Utility of trio‐based prenatal exome sequencing incorporating splice‐site and mitochondrial genome assessment in pregnancies with fetal ultrasound anomalies: prospective cohort study

Zhu, Xuejun; Gao, Zhi; Wang, Y; Huang, Wei; Li, Q; Jiao, Zhen; Liu, N; Kong, Xiangdong

doi:10.1002/uog.24974

Cited by 7 publications

(4 citation statements)

References 51 publications

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“…In 2021, Mellis et al published a systematic review of 72 studies on prenatal ES, 23 of which reported incidental findings with a 6.3% (129/2062) mean yield, with 5 studies yielding above 10% [ 12 ]. One of these groups, Zhu et al, reported 4 (4.4%) incidental findings among 90 pregnancies undergoing trio-based ES incorporating splice-site and mitochondrial genome analysis among fetuses with structural abnormalities [ 13 ] All findings had clinical relevance because the four couples chose to terminate their pregnancies [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Prenatal Exome Sequencing Analysis in Fetuses with Various Ultrasound Findings

Borrell,

Ordoñez,

Pauta

et al. 2023

JCM

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Objectives: To evaluate the use of Exome Sequencing (ES) for the detection of genome-wide Copy Number Variants (CNVs) and the frequency of SNVs-InDels in selected genes related to developmental disorders in a cohort of consecutive pregnancies undergoing invasive diagnostic procedures for minor or simple ultrasound findings with no indication of ES. Methods: Women undergoing invasive diagnostic testing (chorionic villus sampling or amniocentesis) for QF-PCR and chromosomal microarray analysis (CMA) due to prenatal ultrasound findings without an indication for ES were selected over a five-month period (May–September 2021). ES was performed to compare the efficiency of genome-wide CNV detection against CMA analysis and to detect monogenic disorders. Virtual gene panels were selected to target genes related to ultrasound findings and bioinformatic analysis was performed, prioritizing variants based on the corresponding HPO terms. The broad Fetal Gene panel for developmental disorders developed by the PAGE group was also included in the analysis. Results: A total of 59 out of 61 women consented to participate in this study. There were 36 isolated major fetal anomalies, 11 aneuploidy markers, 6 minor fetal anomalies, 4 multiple anomalies, and 2 other ultrasound signs. Following QF-PCR analysis, two uncultured samples were excluded from this study, and six (10%) common chromosome aneuploidies were detected. In the remaining 51 cases, no pathogenic CNVs were detected at CMA, nor were any pathogenic variants observed in gene panels only targeting the ultrasound indications. Two (3.9%) monogenic diseases, apparently unrelated to the fetal phenotype, were detected: blepharo-cheilo-odontic syndrome (spina bifida) and Duchenne muscular dystrophy (pyelocaliceal dilation). Conclusions: In our series of pregnancies with ultrasound findings, common aneuploidies were the only chromosomal abnormalities present, which were detected in 10% of cases. ES CNV analysis was concordant with CMA results in all cases. No additional findings were provided by only targeting selected genes based on ultrasound findings. Broadening the analysis to a larger number of genes involved in fetal developmental disorders revealed monogenic diseases in 3.9% of cases, which, although apparently not directly related to the indications, were clinically relevant.

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Section: Discussionmentioning

confidence: 99%

Prenatal Exome Sequencing Analysis in Fetuses with Various Ultrasound Findings

Borrell,

Ordoñez,

Pauta

et al. 2023

JCM

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“…All fetal samples were tested for maternal cell contamination using a PowerPlex 21 HS System Kit (Promega Corporation, Madison, WI, USA). Exome capture and sequencing, read alignment, and bioinformatics analyses were performed as previously described [11].…”

Section: Dna Preparation and Trio-based Esmentioning

confidence: 99%

Prenatal ultrasonic presentation in fetuses with monogenic neurologic and neuromuscular diseases: a retrospective study

