CffDNA screening for Niemann-pick disease, type C1: a case series

Area of Science:

• Genetics
• Molecular Biology
• Prenatal Diagnostics

Background:

• Cell-free fetal DNA (cffDNA) screening is established for chromosomal and autosomal dominant (AD) conditions.
• Autosomal recessive (AR) disorders, such as Niemann-Pick disease type C1 (NPC), pose diagnostic challenges in prenatal settings.
• Early detection of AR conditions is crucial for managing high-risk pregnancies and parental counseling.

Purpose of the Study:

• To develop and validate a proof-of-concept assay for autosomal recessive (AR) cffDNA screening.
• To assess the feasibility of detecting NPC1 gene variants using cffDNA in pregnant individuals.
• To demonstrate the clinical utility of non-invasive AR cffDNA screening for managing high-risk pregnancies.

Main Methods:

• Development of a novel amplicon-based next-generation sequencing (NGS) assay for AR cffDNA screening.
• Analysis of cffDNA extracted from maternal peripheral blood in three high-risk participants.
• Utilized a custom data analysis pipeline combining in-house scripts and standard software for variant detection and zygosity analysis.

Main Results:

• The AR cffDNA screening assay demonstrated concordance with standard invasive diagnostic testing in all three cases.
• The non-invasive method successfully identified zygosity and pathogenic variants in the NPC1 gene.
• Results were obtained consistently across all tested participants, validating the assay's performance.

Conclusions:

• The novel AR cffDNA screening assay is a viable non-invasive tool for detecting genetic conditions like NPC.
• This approach provides critical genetic information earlier in pregnancy, potentially reducing parental anxiety.
• Future applications may include screening for other common AR conditions with known familial variants.