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

Background.Fetal malformations and other structural abnormalities are relatively frequent findings in the course of routine prenatal ultrasonographic examination. Due to their considerable genetic and clinical heterogeneity, the underlying genetic cause is often elusive and the resulting inability to provide a precise diagnosis precludes proper reproductive and fetal risk assessment. We report the development and first applications of an expanded exome sequencing-based test, coupled to a bioinformatics-driven prioritization algorithm, targeting gene disorders presenting with abnormal prenatal ultrasound findings.Methods.We applied the testing strategy to14 euploid fetuses, from 11 on-going pregnancies and three products of abortion, all with various abnormalities or malformations detected through prenatal ultrasound examination. Whole exome sequencing (WES) was followed by variant prioritization, utilizing a custom analysis pipeline (Fetalisalgorithm), targeting 758 genes associated with genetic disorders which may present with abnormal fetal ultrasound findings.Results.A definitive or highly-likely diagnosis was made in 6 of 14 cases (43%), of which 3 were abortuses (Ellis-van Creveld syndrome, Ehlers-Danlos syndrome and Nemaline myopathy 2) and 3 involved on-going pregnancies (Citrullinemia, Noonan syndrome,PROKR2-related Kallmann syndrome). In the remaining eight on-going pregnancy cases (57%), aZIC1variant of unknown clinical significance was detected in one case, while in seven cases testing did not reveal any pathogenic variant(s). Pregnancies were followed-up to birth, resulting in one neonate harboring thePROKR2mutation, presenting with isolated minor structural cardiac abnormalities, and in seven apparently healthy neonates.Discussion.The expanded targeted exome sequencing-based approach described herein (Fetalis), provides strong evidence suggesting a definite and beneficial increase in our diagnostic capabilities in prenatal diagnosis of otherwise chromosomally balanced fetuses with troubling ultrasound abnormalities. Furthermore, the proposed targeted exome sequencing strategy, designed primarily as a diagnostic rather than a research discovery tool, overcomes many of the problems and limitations associated with clinical wide-scale WES testing in a prenatal setting.

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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

10.7287/peerj.preprints.1811 ◽

2016 ◽

Author(s):

Constantinos Pangalos ◽

Birgitta Hagnefelt ◽

Konstantinos Lilakos ◽

Christopher Konialis

Keyword(s):

Exome Sequencing ◽

Genetic Disorders ◽

Nemaline Myopathy ◽

Prenatal Ultrasound ◽

Fetal Ultrasound ◽

Ehlers Danlos Syndrome ◽

Targeted Exome Sequencing ◽

Ultrasound Findings ◽

Fetal Malformations ◽

Ellis Van Creveld Syndrome

Background : Fetal malformations and other structural abnormalities are relatively frequent findings in the course of routine prenatal ultrasonographic examination. Due to their considerable genetic and clinical heterogeneity, the underlying genetic cause is often elusive and the resulting inability to provide a precise diagnosis precludes proper reproductive and fetal risk assessment. We report the development and first applications of an expanded exome sequencing-based test, coupled to a bioinformatics-driven prioritization algorithm, targeting gene disorders presenting with abnormal prenatal ultrasound findings. Methods : We applied the testing strategy to14 euploid fetuses, from 11 on-going pregnancies and 3 products of abortion, all with various abnormalities or malformations detected through prenatal ultrasound examination. Whole exome sequencing (WES) was followed by variant prioritization, utilizing a custom analysis pipeline (Fetalis algorithm), targeting 758 genes associated with genetic disorders which may present with abnormal fetal ultrasound findings. Results :A definitive or highly-likely diagnosis was made in 6 of 14 cases (43%), of which 3 were abortuses (Ellis-van Creveld syndrome, Ehlers-Danlos syndrome and Nemaline myopathy 2) and 3 involved on-going pregnancies (Citrullinemia, Noonan syndrome, PROKR2-related Kallmann syndrome). In the remaining 8 on-going pregnancy cases (57%), a ZIC1 variant of unknown clinical significance was detected in one case, while in 7 cases testing did not reveal any pathogenic variant(s). Pregnancies were followed-up to birth, resulting in one neonate harboring the PROKR2 mutation, presenting with isolated minor structural cardiac abnormalities, and in 7 apparently healthy neonates. Discussion : The expanded targeted exome sequencing-based approach described herein (Fetalis), provides strong evidence suggesting a definite and beneficial increase in our diagnostic capabilities in prenatal diagnosis of otherwise chromosomally balanced fetuses with troubling ultrasound abnormalities. Furthermore, the proposed targeted exome sequencing strategy, designed primarily as a diagnostic rather than a research discovery tool, overcomes many of the problems and limitations associated with clinical wide-scale WES testing in a prenatal setting.

