Exome sequencing as first‐tier test for fetuses with severe central nervous system structural anomalies

Yaron, Yuval; Glassner, V Ofen; Mory, Adi; Henig, Noa Zunz; Kurolap, Alina; Shira, Anat Bar; Goldstein, DB; Marom, Daphna; Ben-Sira, Liat; Feldman, Hagit Baris; Malinger, G.; Haratz, Karina Krajden; Reches, Adi

doi:10.1002/uog.24885

Cited by 40 publications

(46 citation statements)

References 38 publications

(49 reference statements)

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“…Each sample was processed in order to find carrier P/LP variants. The entire bioinformatics pipeline from FASTQ files to final results was performed using the Franklin genetic analysis platform, as previously described [ 9 ]. In brief, we aligned FASTQ files against the GRCh37/hg19 reference genome with BWA version 0.7.17 [ 10 ]; variant calling for single nucleotide variants and indels was performed using GATK version 4.0.12.0 and FreeBayes version 1.3.1 [ 11 , 12 ].…”

Section: Methodsmentioning

confidence: 99%

Community data-driven approach to identify pathogenic founder variants for pan-ethnic carrier screening panels

Einhorn¹,

Einhorn²,

Kurolap

et al. 2023

Hum Genomics

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Background The American College of Medical Genetics and Genomics (ACMG) recently published new tier-based carrier screening recommendations. While many pan-ethnic genetic disorders are well established, some genes carry pathogenic founder variants (PFVs) that are unique to specific ethnic groups. We aimed to demonstrate a community data-driven approach to creating a pan-ethnic carrier screening panel that meets the ACMG recommendations. Methods Exome sequencing data from 3061 Israeli individuals were analyzed. Machine learning determined ancestries. Frequencies of candidate pathogenic/likely pathogenic (P/LP) variants based on ClinVar and Franklin were calculated for each subpopulation based on the Franklin community platform and compared with existing screening panels. Candidate PFVs were manually curated through community members and the literature. Results The samples were automatically assigned to 13 ancestries. The largest number of samples was classified as Ashkenazi Jewish (n = 1011), followed by Muslim Arabs (n = 613). We detected one tier-2 and seven tier-3 variants that were not included in existing carrier screening panels for Ashkenazi Jewish or Muslim Arab ancestries. Five of these P/LP variants were supported by evidence from the Franklin community. Twenty additional variants were detected that are potentially pathogenic tier-2 or tier-3. Conclusions The community data-driven and sharing approaches facilitate generating inclusive and equitable ethnically based carrier screening panels. This approach identified new PFVs missing from currently available panels and highlighted variants that may require reclassification.

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Section: Methodsmentioning

confidence: 99%

Community data-driven approach to identify pathogenic founder variants for pan-ethnic carrier screening panels

Einhorn¹,

Einhorn²,

Kurolap

et al. 2023

Hum Genomics

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“…Following genetic counseling and informed consent, trio exome sequencing was performed in‐house on a NovaSeq6000 sequencer (Illumina, San Diego, CA, USA). The bioinformatic pipeline was performed using the Franklin data analysis platform (Genoox, Tel Aviv, Israel), as previously described 1 . The potential effect of the paternal intronic variant on mRNA splicing was studied using parental peripheral blood mononuclear cells (a fetal sample was unavailable).…”

Section: Diagnostic Methodsmentioning

confidence: 99%

“…The bioinformatic pipeline was performed using the Franklin data analysis platform (Genoox, Tel Aviv, Israel), as previously described. 1 The potential effect of the paternal intronic variant on mRNA splicing was studied using parental peripheral blood mononuclear cells (a fetal sample was unavailable). RNA was extracted using the High Pure RNA Isolation Kit (Roche, Basel, Switzerland) and cDNA was synthesized with the qScript cDNA Synthesis kit (Quantbio, Gaithersburg, MA, USA).…”

Section: Diagnostic Methodsmentioning

confidence: 99%

Upgrading an intronic TMEM67 variant of unknown significance to likely pathogenic through RNA studies and community data sharing

et al. 2022

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Fetal phenotype: A couple of Ashkenazi Jewish descent was referred for an early anatomy scan at 14 + 2 weeks of gestation following a previous pregnancy termination due to posterior encephalocele and enlarged kidneys. The index pregnancy was also positive for several fetal abnormalities, including enlarged kidneys with cystic dysplasia and abnormal cerebellar morphology highly suggestive of Joubert syndrome.Genetic diagnostic test performed, result, and interpretation: Trio exome sequencing revealed compound heterozygosity for variants in the TMEM67 gene: a known pathogenic maternally inherited variant found in trans with a paternal intronic variant of unknown significance. RNA analysis revealed that the intronic variant creates a cryptic acceptor splice site in intron 12, leading to the insertion of 22 bp and causing a frameshift with a premature stop codon. This analysis enabled the reclassification of the intronic variant to likely pathogenic. Implications and novelty:This information empowered the couple to make informed reproductive choices and opt for preimplantation genetic testing (PGT) for future pregnancies. Key pointsWhat's already known about this topic? � Intronic variants are often classified as variants of unclear significance (VUS). What does this study add?� This report highlights the importance of RNA analysis in cases where an intronic VUS is found in trans with a pathogenic or likely pathogenic variant in an autosomal recessive gene compatible with the fetal phenotype.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…A recent study by Yaron et al . compared the diagnostic yield of ES and CMA in 114 fetuses following termination of pregnancy (TOP) due to a major central nervous system (CNS) anomaly 7 . They reported a diagnostic yield of 10% by CMA in all cases and 44% by ES in CMA‐negative cases.…”

Section: Figurementioning

confidence: 99%

Prenatal genetic evaluation of fetuses with structural anomaly: is it time to shift from microarray to exome sequencing as a first‐tier test?

Lin

2023

Ultrasound in Obstet & Gyne

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Exome sequencing as first‐tier test for fetuses with severe central nervous system structural anomalies

Cited by 40 publications

References 38 publications

Community data-driven approach to identify pathogenic founder variants for pan-ethnic carrier screening panels

Community data-driven approach to identify pathogenic founder variants for pan-ethnic carrier screening panels

Upgrading an intronic TMEM67 variant of unknown significance to likely pathogenic through RNA studies and community data sharing

Prenatal genetic evaluation of fetuses with structural anomaly: is it time to shift from microarray to exome sequencing as a first‐tier test?

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