Development and validation of a haplotype‐free technique for non‐invasive prenatal diagnosis of spinal muscular atrophy

Abstract

Objective To develop a technique for non‐invasive prenatal diagnosis of spinal muscular atrophy and validate its performance. Study Design Pregnant women with 1 copy of SMN1 and male fetuses were enrolled. Seventeen women were included in test set A, and 10 of them were selected into test set B randomly and blinded. The two sets were tested independently by two different researchers blinded to fetal genotypes. Fetal DNA fractions were calculated based on the relative proportion of mapped chromosome Y sequencing reads. An algorithm was developed to decide fetal SMN1 copy numbers. Results The concordance rate with the results of MLPA testing of amniocyte DNA was 94.12% in test set A and 90% in set B. For all tests with a classifiable result, the percent of agreement with the results of MLPA testing of amniocyte DNA was up to 100% (25/25). Conclusion We have developed a direct, rapid, and low‐cost technique, which has a potential to be utilized for first‐trimester non‐invasive prenatal diagnosis and screening for spinal muscular atrophy with considerable reliability and feasibility.

Genome-wide noninvasive prenatal diagnosis of monogenic disorders: Current and future trends

“…These methods either require haplotype information from another family member to reconstruct maternal haplotypes, or they rely on complex experimental technologies that are not widely available, that require significant expertise and that are time consuming. In addition, none of these methods could phase the entire parental genomes, due to various reasons, such as a low density of informative genomic markers [31] , [32] . The use of haplotypes also requires dealing with recombination events and phasing errors.…”

“…The use of haplotypes also requires dealing with recombination events and phasing errors. When these occur near a mutation, they may result in incorrect fetal genotype classification [31] , [32] . Recombination assessment comprises a prominent portion of the computational efforts in the aforementioned methods.…”

Investigating attitudes toward prenatal diagnosis and fetal therapy for spinal muscular atrophy

“…Prenatal SMA testing is voluntary in the United States but leads to an earlier diagnosis and initiation of therapy 27,28 . In addition to standard fetal testing with CVS and amniocentesis, techniques for noninvasive prenatal diagnosis of SMA have also been piloted, 29 but the widespread adoption of fetal screening is not yet present. In other surveys, respondents have supported early testing for SMA due to its ability to prepare parents for caring for a disabled child and reduce the potential emotional impact of the disease 30 .…”

Non-invasive prenatal diagnosis (NIPD): how analysis of cell-free DNA in maternal plasma has changed prenatal diagnosis for monogenic disorders

“…However, this approach has shown clinical promise in several proof-of-concept studies for the detection of both paternally and maternally inherited variants, including for haemophilia [ 73 , 74 ], sickle cell disease [ 54 , 75 ], monogenic diabetes [ 76 ], β-thalassaemia [ 77–79 ], CF [ 80 , 81 ], inherited deafness [ 82 ], achondroplasia [ 83 ], and others [ 84 , 85 ] ( Figure 2 ). The utility of haplotype-free RMD using dPCR is being considered for copy number variation (CNV) detection in autosomal recessive diseases, such as SMA, where gene copy number is negatively correlated with disease severity [ 86 ].…”