Introduction
Pregnancy loss is a common
obstetric complication leading to significant economic and emotional
burden for affected families and the health care
system.1 Women experiencing pregnancy loss are at
increased risk of its recurrence, as well as other obstetric
complications in subsequent pregnancies.2-4 Recurrent
pregnancy loss occurs in 1-2% of couples who are trying to
conceive.5,6 Recurrent pregnancy loss is commonly
defined by the American Society of Reproductive Medicine as ≥ 2
pregnancy losses,7 and because the etiologies of
pregnancy loss vary across gestational age, more specific
characterizations of losses by gestational age have been
recommended.8 Thus, pregnancy loss can be divided into
three epochs: embryonic loss (<10 weeks’ gestation), fetal
death (10-20 weeks’ gestation) and/or stillbirth (≥20 weeks’ gestation).
Though known and suspected causes of recurrent pregnancy loss include
autoimmune, endocrine, uterine, and genetic abnormalities, over half are
not currently explained by these mechanisms.9-11 Among
genetic abnormalities, the most clearly associated with recurrent
pregnancy loss is parental balanced translocation.12However, this abnormality is found in fewer than 5% of couples with
recurrent pregnancy loss.13,14 Embryonic losses
(<10 weeks) are often due to spontaneously-occurring
aneuploidy which result from errors in maternal
meiosis.7 Such cases are identified by karyotype but
often have a low recurrence risk.15
Many previous studies of pregnancy loss did not distinguish gestational
ages of the losses and focused on sporadic losses <10
weeks.7,16 However, systematic evaluation of
unexplained embryonic loss, fetal death and stillbirth cases is critical
to identify genetic abnormalities that are not detected by karyotype and
may influence specific developmental epochs. Whole-genome sequencing
(WGS) allows identification of previously unrecognized genetic
abnormalities (e.g., copy number changes, single gene mutations, single
nucleotide variants [SNVs] and/or structural variants [SVs])
that may cause unexplained pregnancy loss.10 Few
studies included DNA from parents, losses, and live births. The power of
WGS technology can be further amplified by examining DNA from family
pedigrees to clarify autosomal-dominant transmission of risk alleles and
prove whether variants appeared in the germline of the probands asde novo , which will be critical for interpretation and
determination of genetic causes of recurrent and sporadic pregnancy
loss.
Therefore, we conducted a pilot WGS study of four families with several
unexplained pregnancy losses, which included embryonic loss, fetal death
and stillbirth. We applied best practice standards of WGS and analyses
to identify variants using DNA from couples and their products of
conception (pregnancy losses and live births). We hypothesized that
pathogenic SNVs and/or SVs that may be inherited or occur de novoin the offspring will be relevant to the losses.