Fetal exome sequencing: yield and limitations in a  tertiary referral center

Daum, Hagit; Meiner, Vardiella; Elpeleg, Orly; Harel, Tamar

doi:10.1002/uog.19168

Cited by 48 publications

(55 citation statements)

References 24 publications

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“…The first woman underwent amniocentesis due to multiple fetal malformations including unilateral cleft lip and palate, unilateral renal agenesis, abnormal small folded auricle, mild unilateral ventriculomegaly, suspected atrial septal defect and persistent left superior vena cava. Trio exome sequencing showed a de‐novo stop mutation (p.Q788X) in the CHD7 gene, compatible with fetal CHARGE syndrome. Based on this information, the couple chose to terminate the pregnancy (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Six couples decided to terminate the pregnancy despite normal CMA results (6/271, 2.2%), based on diagnosis of worsening sonographic findings, specifically cardiovascular and brain malformations, and in one instance because of fetal CMV infection ( Table 5). Median gestational age at pregnancy termination was 32 (range, [25][26][27][28][29][30][31][32][33][34][35][36][37] weeks. Three of the seven pregnancies with trisomy 21 were continued, of which one ended in IUFD.…”

Section: Fetal Exome Sequencingmentioning

confidence: 99%

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Role of late amniocentesis in the era of modern genomic technologies

Daum

David

Nadjari

et al. 2019

Ultrasound in Obstet & Gyne

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CMA increased detection rates and had a shorter turnaround time; therefore, late amniocentesis may serve as an extremely helpful tool for detecting abnormalities or reassuring parents following late appearing abnormal sonographic findings. However, CMA may expose uncertain findings for which the couple should be pre-counselled. The procedure appears safe. This article is protected by copyright. All rights reserved.

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Section: Resultsmentioning

confidence: 99%

Section: Fetal Exome Sequencingmentioning

confidence: 99%

Role of late amniocentesis in the era of modern genomic technologies

Daum

David

Nadjari

et al. 2019

Ultrasound in Obstet & Gyne

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“…In our study we focused on direct Sanger sequencing of the pathogenic allele in the fetus that was previously identified in an older sibling(s). An alternative approach utilizing NGS of fetal DNA directly in disease-naïve families would expand the benefit of PND [26], but suffer from nonpenetrant variants, as was recently reported for cystic fibrosis or Krabbe diseases [27,28]. Consanguineous families might especially profit from this approach due to the higher risk of recessive diseases, or risk of more than one recessive disease [29].…”

Section: Discussionmentioning

confidence: 99%

Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families

et al. 2020

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Background: The causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease. Methods: Retrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease. Results: Between 2010 and 2016, 1172 families presented with a child a likely rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive for the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25% to the observed 12% ([95% CI 0•04 to 0•20], p = 0•011). Conclusions: Molecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence.

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“…The earliest clue to diagnosis was the finding of increased NT, which has been previously described for PMM2‐CDG (Leticee et al, ). Most studies that have evaluated increased NT with exome sequencing have used a cut off value of 3–3.5 mm (Best et al, ; Daum, Meiner, Elpeleg, & Harel, ; Drury et al, ). If we had followed this practice exome sequencing would not have been recommended, leading to a missed diagnosis.…”

Section: Discussionmentioning

confidence: 99%

The first case of antenatal presentation in COG8‐congenital disorder of glycosylation with a novel splice site mutation and an extended phenotype

Arora

Puri

Bhai

et al. 2019

American J of Med Genetics Pt A

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Congenital disorders of glycosylation (CDG) are an extremely rapidly growing and phenotypically versatile group of disorders. Conserved oligomeric Golgi (COG) complexes are hetero-octameric proteins involved in retrograde trafficking within the Golgi. Seven of its eight subunits have a causal role in CDG. To date, only three cases of COG8-CDG have been published but none in the antenatal period. We present the first case of antenatally diagnosed COG8-CDG with facial dysmorphism and additional features such as Dandy-Walker malformation and arthrogryposis multiplex congenita, thus expanding the phenotype of this rare disorder. Trio whole exome sequencing revealed a novel homozygous variant in COG8, which creates a new splice site in exon 5 and protein truncation after 12 amino acids downstream to the newly generated splice site. As the mutations of the previous three patients were also identified in exon 5, it is likely to be a potential mutational hotspot in COG8. An association between antenatally increased nuchal translucency and COG8-CDG is also established, which would alert clinicians to its diagnosis early in gestation.It remains to be seen if this observation can be extended to other COG-CDGs. K E Y W O R D Santenatal presentation, arthrogryposis multiplex congenita, COG8-CDG, Dandy-Walker malformation, increased NT, mutational hotspot

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Fetal exome sequencing: yield and limitations in a tertiary referral center

Cited by 48 publications

References 24 publications

Role of late amniocentesis in the era of modern genomic technologies

Role of late amniocentesis in the era of modern genomic technologies

Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families

The first case of antenatal presentation in COG8‐congenital disorder of glycosylation with a novel splice site mutation and an extended phenotype

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