Preimplantation genetic testing for aneuploidies (PGT-A) is used to increase live birth rates following in vitro fertilization. The assessment of different testing methods to date has relied on non-universal parameters, e.g., sensitivity, specificity that must be individually stipulated for each study, typically performed using arbitrarily selected cell lines. Here we present a robust approach that is based on assessment of the median noise in a large dataset of routine clinical samples. Raw sequencing data obtained during PGT-A testing of 973 trophectoderm biopsies was used for comparison of two methods, VeriSeq PGS (Illumina) and AB-PGT (AB Vector). Three times less median noise was a feature of the AB-PGT method; thereby, allowing three times increase in the number of multiplexed samples per sequencing run, thus effectively reducing price per sample without compromising data quality. The improvement is attributed to a novel SuperDOP whole genome amplification technology, combined with a simplified AB-PGT protocol. We show that the median noise level associated with a large dataset of biopsies is a simple, universal metric for assessment of PGT-A methods which has implications for other screening methods, detection of mosaicisms and the improvement of fertility clinic practices.
Molybdenum cofactor deficiency type B (MOCODB; #252160) is an autosomal recessive metabolic disorder that has only been described in 37 affected patients. In this report, we describe the presence of an in-frame homozygous variant (c.471_477delTTTAAAAinsG) in the MOCS2 gene in an affected child, diagnosed with Ohtahara syndrome according to the clinical manifestations. The analysis of the three-dimensional structure of the protein and the amino acid substitutions suggested the pathogenicity of this mutation. To prevent transmitting this mutation to the next generation, we used preimplantation genetic testing for the monogenic disorders (PGT-M) protocol to select MOCS2 gene mutant-free embryos for transfer in an in vitro fertilization (IVF) program. As a result, a healthy child was born. Interestingly, both parents of the proband shared an identical mitochondrial (mt) DNA control region, assuming their close relationship and thus suggesting that both copies of the nuclear rare variant c.471_477delTTTAAAAinsG may have been transmitted from the same female ancestor. Our estimation of the a priori probability of meeting individuals with the same mtDNA haplotype confirms the assumption of a possible distant maternal relationship among the proband’s direct relatives.
Using low-coverage whole genome sequences of trophectoderm biopsy samples from 11610 morphologically good quality embryos we analyzed associations between chromosomal abnormalities and mitochondrial genome. Comparing 6208 aneuploid and 5402 euploid embryos we observed an increased mtDNA content and an excess of ultra-rare potentially deleterious mtDNA variants in aneuploid embryos. The increased mtDNA content was associated with aneuploidy irrespectively of the maternal age, suggesting new age-independent causative mechanisms, based on deleterious germline (or early somatic) variants.
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