists (n=15) and speech-language pathologists (n=12) were frequently requested but did not participate in the diagnosis. CONCLUSION: The present study highlights the difficulty of establishing the diagnosis when the major features of the 22q11.2DS are absent during the 1st months of life. This is particularly true when there is no congenital defect. Special attention must be given to speech disorders in childhood and neuropsychological disorders later in life. The association between 22q11.2DS and early-onset parkinson disease implies that adult neurologists should be aware of this diagnosis. For adult patients, familial occurrence is the most frequent cause of diagnosis in spite of clinical signs suggestive of 22q11.2DS. The management of these patients involves better information of medical and paramedical staff in order to refer them to the geneticist earlier in life.

Pregnancy outcomes of prenatally diagnosed Turner syndrome: a French multicenter retrospective study including a series of 975 cases.

OBJECTIVES: The objectives of this study were to report pregnancy outcomes after prenatal diagnosis of Turner syndrome (TS) and to compare and assess termination of pregnancy rates during two periods. The intervals selected were before and after 1997 when multidisciplinary centers for prenatal diagnosis (MCPDs) were established in France. METHODS: A database of 975 cases of TS diagnosed between 1980 and 2012 was created from 21 French cytogenetics laboratories. For each case, the karyotype indication, maternal age, year of prenatal testing, sampling procedure, karyotype, associated ultrasound findings, and outcomes were recorded. RESULTS: Karyotypes were mainly performed because of abnormal sonographic findings (84%). Before 1997, there were no changes in the rate of termination (90%) of affected fetuses. After 1997, the rate fell to 80%. This decrease was mainly observed in cases of mosaicism, incidental diagnosis, and in later gestations. US abnormalities were more likely to be associated with a full 45,X karyotype. CONCLUSION: There was an evolution in the way genetic counseling was performed following prenatal diagnosis of Turner syndrome that coincided with the opening of MCPDs in France. This resulted in a decrease in the rate of termination of affected fetuses.

A French collaborative survey of 272 fetuses with 22q11.2 deletion: ultrasound findings, fetal autopsies and pregnancy outcomes.

OBJECTIVE: The 22q11.2 deletion (del22q11.2) is one of the most common microdeletions. We performed a collaborative, retrospective analysis in France of prenatal diagnoses and outcomes of fetuses carrying the del22q11.2. METHODS: A total of 272 fetuses were included. Data on prenatal diagnosis, ultrasound findings, pathological features, outcomes and inheritance were analyzed. RESULTS: The mean time of prenatal diagnosis was 25.6 ± 6 weeks of gestation. Most of the diagnoses (86.8%) were prompted by abnormal ultrasound findings [heart defects (HDs), in 83.8% of cases]. On fetal autopsy, HDs were again the most common disease feature, but thymus, kidney abnormalities and facial dysmorphism were also described. The deletion was inherited in 27% of cases. Termination of pregnancy (TOP) occurred in 68.9% of cases and did not appear to depend on the inheritance status. However, early diagnosis was associated with a higher TOP rate. CONCLUSION: This is the largest cohort of prenatal del22q11.2 diagnoses. As in postnatally diagnosed cases, HDs were the most frequently observed abnormalities. However, thymus and kidney abnormalities and polyhydramnios should also be screened for in the prenatal diagnosis of del22q11.2. Only the time of diagnosis appeared to be strongly associated with the pregnancy outcome: the earlier the diagnosis, the higher the TOP rate.

A retrospective study by oligonucleotide array-CGH analysis in 50 fetuses with multiple malformations.

OBJECTIVE: To retrospectively define the frequency and the nature of submicroscopic chromosomal imbalances among fetuses with multiple congenital anomalies (MCA). METHODS: We used oligonucleotide arrays to perform comparative genomic hybridization after termination of pregnancy in 50 polymalformated fetuses with a normal karyotype. These fetuses presented with at least three significant malformations (42 cases) or a severe brain anomaly (eight cases). RESULTS: We identified a deleterious copy number variation (CNV) in five fetuses (10%). De novo genomic imbalances identified in this study consisted of a 6qter deletion in a fetus with brain and renal malformations, a mosaicism for a 8p tetrasomy in a fetus with agenesis of corpus callosum, growth retardation, mild facial dysmorphic features, and vertebral anomalies, a 17p13.3 deletion in a fetus with a complex brain malformation, and a partial 11p trisomy in a fetus with severe growth retardation and oligoamnios. In one case, we identified a partial 17q trisomy resulting from malsegregation of a cryptic-balanced translocation. CONCLUSIONS: This study shows that array comparative genomic hybridization (aCGH) is particularly effective for identifying the molecular basis of the disease phenotype in fetuses with multiple anomalies. Our study should help to define clinical relevant regions that would need to be included in targeted arrays designed for prenatal testing.

Prenatal diagnosis of mosaicism for 11q terminal deletion.

The phenotype of 11q terminal deletion also known as Jacobsen syndrome is a clinically well known entity whose diagnosis in infancy and childhood is based on clinical examination, hematological and cytogenetic findings. Hematological features in Jacobsen syndrome are very similar to those reported in Paris-Trousseau syndrome (PTS) which is also associated with11q terminal deletion. Karyotype analysis shows a variable terminal deletion from 11q23 sub-band extending to the telomere. Most often in patients with Jacobsen syndrome, this chromosomal deletion is present in all metaphases. We report on the identification of a distal 11q deletion in mosaic (20% of deleted cells) in a fetus ascertained after amniocentesis for maternal serum screening test indicative for Down syndrome. The present case is the third prenatal diagnosis of a mosaic for a distal 11q deletion with the lowest mosaicism rate. The 2D-ultrasound examination and cord blood hematological studies were useful to estimate the prognosis at term, considering the contribution of the mosaicism rate to the phenotypic variability in Jacobsen syndrome. The identification of mosaicism for distal 11q deletion is a very rare event in prenatal diagnosis. This case illustrates the complexity in genetic counselling for prenatally ascertained partial monosomy 11qter in mosaic.

Fortuitous FISH diagnosis of an interstitial microdeletion (5)(q31.1q31.2) in a girl suspected to present a cri-du-chat syndrome.

Constitutional interstitial deletions of 5q are relatively rare and most are poorly characterized cytogenetically. Consequently a definite karyotype-phenotype correlation is difficult to establish. We report on a new case of a girl presenting with an abnormal cry, upslanting palpebral fissures, hypertelorism, anteverted nostrils, microretrognathia, growth retardation, and an adenoid cyst at the base of the tongue. The first suspected diagnosis was cri-du-chat syndrome because of the mewing cry. Standard cytogenetic analyses were interpreted as normal, but FISH studies using the probe of cri-du-chat syndrome with the control probe EGR1 (5q31.2)/D5S23 (Abbott) revealed a 5q31.2 microdeletion which was then confirmed by CGH-array (Abbott). FISH studies using PACs and BACs clones (Rocchi, Italia) enabled us to characterize the breakpoints of the deleted region. Cytogenetic analysis with FISH studies revealed a normal karyotype with normal 5q31 region in both parents. This case is compared with the other cases reported in the literature.