Search

Fetal abnormalities are detected in 3% of all pregnancies and are responsible for approximately 20% of all perinatal deaths. Chromosomal microarray analysis (CMA) and exome sequencing (ES) are widely used in prenatal settings for molecular genetic diagnostics with variable diagnostic yields. In this study, we aimed to determine the diagnostic yield of trio-ES in detecting the cause of fetal abnormalities within a highly consanguineous population. In families with a history of congenital anomalies, a total of 119 fetuses with structural anomalies were recruited and DNA from invasive samples were used together with parental DNA samples for trio-ES and CMA. Data were analysed to determine possible underlying genetic disorders associated with observed fetal phenotypes. The cohort had a known consanguinity of 81%. Trio-ES led to diagnostic molecular genetic findings in 59 fetuses (with pathogenic/likely pathogenic variants) most with multisystem or renal abnormalities. CMA detected chromosomal abnormalities compatible with the fetal phenotype in another 7 cases. Monogenic ciliopathy disorders with an autosomal recessive inheritance were the predominant cause of multisystem fetal anomalies (24/59 cases, 40.7%) with loss of function variants representing the vast majority of molecular genetic abnormalities. Heterozygous de novo pathogenic variants were found in four fetuses. A total of 23 novel variants predicted to be associated with the phenotype were detected. Prenatal trio-ES and CMA detected likely causative molecular genetic defects in a total of 55% of families with fetal anomalies confirming the diagnostic utility of trio-ES and CMA as first-line genetic test in the prenatal diagnosis of multisystem fetal anomalies including ciliopathy syndromes. [ABSTRACT FROM AUTHOR]

Fetal structural anomalies have an impact on fetal mortality and morbidity. Next-generation sequencing (NGS) may be incorporated into clinical pathways for investigation of paediatric morbidity but can also be used to delineate the prognosis of fetal anomalies. This paper reviews the role of NGS in the investigation of fetal malformations, the literature defining the clinical utility, the technique most commonly used and potential promise and challenges for implementation into clinical practice. Prospective case selection with informative pre-test counselling by multidisciplinary teams is imperative. Regulated laboratory sequencing, bioinformatic pathways with potential variant identification and conservative matching with the phenotype is important. TWEETABLE ABSTRACT: Prenatal exome sequencing in fetal structural anomalies yields diagnostic information in up to 20% of cases. [ABSTRACT FROM AUTHOR]

Objective: To determine the incremental yield of antenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) or conventional karyotyping in prenatally diagnosed congenital heart disease (CHD). Methods: A prospective cohort study of 197 trios undergoing ES following CMA or karyotyping owing to CHD identified prenatally and a systematic review of the literature were performed. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov (January 2000 to October 2019) databases were searched electronically for studies reporting on the diagnostic yield of ES in prenatally diagnosed CHD. Selected studies included those with more than three cases, with initiation of testing based upon prenatal phenotype only and that included cases in which CMA or karyotyping was negative. The incremental diagnostic yield of ES was assessed in: (1) all cases of CHD; (2) isolated CHD; (3) CHD associated with extracardiac anomaly (ECA); and (4) CHD according to phenotypic subgroup. Results: In our cohort, ES had an additional diagnostic yield in all CHD, isolated CHD and CHD associated with ECA of 12.7% (25/197), 11.5% (14/122) and 14.7% (11/75), respectively (P = 0.81). The corresponding pooled incremental yields from 18 studies (encompassing 636 CHD cases) included in the systematic review were 21% (95% CI, 15–27%), 11% (95% CI, 7–15%) and 37% (95% CI, 18–56%), respectively. The results did not differ significantly when subanalysis was limited to studies including more than 20 cases, except for CHD associated with ECA, in which the incremental yield was greater (49% (95% CI, 17–80%)). In cases of CHD associated with ECA in the primary analysis, the most common extracardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system (23/52 (44.2%)). The greatest incremental yield was in cardiac shunt lesions (41% (95% CI, 19–63%)), followed by right‐sided lesions (26% (95% CI, 9–43%)). In the majority (68/96 (70.8%)) of instances, pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes. The most common (19/96 (19.8%)) monogenic syndrome identified was Kabuki syndrome. Conclusions: There is an apparent incremental yield of prenatal ES in CHD. While the greatest yield is in CHD associated with ECA, consideration could also be given to performing ES in the presence of an isolated cardiac abnormality. A policy of routine application of ES would require the adoption of robust bioinformatic, clinical and ethical pathways. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

The aim of the present study was to assess the practical diagnostic value of whole-exome sequencing (WES) in patients with different phenotypes and to explore possible strategies to increase the capability of WES in identifying disease-causing genes. A total of 1,360 patients (aged from 1 day to 42 years old) with manifestations of genetic diseases were genotyped using WES and statistical analysis was performed on the results obtained. Within this cohort, the overall positive rate of identification of a disease-causing gene alteration was 44.41%. The positive identification rate where trio-samples were used (from the proband and both parents) was higher than that where a single proband sample was used (50.00 vs. 43.71%), and 604 positive cases with 150 genetic syndromes, 510 genes and 718 mutations were detected. Missense mutations were the most common variations (n=335, 45.27%) and visual or auditory abnormalities (58.51%) had the highest rate of association with a genetic abnormality. The positive detection rate of WES was elevated with the increase in the number of clinical symptoms from 1 to 8. The present study indicated that WES may be used as a valuable tool in the clinic and the positive rate depends more on the professional experience of clinicians rather than on the analytical capabilities of the data analyst. At the same time, particular attention must be paid to certain possible factors (such as the age of the patients as well as possible exon deletions), which may affect the diagnostic rate while applying this process. [ABSTRACT FROM AUTHOR]