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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

10.7287/peerj.preprints.1811v1 ◽

2016 ◽

Author(s):

Constantinos Pangalos ◽

Birgitta Hagnefelt ◽

Konstantinos Lilakos ◽

Christopher Konialis

Keyword(s):

Exome Sequencing ◽

Genetic Disorders ◽

Nemaline Myopathy ◽

Prenatal Ultrasound ◽

Fetal Ultrasound ◽

Ehlers Danlos Syndrome ◽

Targeted Exome Sequencing ◽

Ultrasound Findings ◽

Fetal Malformations ◽

Ellis Van Creveld Syndrome

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Prenatal diagnosis of X-linked myopathy associated with aVMA21gene mutation afforded through a novel targeted exome sequencing strategy applied in fetuses with abnormal ultrasound findings

Clinical Case Reports ◽

10.1002/ccr3.822 ◽

2017 ◽

Vol 5 (3) ◽

pp. 308-311 ◽

Cited By ~ 2

Author(s):

Christopher Konialis ◽

Efstratios Assimakopoulos ◽

Birgitta Hagnefelt ◽

Sophia Karapanou ◽

Alexandros Sotiriadis ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Exome Sequencing ◽

Targeted Exome Sequencing ◽

Ultrasound Findings ◽

Sequencing Strategy

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Carrier state for the nebulin exon 55 deletion and abnormal prenatal ultrasound findings as potential signs of nemaline myopathy

Prenatal Diagnosis ◽

10.1002/pd.2905 ◽

2012 ◽

Vol 32 (1) ◽

pp. 70-74 ◽

Cited By ~ 9

Author(s):

Hagith Yonath ◽

Haike Reznik-Wolf ◽

Michal Berkenstadt ◽

Shlomit Eisenberg-Barzilai ◽

Vilma-Lotta Lehtokari ◽

...

Keyword(s):

Nemaline Myopathy ◽

Carrier State ◽

Prenatal Ultrasound ◽

Ultrasound Findings

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Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01937-8 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Gilyazetdinov Kamil ◽

Ju Young Yoon ◽

Sukdong Yoo ◽

Chong Kun Cheon

Keyword(s):

Short Stature ◽

Exome Sequencing ◽

Developmental Delay ◽

Large Scale ◽

Genetic Diseases ◽

Genetic Diagnosis ◽

Connective Tissue Diseases ◽

Cleidocranial Dysplasia ◽

Facial Features ◽

Targeted Exome Sequencing

Abstract Background Large-scale genomic analyses have provided insight into the genetic complexity of short stature (SS); however, only a portion of genetic causes have been identified. In this study, we identified disease-causing mutations in a cohort of Korean patients with suspected syndromic SS by targeted exome sequencing (TES). Methods Thirty-four patients in South Korea with suspected syndromic disorders based on abnormal growth and dysmorphic facial features, developmental delay, or accompanying anomalies were enrolled in 2018–2020 and evaluated by TES. Results For 17 of 34 patients with suspected syndromic SS, a genetic diagnosis was obtained by TES. The mean SDS values for height, IGF-1, and IGFBP-3 for these 17 patients were − 3.27 ± 1.25, − 0.42 ± 1.15, and 0.36 ± 1.31, respectively. Most patients displayed distinct facial features (16/17) and developmental delay or intellectual disability (12/17). In 17 patients, 19 genetic variants were identified, including 13 novel heterozygous variants, associated with 15 different genetic diseases, including many inherited rare skeletal disorders and connective tissue diseases (e.g., cleidocranial dysplasia, Hajdu–Cheney syndrome, Sheldon–Hall, acromesomelic dysplasia Maroteaux type, and microcephalic osteodysplastic primordial dwarfism type II). After re-classification by clinical reassessment, including family member testing and segregation studies, 42.1% of variants were pathogenic, 42.1% were likely pathogenic variant, and 15.7% were variants of uncertain significance. Ultra-rare diseases accounted for 12 out of 15 genetic diseases (80%). Conclusions A high positive result from genetic testing suggests that TES may be an effective diagnostic approach for patients with syndromic SS, with implications for genetic counseling. These results expand the mutation spectrum for rare genetic diseases related to SS in Korea.

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Abnormal prenatal ultrasound findings in mevalonic aciduria

Prenatal Diagnosis ◽

10.1002/pd.1917 ◽

2008 ◽

Vol 28 (3) ◽

pp. 257-258 ◽

Cited By ~ 7

Author(s):

V. Schwarzer ◽

D. Haas ◽

G. F. Hoffmann ◽

H. Meyberg ◽

U. Gembruch

Keyword(s):

Prenatal Ultrasound ◽

Ultrasound Findings ◽

Mevalonic Aciduria

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Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes

Archives of Disease in Childhood ◽

10.1136/archdischild-2018-316547 ◽

2019 ◽

Vol 105 (4) ◽

pp. 384-389 ◽

Cited By ~ 1

Author(s):

Adam Jackson ◽

Heather Ward ◽

Rebecca Louise Bromley ◽

Charulata Deshpande ◽

Pradeep Vasudevan ◽

...

Keyword(s):

Exome Sequencing ◽

Copy Number ◽

Developmental Disorders ◽

Drug Exposure ◽

Genetic Disorders ◽

Copy Number Variants ◽

Copy Number Variant ◽

In Utero ◽

Developmental Problems ◽

Number Of Children

IntroductionFetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential.MethodsWe reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service.ResultsSeven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10).ConclusionsThis study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.

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