Liu,

Li,

Sun

et al. 2024

Preprint

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Background: The prenatal phenotype of neurological and neuromuscular monogenic diseases remains unclear. This study aimed to identify and explore prenatal ultrasonic presentation in fetuses with monogenic neurologic and neuromuscular diseases and to increase our knowledge on causal variants and novel candidate genes associated with fetal phenotypes. Methods: This retrospective study included 30 fetuses genetically diagnosed with or suspected of having neurologic and neuromuscular monogenic diseases who underwent prenatal trio-exome sequencing between January 2018 and May 2023. We systematically reviewed data on prenatal ultrasonic presentation, genetic characteristics, and genotype-phenotype relationships in a cohort of 30 fetuses. Some cases in this cohort study have been previously published as separate studies. Results: The disease spectrum of the 30 families included 27 diseases, including central nervous system diseases, neuromuscular diseases, congenital myopathy, mitochondrial diseases, and neurological genetic syndromes. The ultrasound abnormalities of the fetuses included abnormal fetal gestures and movements(18/30), polyhydramnios (15/30), increased nuchal translucency or nuchal fold (11/30), dysmorphic facial features (8/30), and brain malformations (6/30). Of the 40 variants detected, 35 were classified as pathogenic or likely pathogenic and 5 were of undetermined significance according to the American College of Medical Genetics and Genomics guidelines. The inheritance patterns were autosomal dominant (17/30; 57%), autosomal recessive (10/30; 33%), and X-linked recessive (3/30; 10%). Thirteen (13/30; 43%) fetuses achieved a definite genetic diagnosis, including known or novel variants of the recognized disease genes. Sixteen (16/30, 54%) fetuses were highly or probably suspected to be associated with genetic variants, and one fetus was found to have gene variants that did not explain the phenotype. Conclusions: The main clinical manifestations of prenatal ultrasonic presentation of neurological and neuromuscular monogenic diseases are abnormal fetal gestures, movements, and amniotic fluid volume, which might provide important clues for prenatal diagnosis. Trio-exome sequencing comprehensively detected and delineated various genomic variants that are causative. Our study expands our understanding of the prenatal phenotypic spectrum of monogenic neurological and neuromuscular diseases.

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“…Small (one or two) exon deletions and single nucleotide variation in areas with poor coverage may also be missed. A potential remedy for this problem is whole-genome sequencing, but it is more expensive than whole-exome sequencing and results in a depth of sequence coverage that is lower than that achieved by whole-exome sequencing (Zhu et al 2022).…”

Section: Mitochondrial Genome Variantmentioning

confidence: 99%

Molecular Findings Among Patients for Whole Exome Sequencing and mitochondrial genome assessment

Sun,

Huang,

Wang

et al. 2023

Preprint

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Objective: Whole exome sequencing (WES) is increasingly used as a diagnostic tool in medicine. We report the diagnostic yield of WES and mitochondrial genome in 2226 consecutive cases at a single clinical laboratory. Methods: We performed a retrospective analysis of consecutive WES reports of 2226 patients affected by a range of genetic disorders. The WES was performed solely for the probands and in a higher diagnostic capacity. We determined the diagnostic rate of WES overall as well as by phenotypic category, mode of inheritance, mitochondrial genome variant, and copy number variants (CNVs). Results: Of 2226 individuals having diagnostic WES proband-only, the overall diagnostic yield of WES was 34.59%. autosomal dominant (45.58%), followed by autosomal recessive (31.95%), X-linked (9.61%), and mitochondrial (0.65%), The remaining diagnoses were based on a total of 94 copy number variants (12.21%) reported from WES data. The CNV variation in children accounted for 67.02% of the total CNV variation. Molecular diagnoses were reported for 31.14% (373/1198) of adults, lower than a primarily pediatric population (38.62%, 397/1028). A While the majority of molecular diagnoses were related to nuclear genes, mitochondrial genome sequencing included in the WES test yielded five diagnoses, and all confirmed mitochondrial diseases were detected in adults. The highest positivity rate was observed in children aged 1-4 years old (43.72%, 80/183). Patients with integument system disorders had the highest diagnostic yield (58.33%, 59/151). The endocrine and metabolic disorders were the most common systems in both adults and children (261, 217). However, in adults, the highest diagnosis rate was for integument system disorders (71.43%, 30/42), while in children, the highest diagnosis rate was for disorders involving hearing (61.73%, 50/81). In addition to cases with a definitive diagnosis, in 8.4% of cases a candidate gene was reported that may later be reclassified as being associated with a definitive diagnosis. Conclusions: WES proband-only provided a definitive molecular diagnosis for 34.59% of a large cohort of patients referred for evaluation for evaluation of suspected genetic conditions, that analysis of WES simultaneously analyze the SNVs, Exons, mitochondrial genome and CNVs significantly improves the diagnostic yield compared with WES single detection method, and facilitates identification of novel candidate genes. The yield of whole exome sequencing in this study may have advantages over reported molecular diagnostic methods.

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Utility of trio‐based prenatal exome sequencing incorporating splice‐site and mitochondrial genome assessment in pregnancies with fetal ultrasound anomalies: prospective cohort study

Cited by 7 publications

References 51 publications

Prenatal Exome Sequencing Analysis in Fetuses with Various Ultrasound Findings

Prenatal Exome Sequencing Analysis in Fetuses with Various Ultrasound Findings

Prenatal ultrasonic presentation in fetuses with monogenic neurologic and neuromuscular diseases: a retrospective study

Molecular Findings Among Patients for Whole Exome Sequencing and mitochondrial genome assessment

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