Abstract

Background: A non-consanguineous couple approached us with a history of 6 first trimester unexplained miscarriages (4 natural conceptions, 1 intrauterine insemination (IUI) cycle conception and 1 in-vitro fertilization (IVF) cycle conception. No genetic testing was carried out for abortuses. Clinical data: Couple karyotyping was normal. Couple carrier screening revealed that the husband was heterozygous for a variants c.3829A>G in RELN gene exon 27 and the wife was compound heterozygous for 2 variant c.4739C>G exon 32 and c.5156C>T exon 34 in RELN gene with autosomal recessive (AR) inheritance, responsible for Lissencephaly 2. All were reported as variants of uncertain significance (VUS). As the wife was unaffected, both variants must have been in cis. The husband was also heterozygous for AR SMN1 variant. No preimplantation genetic testing (PGT) was offered previously. Investigation: The couple underwent 3 IVF cycles with PGT for chromosomal aneuploidy (PGT-A) followed by PGT for monogenic disorder (PGT-M) for RELN gene variants. Results: Of 9 blastocyst embryos tested, only one euploid heterozygous embryo with a single variant was available for implantation. Frozen embryo transfer led to a singleton pregnancy and birth of a healthy boy Discussion: As there was no family history of lissencephaly, the findings of RELN variants on carrier screening were not further evaluated. No possible correlation was made with RELN variants or presence of aneuploidy in the embryos and first trimester recurrent pregnancy loss. Hence PGT-M was not offered previously for VUS neither PGT-A. However, as the classification of VUS may change to pathogenic in future after availability of sufficient data, we offered PGT. In this case as the couple had 3 VUS in RELN gene, a compound heterozygous future child could be affected with cobblestone lissencephaly. Hence PGT-M was important in this case. Due to the history of failed IUI-IVF cycles and 6 miscarriages, PGT-A was also very important to use euploid embryos for successful implantation and to reduce miscarriage risk due to aneuploidy. Recent literature shows that RELN gene variant may impair embryonic microenvironment homeostasis leading to early miscarriages and the possible cause of miscarriages. This shows the importance of genetic counselling to offer specific investigations, to deliver a healthy child to couples.

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