Relationship between paternal factors and embryonic aneuploidy of paternal origin.

OBJECTIVE: To determine if there is a relationship between paternal factors and embryonic aneuploidy of paternal origin using preimplantation genetic testing for aneuploidy (PGT-A). DESIGN: Retrospective cohort. SETTING: Academic. PARTICIPANTS: Couples undergoing in vitro fertilization with PGT-A. INTERVENTIONS: None. MAIN OUTCOME MEASURE: To determine if there is an association between paternal age, body mass index (BMI), or semen analysis parameters and paternal aneuploidy. RESULTS: From January 2015-2020, 453 in vitro fertilization cycles (1,720 embryos) underwent PGT-A using single nucleotide polymorphism microarrays with parental support bioinformatics. The mean (±SD) was 36.5 (±3.5) years for maternal age, 39.5 (±5.5) years for paternal age, 24.7 (±5.0) kg/m2 for maternal BMI, and 27.6 (±4.3) kg/m2 for paternal BMI. Embryonic aneuploidy of paternal origin was found in 8.4% (144/1,720) embryos. There were 1,533 embryos with a recorded paternal BMI. Rates of embryonic aneuploidy of paternal origin were similar between men across BMI groups: BMI 18-24.9 kg/m2 was 7.2% (referent); BMI 25-29.9 kg/m2 was 8.4% (odds ratio [OR], 1.12; 95% confidence interval [CI], 0.79-1.82); and BMI ≥30 kg/m2 was 9.1% (OR, 1.31; 95% CI, 0.83-2.08). There were 854 embryos from men with a normal and 866 from men with an abnormal semen analysis. No differences were found in the rate of embryonic aneuploidy of paternal origin between men with normal and abnormal sperm concentration, total count, motility, progressive motility, or morphology. No significant difference was seen in rates of aneuploidy between men aged <50 years and those aged ≥50 years (OR, 1.69; 95% CI, 0.96-2.98). CONCLUSION: No association was found between paternal age, BMI, or semen analysis parameters and paternal aneuploidy.

Maternal body mass index is not associated with increased rates of maternal embryonic aneuploidy.

OBJECTIVE: To evaluate the relationship between maternal body mass index (BMI) and embryonic aneuploidy of maternal origin. DESIGN: Retrospective cohort analysis. SETTING: University hospital-based reproductive center. PATIENTS: Maternal origin of aneuploidy was available for 453 cycles and 1,717 embryos. INTERVENTIONS: Data regarding BMI were collected before egg retrieval. Comparison groups included underweight (BMI, <18.5 kg/m2), normal weight (BMI, 18.5-24.9 kg/m2), overweight (BMI, 25-29.9 kg/m2), and obese (BMI, ≥30 kg/m2). Overall embryonic aneuploidy and maternal aneuploidy rates were compared. The aneuploidy rate was the number of embryos with either maternal or mixed (maternal and paternal) aneuploidy divided by the total number of embryos tested. MAIN OUTCOME MEASURES: Overall embryonic aneuploidy and maternal aneuploidy rates. RESULTS: Maternal aneuploidy rate was 51.5% for BMI of ≥30 kg/m2 and 39.3% for BMI of <30 kg/m2. Female age as well as several in vitro fertilization characteristics were significantly different across groups and were included in the adjusted model. Both the overall embryonic aneuploidy rate (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.11-1.59) and the maternal aneuploidy rate (OR, 1.64; 95% CI, 1.25-2.16) increased with increasing maternal BMI. However, after controlling for significant confounders, BMI did not significantly predict the rate of maternal aneuploidy (OR, 1.16; 95% CI, 0.85-1.59). CONCLUSIONS: Maternal BMI did not correlate with embryonic aneuploidy of maternal origin after adjusting for confounders.

Pericentric inversion (Inv) 9 variant-reproductive risk factor or benign finding?

PURPOSE: To report the unbalanced chromosome rearrangement rate and overall aneuploidy rate in day 5/6 embryos from a series of patients who underwent in vitro fertilization (IVF) with preimplantation genetic testing for structural rearrangements (PGT-SR) for the pericentric inversion 9 variant, inv(9)(p11q13) or inv(9)(p12q13), with concurrent 24 chromosome preimplantation genetic testing for aneuploidy (PGT-A). METHODS: This was a retrospective cohort analysis. IVF cycles and embryo biopsies were performed by referring clinics. Fifty-two trophectoderm biopsy samples from seven couples were sent to a single lab for PGT-SR for an inversion 9 variant with concurrent 24 chromosome PGT-A using single-nucleotide polymorphism (SNP) microarrays with bioinformatics. RESULTS: The unbalanced rearrangement rate for this embryo cohort was 0/52 (0.0%); mean maternal age per embryo was 33.3 years (range 21-39 years). The overall euploid rate was 61.5% and aneuploidy rate was 38.5%. CONCLUSIONS: Chromosome 9 pericentric inversions did not result in unbalanced structural rearrangements in day 5/6 embryo samples, supporting that this population variant is not associated with increased reproductive risks.

Single-nucleotide polymorphism microarray detects molar pregnancies in 3% of miscarriages.

