Noninvasive prenatal testing for autosomal recessive conditions by maternal plasma sequencing in a case of congenital deafness

Haplotype-based approach for noninvasive prenatal tests of Duchenne muscular dystrophy using cell-free fetal DNA in maternal plasma

“…In the process of decoding this HMM chain, we used the Viterbi algorithm to find the most likely sequence of hidden states. [20][21][22][23]26 Finally, we could predict the inherited haplotype and recombination breakpoints in the fetus. The detailed calculations that were used to construct the fetal genome and to determine the recombination breakpoints are available in the Supplementary Methods online.…”

“…20 To infer the fetal haplotype, we used a haplotype-based approach with a linkage relationship that was obtained from the parental haplotypes and allele frequencies that were calculated from the plasma sequencing data, as previously described. [20][21][22][23] Because the candidate mutant allele X a was inherited from the maternal chromosome X, we focused on the fetal maternalinherited chromosome X in the following analysis process. The informative SNPs that were used to infer fetal haplotype and construct the model were those maternal heterozygous SNP sites on chromosome X.…”

“…20 Using this approach, we successfully predicted the fetal mutation status of many autosomal recessive disorders based on the maternal plasma, including congenital adrenal hyperplasia, maple syrup urine disease, and congenital deafness. [21][22][23] However, the application of this approach to noninvasively predict the fetal mutation status in X-linked diseases has never been demonstrated.…”

Reproductive management through integration of PGD and MPS-based noninvasive prenatal screening/diagnosis for a family with GJB2-associated hearing impairment

“…SNPs, homozygous in both parents, but with different genotypes, were used for calculating fetal DNA fraction using the formula: fetal DNA fraction=2d father /(d mother +d father ), where d mother and d father stand for the allele count of the special base of the mother and the father respectively. A strategy of trios analysis based on Mendel′s law was used to deduce the parental haplotype, and a Hidden Markov Model and Viterbi algorithm were used to calculate the inherited status of maternal haplotype or paternal haplotype respectively [8,13,14].…”

“…For instance, Altarescu et al reported PGD for nonsyndromic deafness by Sanger sequencing and short tandem repeat (STR) linkage analysis of polar body and blastomere [7]. Recently, Meng et al also demonstrated that by massively parallel sequencing (MPS) of genomic DNA (gDNA) from a family with autosomal recessive congenital deafness and maternal plasma DNA, the fetal condition of the deafness causative mutation can be accurately predicated by NIPD using single nucleotide polymorphism (SNP)-based chromosome phasing and haplotype-assisted analysis [8]. Welldesigned integration of such technologies can improve the reproductive care for patients and their families.…”