Genomic Imbalance in a Foetus and Recurrent Spontaneous Abortions

Research Story- Anushka

Dr Anushka Shrivastava is a certified cytogenetics technologist by the NABL (National Accreditation Board for Laboratory) and PNDT (Pre-Natal Diagnostic Act) based in New Delhi. Dr Shrivastava was interested in researching the genetic causes of abortions for better clinical management.

Recurrent pregnancy loss is a concern for the female and her family members. There are multiple risk factors, the genetic abnormality being responsible for 50% of the cases. There are several reports on the chromosomal analysis of Products of Conception (POC) in the Indian population, but studies using chromosomal microarray are rare.

The focus of cytogenetic research in spontaneous abortions has changed from a chromosomal abnormality in couples experiencing recurrent pregnancy loss to cytogenomic analysis in POC. A question may arise regarding the need for using high-end and expensive testing methods for the POC (dead aborted material), like conventional and molecular cytogenetics and high-resolution chromosomal microarrays. The genetically abnormal embryo indicates a higher risk of recurrence in future pregnancies, so awareness of underlying genetic causes can help to plan further pregnancies. The genome-wide analysis in POC is like exploring the uncharted waters of the ocean. Identifying the nature and frequency of the Copy Number Variation (CNV), whether pathogenic, benign or Variant of Uncertain Significance (VUS), are worth sharing on the genetic databases as with enough time and data, the pathogenicity and genotype-phenotype correlation is established to be clinically useful.

Dr Shrivastava carried out her doctoral research work under Dr Sonal Bakshi, Assistant Professor at the Institute of Science, Nirma University. The study included 300 aborted foetuses with abnormal maternal serum screening and abnormal foetal ultrasound results. The objective was to study the frequency and distribution of chromosomal abnormality in 300 POC samples, using conventional karyotyping and FISH with clinically significant probe sets e.g., aneuploidy of certain specific chromosomes and sub-microscopic deletions, duplications using chromosomal microarray on selected (Normal by FISH/Karyotype, with significant clinical history) samples. The parental karyotype was carried out in certain genetically abnormal POCs. Cytogenetic results showed abnormal chromosomal numbers and balanced translocations in POC. The microarray results showed unbalanced chromosomal rearrangements and submicroscopic deletions and duplications. Five pathogenic CNVs, one likely pathogenic and two VUS were observed. The pathogenic CNVs were associated with multiple congenital anomalies, neurodevelopmental disorders etc., consistent with the ultrasonography findings in POC. In five couples with a history of RSA, either of the parents was a carrier for balanced chromosomal rearrangements.

The study shows that genetic analysis of dead aborted material can be valuable for uncovering pathogenic CNVs. The correlation of genetic anomalies with ultrasonography findings can also be very useful when recurrent. Psychologically, the knowledge of genetic anomaly as a cause of pregnancy loss is crucial. Since recurrent spontaneous abortions are not like a disease that can be cured, the next step is genetic counselling that not only helps in assessing risk in future pregnancies, but also helps in clinical interventions like in-vitro fertilisation and pre-implantation genetic diagnosis, sperm or ovum donor, etc.