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. 2024 Feb;143(2):185-195.
doi: 10.1007/s00439-023-02637-y. Epub 2024 Feb 1.

Miscarriage risk assessment: a bioinformatic approach to identifying candidate lethal genes and variants

Mona Aminbeidokhti  1 , Jia-Hua Qu  1 , Shweta Belur  1 , Hakan Cakmak  2 , Eleni Jaswa  3 , Ruth B Lathi  4 , Marina Sirota  5   6 , Michael P Snyder  7 , Svetlana A Yatsenko  8   9   10 , Aleksandar Rajkovic  11   12   13
Affiliations

Miscarriage risk assessment: a bioinformatic approach to identifying candidate lethal genes and variants

Mona Aminbeidokhti et al. Hum Genet. 2024 Feb.

Abstract

Purpose: Miscarriage, often resulting from a variety of genetic factors, is a common pregnancy outcome. Preconception genetic carrier screening (PGCS) identifies at-risk partners for newborn genetic disorders; however, PGCS panels currently lack miscarriage-related genes. In this study, we evaluated the potential impact of both known and candidate genes on prenatal lethality and the effectiveness of PGCS in diverse populations.

Methods: We analyzed 125,748 human exome sequences and mouse and human gene function databases. Our goals were to identify genes crucial for human fetal survival (lethal genes), to find variants not present in a homozygous state in healthy humans, and to estimate carrier rates of known and candidate lethal genes in various populations and ethnic groups.

Results: This study identified 138 genes in which heterozygous lethal variants are present in the general population with a frequency of 0.5% or greater. Screening for these 138 genes could identify 4.6% (in the Finnish population) to 39.8% (in the East Asian population) of couples at risk of miscarriage. This explains the cause of pregnancy loss in approximately 1.1-10% of cases affected by biallelic lethal variants.

Conclusion: This study has identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The variation of these genes across ethnic groups underscores the need for a comprehensive, pan-ethnic PGCS panel that includes genes related to miscarriage.

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Conflict of interest statement

The authors have no relevant financial or non-financial interests to disclose.

Figures

Fig. 1
Fig. 1
Bioinformatic Workflow for Identifying Genes Associated with Human Lethality. This figure illustrates a bioinformatic pipeline used to delineate known and candidate genes implicated in human lethality. Starting on the left, the Online Mendelian Inheritance in Man (OMIM) database was queried to isolate genes implicated in human lethality, yielding 624 known lethal human genes. From these, genes with autosomal recessive patterns were isolated for an in-depth analysis of their associated pathogenic/likely pathogenic (P/LP) and loss-of-function (LoF) variants, excluding those already classified as P/LP. Moving to the right side of the workflow, we identified candidate genes (potentially lethal in humans) informed by lethal phenotypes observed in mouse knock-out (KO) studies. Within the OMIM database, 1,299 of the 3,684 genes had documented human phenotypes, including 350 genes previously recognized for their association with prenatal lethality. These 350 genes were thus excluded from the candidate gene set, as they were already accounted for among the known lethal genes. The remaining 949 genes have human phenotypes documented in OMIM but have not yet been reported as lethal. Out of these, 490 genes demonstrating recessive inheritance were earmarked for additional investigation. The other 2,385 genes out of the 3,684 total did not have OMIM entries, lacked associated clinical phenotypes, or had undefined modes of inheritance. In total, 2,875 (490 + 2,385) candidate genes underwent population-based analysis and a search for LoF variants in the gnomAD database, which led to findings on 2,612 genes. The cumulative count of genes along with their P/LP and LoF variants are displayed at the bottom of the figure. Highlighted in yellow are three datasets that were analyzed
Fig. 2
Fig. 2
Distribution of Gene Carrier Rates for Pathogenic Variants in the General Population. Panel A displays the gene carrier rate (GCR) for pathogenic/likely pathogenic (P/LP) variants within known lethal genes, highlighting that 0.5% of the general population carries a P/LP variant in one of the nine identified lethal genes, corresponding to a frequency of 0.005. Panel B details the GCR for loss-of-function (LoF) variants in known lethal genes, with LoF variants present in 0.5% of the population for seven of these genes. Panel C illustrates the GCR for LoF variants in candidate lethal genes, showing that LoF variants in 77 candidate lethal genes are found in 0.5% of the general population
Fig. 3
Fig. 3
Prevalence of Gene Carrier Rates for Lethal Variants Across Populations. The figure illustrates the top five lethal genes with the highest gene carrier rates (GCR). Panel A represents GCR values for pathogenic/likely pathogenic (P/LP) variants in known lethal genes, while panel B shows GCR values for loss-of-function (LoF) variants in the same set of genes. Panel (C) pertains to LoF variants in candidate lethal genes. The most significant GCR values across the overall population are marked in black. Furthermore, the figure identifies the top five genes within seven ethnic groups: African/African American (afr), Latino/Admixed American (amr), Ashkenazi Jewish (asj), East Asian (eas), Finnish (fin), Non-Finnish European (nfe), and South Asian (sas). Detailed information regarding genes with a GCR of 0.005 or greater, whether in all populations combined or in individual ethnic groups, can be found in Table S2
Fig. 4
Fig. 4
At-risk couple rates (ACRs). This figure presents the cumulative probability curves for couples at genetic risk within various populations based on A pathogenic/likely pathogenic (P/LP) variants and B loss-of-function (LoF) variants in known lethal genes. Panel C illustrates the cumulative risk for couples concerning LoF variants in candidate lethal genes across ethnic groups: African/African American (afr), Latino/Admixed American (amr), Ashkenazi Jewish (asj), East Asian (eas), Finnish (fin), Non-Finnish European (nfe), and South Asian (sas). The general population curve is accentuated in black. Panels D–F detail the rates of at-risk couples within and between ethnicities, calculated for 138 genes. The at-risk couple rates (ACRs) for intra-ancestry couples, those from the same ancestry, and inter-ancestry couples, those from different ancestries, are shown as the number of couples per 10,000. Panel D shows the number of couples at risk of conceiving an embryo with two P/LP variants, and panel E with two LoF variants, for genes on the list of known lethal genes. Panel F presents the number of couples at risk of having a conception with two inherited LoF variants in a candidate lethal gene
Fig. 5
Fig. 5
Protein Class Distributions Among Known and Candidate Lethal Genes. This figure utilizes the PANTHER classification system to analyze gene ontology within two categories of lethal genes. Panel A illustrates the primary protein classes within known lethal genes. Panel B details the primary protein classes within candidate lethal genes, offering insights into the diverse biological functions these genes may influence
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Web resources
    1. International Mouse Phenotyping Consortium http://www.mousephenotype.org/
    1. MGI-Mouse Genome Informatics http://www.informatics.jax.org/
    1. OMIM http://www.omim.org/
    1. PANTHER http://www.pantherdb.org/
    1. The Genome Aggregation Database (gnomAD) http://www.gnomad-sg.org/