Tags

Type your tag names separated by a space and hit enter

Fetal exome sequencing: yield and limitations in a tertiary referral center.
Ultrasound Obstet Gynecol. 2019 Jan; 53(1):80-86.UO

Abstract

OBJECTIVE

To explore the indications for and diagnostic outcomes of fetal exome sequencing in a tertiary referral center.

METHODS

Between 2012 and 2017, 77 unrelated fetal samples from pregnancies referred to our center underwent exome sequencing. The cohort included 37 fetuses, 36 products of conception (from cases of pregnancy termination or intrauterine fetal death), one case with DNA from both the fetus and a previous termination of pregnancy, and three cases with DNA of unknown origin. Exome sequencing was performed on DNA extracted from amniocytes or fetal tissue and, in some cases, from parental peripheral blood. Indications, turnaround time, diagnostic rates and pregnancy outcomes were investigated. Diagnostic yield was analyzed according to consanguinity (yes or no), sample type (proband only, or trio or other) and referral indication (malformation or isolated nuchal translucency (NT)).

RESULTS

The most common indication for fetal exome sequencing was multiple malformations (21/77, 27%), followed by isolated brain malformation (15/77, 19%). Twelve (16%) fetuses were referred for isolated increased NT. Exome analysis was diagnostic for 16 fetuses (21%); when subclassified into fetal malformations vs isolated increased NT it became clear that exome analysis did not reveal any known or probable pathogenic variants in cases referred for isolated increased NT, whereas, among the remaining fetuses, a molecular diagnosis was reached in 16/65 (25%). Proband-only cases received a diagnosis more often than did cases that had trio exome sequencing.

CONCLUSIONS

Exome sequencing has the potential to provide molecular diagnoses in cases in which conventional prenatal cytogenetic testing is negative. Referral bias of consanguineous cases could account for the high diagnostic rate of proband-only sequencing. Syndrome-specific prognostic information enables parents to make informed decisions, whereas challenges include time limitations and variant interpretation in the setting of non-specific fetal findings. As we report only established disease-gene associations, further segregation and functional studies in a research setting are expected to increase significantly the diagnostic yield. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Authors+Show Affiliations

Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.No affiliation info available

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

29947050

Citation

Daum, H, et al. "Fetal Exome Sequencing: Yield and Limitations in a Tertiary Referral Center." Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology, vol. 53, no. 1, 2019, pp. 80-86.
Daum H, Meiner V, Elpeleg O, et al. Fetal exome sequencing: yield and limitations in a tertiary referral center. Ultrasound Obstet Gynecol. 2019;53(1):80-86.
Daum, H., Meiner, V., Elpeleg, O., & Harel, T. (2019). Fetal exome sequencing: yield and limitations in a tertiary referral center. Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology, 53(1), 80-86. https://doi.org/10.1002/uog.19168
Daum H, et al. Fetal Exome Sequencing: Yield and Limitations in a Tertiary Referral Center. Ultrasound Obstet Gynecol. 2019;53(1):80-86. PubMed PMID: 29947050.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fetal exome sequencing: yield and limitations in a tertiary referral center. AU - Daum,H, AU - Meiner,V, AU - Elpeleg,O, AU - Harel,T, AU - ,, PY - 2018/02/08/received PY - 2018/06/08/revised PY - 2018/06/11/accepted PY - 2018/6/28/pubmed PY - 2019/1/24/medline PY - 2018/6/28/entrez KW - chromosomal microarray KW - fetal exome KW - fetal malformations SP - 80 EP - 86 JF - Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology JO - Ultrasound Obstet Gynecol VL - 53 IS - 1 N2 - OBJECTIVE: To explore the indications for and diagnostic outcomes of fetal exome sequencing in a tertiary referral center. METHODS: Between 2012 and 2017, 77 unrelated fetal samples from pregnancies referred to our center underwent exome sequencing. The cohort included 37 fetuses, 36 products of conception (from cases of pregnancy termination or intrauterine fetal death), one case with DNA from both the fetus and a previous termination of pregnancy, and three cases with DNA of unknown origin. Exome sequencing was performed on DNA extracted from amniocytes or fetal tissue and, in some cases, from parental peripheral blood. Indications, turnaround time, diagnostic rates and pregnancy outcomes were investigated. Diagnostic yield was analyzed according to consanguinity (yes or no), sample type (proband only, or trio or other) and referral indication (malformation or isolated nuchal translucency (NT)). RESULTS: The most common indication for fetal exome sequencing was multiple malformations (21/77, 27%), followed by isolated brain malformation (15/77, 19%). Twelve (16%) fetuses were referred for isolated increased NT. Exome analysis was diagnostic for 16 fetuses (21%); when subclassified into fetal malformations vs isolated increased NT it became clear that exome analysis did not reveal any known or probable pathogenic variants in cases referred for isolated increased NT, whereas, among the remaining fetuses, a molecular diagnosis was reached in 16/65 (25%). Proband-only cases received a diagnosis more often than did cases that had trio exome sequencing. CONCLUSIONS: Exome sequencing has the potential to provide molecular diagnoses in cases in which conventional prenatal cytogenetic testing is negative. Referral bias of consanguineous cases could account for the high diagnostic rate of proband-only sequencing. Syndrome-specific prognostic information enables parents to make informed decisions, whereas challenges include time limitations and variant interpretation in the setting of non-specific fetal findings. As we report only established disease-gene associations, further segregation and functional studies in a research setting are expected to increase significantly the diagnostic yield. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. SN - 1469-0705 UR - https://www.unboundmedicine.com/medline/citation/29947050/Fetal_exome_sequencing:_yield_and_limitations_in_a_tertiary_referral_center_ L2 - https://doi.org/10.1002/uog.19168 DB - PRIME DP - Unbound Medicine ER -