First applications of a targeted exome sequencing approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with associated gene defects

Pangalos, Constantinos; Hagnefelt, Birgitta; Λιλάκος, Κωνσταντίνος; Konialis, Christopher

doi:10.7287/peerj.preprints.1811

Cited by 9 publications

(13 citation statements)

References 3 publications

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“…In targeting specific trios for testing, the diagnostic rate with WES was 80%. This is higher than previously reported in the literature for ultrasound anomalies (Alamillo, ; Best et al, ; Carss et al, ; Drury et al, ; Pangalos et al, ).…”

Section: Discussioncontrasting

confidence: 51%

“…While many fetal anomalies will have no identifiable genetic cause, WES can improve the diagnosis rate in cases with normal microarray. The reported yield for whole exome with a fetal anomaly on ultrasound ranges from 6.2% to 57% (Alamillo, ; Best et al, ; Carss et al, ; Drury et al (); Pangalos, Hagnefelt, Lilakos, & Konialis, ). In each of these reports, WES was done after initial studies with karyotype and microarray were normal.…”

Section: Introductionmentioning

confidence: 99%

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Whole exome sequencing for prenatal diagnosis in cases with fetal anomalies: Criteria to improve diagnostic yield

Yadava

Ashkinadze

2018

Journal of Genetic Counseling

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Whole exome sequencing (WES) for prenatal diagnosis has a reported diagnostic yield of 6.2%–57%. Our aim was to identify patients with a high likelihood of genetic diagnosis using WES in cases with fetal ultrasound anomalies. This is a series of five selected cases for prenatal WES at our institution. Pregnant couples were initially identified due to fetal ultrasound anomalies. Candidates for WES for fetal diagnosis had a normal fetal karyotype and negative microarray with at least one of the following: parental consanguinity, large regions of homozygosity on fetal microarray, or high likelihood of single gene disorder based on ultrasound findings. All trios underwent sequencing of parental and fetal samples. WES was diagnostic in four of the five cases (80%). We identified two recessive conditions and two de novo mutations. Four couples consented to secondary findings and in one case, the father was found to have an MSH2 mutation associated with Lynch syndrome. The use of specific selection criteria for WES increased diagnostic yield to 80%. This is higher than previously reported. Wide application of our criteria can help identify those who may benefit most from this testing in prenatal diagnosis.

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Section: Discussioncontrasting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Whole exome sequencing for prenatal diagnosis in cases with fetal anomalies: Criteria to improve diagnostic yield

Yadava

Ashkinadze

2018

Journal of Genetic Counseling

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“…Recently, next‐generation sequencing has been applied to the discovery of disease‐associated genes in fetal malformations in clinical practice (Drury et al, ; Filges & Friedman, ; Pangalos, Hagnefelt, Lilakos, & Konialis, ; van den Veyver & Eng, ). Whole‐exome sequencing (WES) has become a front‐line molecular detection technique for diagnosis of Mendelian disorders in neonatal and pediatric patients (Bamshad et al, ; Boycott et al, ; Choi et al, ; Stark et al, ).…”

Section: Introductionmentioning

confidence: 99%

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

et al. 2019

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Whole-exome sequencing (WES) is widely used to detect genetic mutations that cause Mendelian diseases, and has been successfully applied in combination with preimplantation genetic diagnosis (PGD) to avoid the transmission of genetic defects.We investigated 40 nonconsanguineous families with unexplained, recurrent fetal malformations (two or more malformed fetuses) from May 2016 to December 2018.Using Trio-WES, we identified 32 disease-associated variants in 40 families (80% positive rate), which were subsequently verified. Known Mendelian diseases were identified in 12 families (30%), highly suspected Mendelian diseases in 12 families (30%), variants with uncertain significance in 8 families (20%), and no noticeable variants for 8 families (20%). Further analysis showed variants in 22 genes may cause fetal malformations. Four gene variants were detected in fetuses for the first time, which expanded the spectrum of the disease phenotype. Two novel candidate genes may be related to fetal malformations. Of 26 couples receiving PGD on diseaseassociated genes, 3 healthy newborns were delivered, and 4 couples are undergoing pregnancies. We reported the fetal data and developed an optimized genetic testing strategy. Our finding strongly suggests the presence of single gene Mendelian disorders in 60% of those families, and PGD services for couples to have healthy babies.

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“…Massive parallel sequencing of whole genomes and exomes is nowadays an effective tool for direct assessment of causative genetic variations, enabling the identification of genetic factors involved in rare diseases with mendelian inheritance patterns. The diagnostic yield of trio–whole‐exome sequencing pursued for fetuses with US abnormalities has been reported to range from 21% to 57%, based on small published cohorts, although the diagnostic rates differ according to phenotype and consanguineous versus nonconsanguineous families and are also subject to a well‐described ascertainment bias.…”

Section: Discussionmentioning

confidence: 99%

LMOD3‐Associated Nemaline Myopathy: Prenatal Ultrasonographic, Pathologic, and Molecular Findings

Berkenstadt

Pode‐Shakked

Barel

et al. 2018

J of Ultrasound Medicine

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To describe the prenatal presentation, including ultrasonographic, histologic, and molecular findings, in 2 fetuses affected with LMOD3-related nemaline myopathy. Prenatal ultrasonographic examinations and histopathologic studies were performed on 2 fetuses with evidence of nemaline myopathy. To establish a molecular diagnosis, whole-exome sequencing was pursued for the affected fetuses. Nemaline myopathy is a common form of congenital myopathy manifesting with nonprogressive generalized muscle weakness, hypotonia, and electron-dense protein inclusions in skeletal myofibers. Although clinically, nemaline myopathy can be viewed as a common pathway phenotype, its molecular basis is heterogeneous, with mutations in 11 identified genes implicated in its pathogenesis so far. Whole-exome sequencing revealed that the affected fetuses were compound heterozygous for 2 newly reported pathogenic variants in the LMOD3 gene, which encodes leiomodin 3. To our knowledge, this article is the first report of LMOD3-related nemaline myopathy since the original reported cohort. We provide a detailed description of the prenatal imaging of these affected fetuses, which we hope, in combination with next-generation sequencing, may contribute to further diagnosis in additional families.

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First applications of a targeted exome sequencing approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with associated gene defects

Abstract: View the peer-reviewed version (peerj.com/articles/1955), which is the preferred citable publication unless you specifically need to cite this preprint.

Cited by 9 publications

References 3 publications

Whole exome sequencing for prenatal diagnosis in cases with fetal anomalies: Criteria to improve diagnostic yield

Whole exome sequencing for prenatal diagnosis in cases with fetal anomalies: Criteria to improve diagnostic yield

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

LMOD3‐Associated Nemaline Myopathy: Prenatal Ultrasonographic, Pathologic, and Molecular Findings

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