Noninvasive prenatal diagnosis of cobalamin C (cblC) deficiency through target region sequencing of cell‐free DNA in maternal plasma

Abstract

Objective This study aimed to validate the feasibility of haplotype‐based noninvasive prenatal diagnosis (NIPD) of cobalamin C (cblC) deficiency. Method This method includes three steps: First, targeted sequencing was performed on 21 families affected by cblC deficiency (including the couples and probands). Second, parental haplotypes linked with the pathogenic variant were determined using the genotypes of trios. Then, the fetal haplotypes were inferred through a parental haplotype assisted hidden Markov model (HMM). The NIPD results were confirmed by using the invasive procedures. Results Twenty‐one fetal genotypes were successfully inferred by NIPD including three compound heterozygotes with cblC deficiency, nine heterozygote carriers of cblC deficiency, and nine normal fetuses. The NIPD results were confirmed using the invasive procedures with 100% concordant rate. Conclusion This result has shown that haplotype‐based NIPD of cblC deficiency has high concordant rate and indicated potential clinical utility as a pregnancy diagnosis method for high‐risk carrier couples.

Noninvasive Prenatal Testing of Methylmalonic Acidemia cblC Type Using the cSMART Assay for MMACHC Gene Mutations

“…This is the first report of the clinical application of a direct sequencing method, unlike the haplotype-based indirect methods, in NIPT for cblC type MMA (Han et al, 2020). It is proven again that the cSMART assay can be easily customized to target exonic coding sequences and the exon proximal intronic regions of interesting genes (Lv et al, 2019).…”

“…cSMART assay testing informative SNPs from targeted LRS of couples with RHDO analysis would provide a novel and precise proband-free NIPT way. Besides, the unique total read of cSMART that passed the QC was as ≥500, which is higher than the sequencing depth of current hybridization captured with haplotype-based relative haplotype dosage methods (200-400 ×) (Parks et al, 2017;Ye et al, 2018;Che et al, 2020;Han et al, 2020). More unique reads indicate less informative SNPs would be enough for future cSMART assay testing informative SNPs from targeted LRS of couples with RHDO analysis.…”

Newborn Screening for Methylmalonic Acidemia/propionic Acidemia: Systematic Evaluation of a Two-pronged Approach Based on MS/MS and UPLC-MS/MS

“…Thus, further study is needed in a large-scale newborn population to test these hypotheses. Interestingly, molecular genetic analysis for individuals with MMAs/PA is strongly recommended for cases in which the plasma Met and C3/C2 values are signi cantly lower (as seen with mild alterations with compound heterozygotes compared to homozygotes in cblC de ciency 24 ). Moreover, the detection of C3 is now well recognized as a complicating factor in initial MS/MS screening, primarily because most cases of MMA/PA de ciency may present with elevated C3 concentrations.…”

Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease

“…Molecular genetic analysis then is performed on amniotic cells or chorionic villi samples. A recent study proposed haplotype-based non-invasive prenatal diagnosis (NIPD) as a promising alternative ( Han et al., 2019 ). Metabolites in maternal urine or amniotic fluid may be measured as follow-up during pregnancy.…”