Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Oddsson, Asmundur; Sulem, Patrick; Sveinbjornsson, Gardar; Arnadottir, Gudny A.; Steinthorsdottir, Valgerdur; Halldorsson, Gisli H.; Atlason, Bjarni A.; Oskarsson, Gudjon R.; Helgason, Hannes; Nielsen, Henriette Svarre; Westergaard, David; Karjalainen, Juha M.; Katrinardottir, Hildigunnur; Fridriksdottir, Run; Jensson, Brynjar O.; Tragante, Vinicius; Ferkingstad, Egil; Jonsson, Hakon; Gudjonsson, Sigurjon A.; Beyter, Doruk; Moore, Kristjan H. S.; Thordardottir, Helga B.; Kristmundsdottir, Snaedis; Stefansson, Olafur A.; Rantapää-Dahlqvist, Solbritt; Sonderby, Ida Elken; Didriksen, Maria; Stridh, Pernilla; Haavik, Jan; Tryggvadottir, Laufey; Frei, Oleksandr; Walters, G. Bragi; Kockum, Ingrid; Hjalgrim, Henrik; Olafsdottir, Thorunn A.; Selbaek, Geir; Nyegaard, Mette; Erikstrup, Christian; Brodersen, Thorsten; Saevarsdottir, Saedis; Olsson, Tomas; Nielsen, Kaspar Rene; Haraldsson, Asgeir; Bruun, Mie Topholm; Hansen, Thomas Folkmann; ,; Brunak, Søren; Nielsen, Kasper Rene; Brun, Mie Topholm; Stefánsson, Hreinn; Þorsteinsdóttir, Unnur; Steingrimsdottir, Thora; Jacobsen, Rikke Louise; Lie, Rolv T.; Djurovic, Srdjan; Alfredsson, Lars; Lopez de Lapuente Portilla, Aitzkoa; Brunak, Soren; Melsted, Pall; Halldorsson, Bjarni V.; Saemundsdottir, Jona; Magnusson, Olafur Th.; Padyukov, Leonid; Banasik, Karina; Rafnar, Thorunn; Askling, Johan; Klareskog, Lars; Pedersen, Ole Birger; Masson, Gisli; Havdahl, Alexandra; Nilsson, Bjorn; Andreassen, Ole A.; Daly, Mark; Ostrowski, Sisse Rye; Jonsdottir, Ingileif; Stefansson, Hreinn; Holm, Hilma; Helgason, Agnar; Thorsteinsdottir, Unnur; Stefansson, Kari; Gudbjartsson, Daniel F.

doi:10.1038/s41467-023-38951-2

Cited by 8 publications

(3 citation statements)

References 83 publications

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“…This assumption was confirmed by the fact that carrier couples for that particular variant had a high incidence of early miscarriage. In another similar study, Oddsson et al 31 found that disease-causing LoF variants in the DHCR7, GBE1, GLE1, PMM2, PNKP , and TSFM genes have homozygous deficits and have only been reported in compound heterozygous cases, along with a hypomorphic allele that causes partial loss of function. They proposed that variants with a minimum activity level are necessary for successful embryonic development.…”

Section: Discussionmentioning

confidence: 91%

High Incidence of CPLANE1-Related Joubert Syndrome in the Products of Conceptions from Early Pregnancy Losses

Bozhinovski,

Terzikj,

Kubelka-Sabit

et al. 2024

Balkan Med J

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Background: The fetal monogenic causes of early pregnancy losses (EPLs) are mainly unknown, with only a few articles on the subject published. In our previous study of EPLs using whole-exome sequencing analysis, we confirmed a genetic diagnosis of CPLANE1 -related Joubert syndrome (JS) in three EPLs from two couples and identified a relatively common CPLANE1 allele among our population (NM_001384732.1:c.1819delT;c.7817T>A, further after referred as “complex allele”). Pathogenic variants in the CPLANE1 (C5orf42) gene are reported to cause JS type 17, a primary ciliopathy with various system defects. Aims: To examine the hypothesis that the CPLANE1 “complex allele,” whether homozygous or compound heterozygous, is a common cause of EPLs in our population. Study Design: Cohort study/case-control study. Methods: In this study, we used polymerase chain reaction-based methods to screen for CPLANE1 “complex allele” presence among 246 euploid EPLs (< 12 gestational weeks) from families in North Macedonia. We also investigated the impact of this allele in 650 women with EPLs versus 646 women with no history of pregnancy loss and at least one livebirth, matched by ethnic origin. Results: We found a high incidence of JS in the total study group of EPLs (2.03%), with a considerably higher incidence among Albanian families (6.25%). Although not statistically significant, women with EPLs had a higher allele frequency of the CPLANE1 “complex allele” (AF = 1.38%) than the controls (AF = 0.85%; p = 0.2). Albanian women had significantly higher frequency of the “complex allele” than the Macedonians (AF = 1.65% and 0.39%, respectively; p = 0.003). Conclusion: To the best of our knowledge, this is the highest reported incidence of fetal monogenic disease that might cause EPLs. Targeted screening for the CPLANE1 “complex allele” would be warranted in Albanian ethnic couples because it would detect one JS in every 16 euploid EPLs. Our findings have a larger impact on the pathogenesis of pregnancy loss and contribute to a better understanding of the pathogenicity of the variants in the CPLANE1 gene.