OBJECTIVE: To determine the frequency of molar pregnancy in miscarriage cases based on single-nucleotide polymorphism (SNP) microarray testing on products of conception (POC) tissue and to estimate the sensitivity of ultrasound and histopathologic evaluation for cases identified to be at risk for gestational trophoblastic disease. DESIGN: Retrospective cohort analysis. SETTING: Reference laboratory. PATIENT(S): POC specimens from 26,101 consecutive miscarriages. INTERVENTION(S): POC samples were sent to a single laboratory for analysis. Maternal age, gestational age, egg donor use, indication for testing, and additional clinical information were obtained from the requisition form and a survey sent to ordering providers. MAIN OUTCOME MEASURE(S): Rates of full paternal uniparental disomy (UPD), indicative of complete molar pregnancy, and triploidy of paternal origin, indicative of partial molar pregnancy, in POC samples. RESULT(S): Paternal triploidy was detected in 638 cases (2.8%) and full paternal UPD in 72 cases (0.3%). Of the cases with complete clinical information (224/710; 31.5%), histopathology and/or ultrasound did not detect 71% of partial molar pregnancies and 30% of complete molar pregnancies. CONCLUSION(S): Molar pregnancy, detected in 3.1% of all miscarriages in this study with the use of 24-chromosome SNP microarray testing, occurred significantly more frequently than previously estimated with the use of ultrasound and/or histopathology.

Incidence of the 22q11.2 deletion in a large cohort of miscarriage samples.

BACKGROUND: The 22q11.2 deletion syndrome is the most common microdeletion syndrome in livebirths, but data regarding its incidence in other populations is limited and also include ascertainment bias. This study was designed to determine the incidence of the 22q11.2 deletion in miscarriage samples sent for clinical molecular cytogenetic testing. RESULTS: Twenty-six thousand one hundred one fresh product of conception (POC) samples were sent to a CLIA- certified, CAP-accredited laboratory from April 2010--May 2016 for molecular cytogenetic miscarriage testing using a single-nucleotide polymorphism (SNP)-based microarray platform. A retrospective review determined the incidence of the 22q11.2 deletion in this sample set. Fetal results were obtained in 22,451 (86%) cases, of which, 15 (0.07%) had a microdeletion in the 22q11.2 region (incidence, 1/1497). Of those, 12 (80%) cases were found in samples that were normal at the resolution of traditional karyotyping (i.e., had no chromosome abnormalities above 10 Mb in size) and three (20%) cases had additional findings (Trisomy 15, Trisomy 16, XXY). Ten (67%) cases with a 22q11.2 deletion had the common ~3 Mb deletion; the remaining 5 cases had deletions ranging in size from 0.65 to 1.5 Mb. A majority (12/15) of cases had a deletion on the maternally inherited chromosome. No significant relationship between maternal age and presence of a fetal 22q11.2 deletion was observed. CONCLUSIONS: The observed incidence of 1/1497 for the 22q11.2 deletion in miscarriage samples is higher than the reported general population prevalence (1/4000-1/6000). Further research is needed to determine whether the 22q11.2 deletion is a causal factor for miscarriage.

Pregnancy outcomes following 24-chromosome preimplantation genetic diagnosis in couples with balanced reciprocal or Robertsonian translocations.

OBJECTIVE: To report live birth rates (LBR) and total aneuploidy rates in a series of patients with balanced translocations who pursued in vitro fertilization (IVF)-preimplantation genetic diagnosis (PGD) cycles. DESIGN: Retrospective cohort analysis. SETTING: Genetic testing reference laboratory. PATIENT(S): Seventy-four couples who underwent IVF-PGD due to a parental translocation. INTERVENTION(S): IVF cycles and embryo biopsies were performed by referring clinics. Biopsy samples were sent to a single reference lab for PGD for the translocation plus 24-chromosome aneuploidy screening with the use of a single-nucleotide polymorphism (SNP) microarray. MAIN OUTCOME MEASURE(S): LBR per biopsy cycle, aneuploidy rate, embryo transfer (ET) rate, miscarriage rate. RESULT(S): The LBR per IVF biopsy cycle was 38%. LBR for patients reaching ET was 52%. Clinical miscarriage rate was 10%. Despite a mean age of 33.8 years and mean of 7 embryos biopsied, there was a 30% chance for no chromosomally normal embryos. Maternal age >35 years, day 3 biopsy, and having fewer than five embryos available for biopsy increased the risk of no ET. CONCLUSION(S): IVF-PGD for translocation and aneuploidy screening had good clinical outcomes. Patients carrying a balanced translocation who are considering IVF-PGD should be aware of the high risk of no ET, particularly in women ≥35 years old.

Deletions flanked by breakpoints 3 and 4 on 15q13 may contribute to abnormal phenotypes.

Non-allelic homologous recombination (NAHR) between segmental duplications in proximal chromosome 15q breakpoint (BP) regions can lead to microdeletions and microduplications. Several individuals with deletions flanked by BP3 and BP4 on 15q13, immediately distal to, and not including the Prader-Willi/Angelman syndrome (PW/AS) critical region and proximal to the BP4-BP5 15q13.3 microdeletion syndrome region, have been reported; however, because the deletion has also been found in normal relatives, the significance of these alterations is unclear. We have identified six individuals with deletions limited to the BP3-BP4 interval and an additional four individuals with deletions of the BP3-BP5 interval from 34 046 samples submitted for clinical testing by microarray-based comparative genomic hybridization (aCGH). Of four individuals with BP3-BP4 deletions for whom parental testing was conducted, two were apparently de novo and two were maternally inherited. A comparison of clinical features, available for five individuals in our study (four with deletions within BP3-BP4 and one with a BP3-BP5 deletion), with those in the literature show common features of short stature and/or failure to thrive, microcephaly, hypotonia, and premature breast development in some individuals. Although the BP3-BP4 deletion does not yet demonstrate statistically significant enrichment in abnormal populations compared with control populations, the presence of common clinical features among probands and the presence of genes with roles in development and nervous system function in the deletion region suggest that this deletion may have a role in abnormal phenotypes in some individuals.