Evaluating Prenatal Exome Sequencing Study

Active, not recruiting

• Conditions: Congenital Anomalies; Mendelian Disorders; Genetic Diseases, Inborn

• Registration Number: NCT05290701
• Lead Sponsor: Leiden University Medical Center

Brief Summary

This study evaluates the impact of the various outcomes of pES (definitive diagnosis, probable diagnosis and IF) on clinical decision making and on parental psychological wellbeing, compared between different analysis strategies to investigate the clinical utility, defined as the balance between potential harms and benefits.

Detailed Description

Foetal anomalies as detected on prenatal ultrasound are present in 2-3% of pregnancies. The diagnosis of a genetic syndrome as the underlying cause often has significant consequences for the prognosis and therefore also a significant impact on parental reproductive decision making. In addition to chromosomal testing, prenatal exome sequencing (pES) is increasingly being offered. Although prenatal diagnostic rates are promising, no studies report on the actual implementation of pES in routine care and thus several important knowledge gaps remain regarding clinical utility (the balance between potential harms and benefits) and the preferred analysis strategy (broad versus targeted analysis). A broad analysis has a possible higher diagnostic yield, but it is unknown whether the increased chance of finding an uncertain diagnosis and Incidental Findings outweighs this benefit when it comes to clinical decision making and parental psychological wellbeing. The central aim of this study is to address the knowledge gaps raised above, and increase clinical utility by using the obtained data to improve analysis strategies and to potentially identify new genes.

Study Timeline

• Study Start: 2022-02-21
• Study First Submitted: 2022-03-11
• Study First Submitted QC: 2022-03-21
• Study First Posted: 2022-03-22
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-04
• Last Update Posted: 2025-03-06
• Primary Completion: 2025-10-01
• Study Completion: 2026-10-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 235

Inclusion Criteria

• At least one fetal anomaly detected in the current pregnancy, irrespective of gestational age;
• Pregnancy ongoing;
• Mother at least 18 years old and providing consent for pES;
• If father is available: father at least 18 years old and providing consent for pES.

Exclusion Criteria

There are no exclusion criteria.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Percentage of definitive diagnoses, probable diagnoses and incidental findings (IF)	2 years

Secondary Outcome Measures

Name	Time	Method
Impact of different analysis strategies on the distribution of the various outcomes of pES (definitive diagnosis, probable diagnosis and incidental findings)	2 years	pES data of all included pregnancies will be retrieved and re-analyzed to minimize differences in variant interpretation and to determine the impact of different analysis strategies on the percentages of various outcomes of pES (definitive diagnoses, probable diagnoses and incidental findings). Different analysis strategies will be employed: analysis of an HPO-based gene panel, analysis of an established gene panel of genes causing multiple congenital anomalies and/or intellectual disability, and analysis of all genes.
Clinical impact of prenatal exome sequencing (pES)	2 years	Clinical impact will be defined as medical or surgical in utero intervention, pregnancy termination, location and mode of delivery, decisions on comfort care and neonatal policy influenced by the results of pES.
Patients perspectives on probable diagnoses and incidental findings including psychological wellbeing as measured by questionnaires.	2 years	We will use validated scales such as the State Trait Anxiety Inventory-6, the Decisional Conflict Scale, the Decisional Regret Scale, the Intolerance of Uncertainty Scale, the Impact of Event Scale and the Pre- and Postnatal Bonding Scale.

Trial Locations

Locations (1)

Leiden University Medical Centre; 🇳🇱 Leiden, Zuid-Holland, Netherlands