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Section: Discussionmentioning

confidence: 91%

High Incidence of CPLANE1-Related Joubert Syndrome in the Products of Conceptions from Early Pregnancy Losses

Bozhinovski,

Terzikj,

Kubelka-Sabit

et al. 2024

Balkan Med J

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“…Again, recommended thresholds can be used to identify highly constrained genes. The presence of homozygous LoF variants 15 or the deficit of homozygosity among protein-altering variants in the general population 16 are other examples on how information from large sequencing studies can be used to understand gene constraint and potential phenotypic impact. Resources compiling clinical reports on single-gene disorders that enable users to conduct queries based on phenotypic criteria, including the Online Mendelian Inheritance in Man 17 (OMIM), the Human Phenotype Ontology 18 (HPO) and the Monarch Initiative 19 repositories. In this case, the essential nature of a gene is defined by records of early death. Human orthologues of essential genes in different unicellular and multicellular organisms, especially genes that are essential for mammalian organism development 20,21 .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lethal phenotypes in Mendelian disorders

Cacheiro,

Lawson,

Van den Veyver

et al. 2024

Preprint

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Essential genes are those whose function is required for cell proliferation and/or organism survival. A gene's intolerance to loss-of-function can be allocated within a spectrum, as opposed to being considered a binary feature, since this function might be essential at different stages of development, genetic backgrounds or other contexts. Existing resources that collect and characterise the essentiality status of genes are based on either proliferation assessment in human cell lines, embryonic and postnatal viability evaluation in different model organisms, and gene metrics such as intolerance to variation scores derived from human population sequencing studies. There are also several repositories available that document phenotypic annotations for rare disorders in humans such as the Online Mendelian Inheritance in Man (OMIM) and the Human Phenotype Ontology (HPO) knowledgebases. This raises the prospect of being able to use clinical data, including lethality as the most severe phenotypic manifestation, to further our characterisation of gene essentiality. Here we queried OMIM for terms related to lethality and classified all Mendelian genes into categories, according to the earliest age of death recorded for the associated disorders, from prenatal death to no reports of premature death. To showcase this curated catalogue of human essential genes, we developed the Lethal Phenotypes Portal (https://lethalphenotypes.research.its.qmul.ac.uk), where we also explore the relationships between these lethality categories, constraint metrics and viability in cell lines and mouse. Further analysis of the genes in these categories reveals differences in the mode of inheritance of the associated disorders, physiological systems affected and disease class. We highlight how the phenotypic similarity between genes in the same lethality category combined with gene family/group information can be used for novel disease gene discovery. Finally, we explore the overlaps and discrepancies between the lethal phenotypes observed in mouse and human and discuss potential explanations that include differences in transcriptional regulation, functional compensation and molecular disease mechanisms. We anticipate that this resource will aid clinicians in the diagnosis of early lethal conditions and assist researchers in investigating the properties that make these genes essential for human development.

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Molecular autopsy for fetal structural anomaly: diagnostic and clinical utility of multidisciplinary team approach

Wall,

Petley,

Mone

et al. 2024

Ultrasound in Obstet & Gyne

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ObjectivesIn the West Midlands Regional Genetic Service, cases of perinatal death with a possible genetic diagnosis are evaluated by the Perinatal Pathology Genetic Multidisciplinary Team (MDT). The MDT assessed autopsy findings and considered genomic assessments. The objective of this retrospective service evaluation was to determine the clinical utility of the MDT. This is the first evaluation since the introduction of whole genome and whole exome sequencing in routine clinical care.MethodThe outcomes for all the perinatal MDT cases from January 2021 to December 2021 were examined. All cases received a full or partial post‐mortem examination (PM) and a chromosomal microarray. Demographics, phenotype, MDT recommendations, genetic testing, diagnoses, outcomes, impact of PM and impact of genetic testing were collected from patient case notes.ResultsOne hundred and twenty‐three cases were discussed at the MDT meeting in 2021. Genetic evaluation was recommended in 84 cases and accepted in 64 cases. A range of genetic tests were requested according to indication and availability. Thirty diagnoses were identified in 29 cases from 26 unrelated families. The diagnostic yield was 24% (29/123) of all cases or 45% (29/64) of the cases with a suspected genetic diagnosis who underwent genetic testing. PM examination added clinically actionable phenotype data in 79% of cases. A genetic diagnosis enabled accurate counselling of recurrence risk and provision of appropriate follow‐up, including prenatal testing and preimplantation diagnosis for patients with inherited conditions.ConclusionsGenomic testing was a clinically useful addition to (but not a substitute for) PM examination in perinatal cases associated with structural anomalies. The MDT model helped assess cases and plan appropriate follow‐up. Expedited whole genome sequencing or panel‐agnostic analysis were most appropriate for heterogeneous presentations. This broad approach can also expand prenatal phenotypes and detect novel disease genes and should be a priority for future research.This article is protected by copyright. All rights reserved.

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Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Cited by 8 publications

References 83 publications

High Incidence of CPLANE1-Related Joubert Syndrome in the Products of Conceptions from Early Pregnancy Losses

High Incidence of CPLANE1-Related Joubert Syndrome in the Products of Conceptions from Early Pregnancy Losses

Lethal phenotypes in Mendelian disorders

Molecular autopsy for fetal structural anomaly: diagnostic and clinical utility of multidisciplinary team approach

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