Whole-exome sequence analysis highlights the role of unmasked recessive mutations in copy number variants with incomplete penetrance

Egloff, M.; Nguyen, Lam Son; Siquier-Pernet, Karine; Cormier‐Daire, Valérie; Baujat, Geneviève; Attié‐Bitach, Tania; Bôle‐Feysot, Christine; Nitschké, Patrick; Vekemans, Michel; Colleaux, Laurence; Malan, Valérie

doi:10.1038/s41431-018-0124-4

Cited by 9 publications

(7 citation statements)

References 23 publications

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“…43 Recent work on recessive variants unmasked by chromosomal deletions has pointed to a single base-pair deletion in human NUP214 as a candidate disease-causing pathogenic variant in the case of a neurodevelopmental disorder. 44 Another recent report 45 describes a similar clinical phenotype to the one in our study, consisting of severe encephalopathy and microcephaly and associated with a different biallelic variant in NUP214. An intriguing new study by Bonin et al identifies biallelic variants in human NUP88 as a novel cause of lethal fetal akinesia deformation sequence (FADS [MIM: 208150]) in two families.…”

Section: Discussionsupporting

confidence: 80%

Pathogenic Variants in NUP214 Cause “Plugged” Nuclear Pore Channels and Acute Febrile Encephalopathy

Fichtman

Harel

Biran

et al. 2019

The American Journal of Human Genetics

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We report biallelic missense and frameshift pathogenic variants in the gene encoding human nucleoporin NUP214 causing acute febrile encephalopathy. Clinical symptoms include neurodevelopmental regression, seizures, myoclonic jerks, progressive microcephaly, and cerebellar atrophy. NUP214 and NUP88 protein levels were reduced in primary skin fibroblasts derived from affected individuals, while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays exhibited defects in the classical protein import and mRNA export pathways in affected cells. Direct surface imaging of fibroblast nuclei by scanning electron microscopy revealed a large increase in the presence of central particles (known as ''plugs'') in the nuclear pore channels of affected cells. This observation suggests that large transport cargoes may be delayed in passage through the nuclear pore channel, affecting its selective barrier function. Exposure of fibroblasts from affected individuals to heat shock resulted in a marked delay in their stress response, followed by a surge in apoptotic cell death. This suggests a mechanistic link between decreased cell survival in cell culture and severe fever-induced brain damage in affected individuals. Our study provides evidence by direct imaging at the single nuclear pore level of functional changes linked to a human disease.

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Section: Discussionsupporting

confidence: 80%

Pathogenic Variants in NUP214 Cause “Plugged” Nuclear Pore Channels and Acute Febrile Encephalopathy

Fichtman

Harel

Biran

et al. 2019

The American Journal of Human Genetics

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“…Whilst researchers are starting to sequence cohorts of individuals with large “Mb-sized” deletions [ 21 , 89 , 90 ] and performing SNV and CNV analysis in one combined WGS assay, it is imperative for clinical and diagnostic genomicists to foster guidelines that facilitate routine genomic sequencing (ES or WGS) on patients who are found to have recurrent genomic deletions, i.e., NAHRdelCNV, that will benefit both the patients and the research human subjects worldwide. Given the great potential in the near future for disease gene discoveries within intervals of genomic disorder deletion CNVs, these patients will benefit from routine or perhaps even more prioritized reanalysis of sequencing data [ 91 ].…”

Section: Discussionmentioning

confidence: 99%

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

et al. 2022

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Background In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics. Methods We constructed a genome-wide map for nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions and used this map to estimate population frequencies of NAHR deletions based on large-scale population cohorts and region-specific studies. We calculated recessive disease carrier burden using high-quality pathogenic or likely pathogenic variants from ClinVar and gnomAD. We developed a NIRD (NAHR deletion Impact to Recessive Disease) score for recessive disorders by quantifying the contribution of NAHR deletion to the overall allele load that enumerated all pairwise combinations of disease-causing alleles; we used a Punnett square approach based on an assumption of random mating. Literature mining was conducted to identify all reported patients with defects in a gene with a high NIRD score; meta-analysis was performed on these patients to estimate the representation of NAHR deletions in recessive traits from contemporary human genomics studies. Retrospective analyses of extant clinical exome sequencing (cES) were performed for novel rare recessive disease trait gene and allele discovery from individuals with NAHR deletions. Results We present novel genomic insights regarding the genome-wide impact of NAHR recurrent segmental variants on recessive disease burden; we demonstrate the utility of NAHR recurrent deletions to enhance discovery in the challenging context of autosomal recessive (AR) traits and biallelic variation. Computational results demonstrate new mutations mediated by NAHR, involving recurrent deletions at 30 genomic regions, likely drive recessive disease burden for over 74% of loci within these segmental deletions or at least 2% of loci genome-wide. Meta-analyses on 170 literature-reported patients implicate that NAHR deletions are depleted from the ascertained pool of AR trait alleles. Exome reanalysis of personal genomes from subjects harboring recurrent deletions uncovered new disease-contributing variants in genes including COX10, ERCC6, PRRT2, and OTUD7A. Conclusions Our results demonstrate that genomic sequencing of personal genomes with NAHR deletions could dramatically improve allele and gene discovery and enhance clinical molecular diagnosis. Moreover, results suggest NAHR events could potentially enable human haploid genetic screens as an approach to experimental inquiry into disease biology.

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“…Even when available subject numbers are limited for recurrent genomic deletions with extremely low penetrance, it is possible to tune the disease gene/allele characterization strategy by targeting specific phenotypes, as demonstrated at the Smith Magenis Syndrome -MYO15 locus two decades ago (Liburd et al 2001). While researchers are starting to sequence cohorts of individuals with large deletions (Egloff et al 2018;Beck et al 2019;Zhao et al 2020), it is imperative for clinical and diagnostic genomicists to foster guidelines that facilitate routine genomic sequencing (ES or WGS) on patients who are found to have recurrent genomic deletions, which will benefit both the patients and the research enterprises worldwide. Given the great potential in the near future for disease gene discoveries within intervals of genomic deletions, these patients will benefit from routine or perhaps even more prioritized reanalysis of sequencing data (Liu et al 2019b).…”

Section: Discussionmentioning

confidence: 99%

“…Whilst researchers are starting to sequence cohorts of individuals with large ‘Mb-sized’ deletions (Egloff et al 2018; Beck et al 2019; Zhao et al 2020) and performing SNV and CNV analysis in one combined WGS assay, it is imperative for clinical and diagnostic genomicists to foster guidelines that facilitate routine genomic sequencing (ES or WGS) on patients who are found to have recurrent genomic deletions, i.e. NAHRdelCNV, that will benefit both the patients and the research human subjects worldwide.…”

Section: Discussionmentioning

confidence: 99%

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

Yuan

Schulze

Batzir

et al. 2021

Preprint

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In medical genetics, discovery and characterization of new "disease genes" and alleles depend on patient ascertainment strategies to enrich previously uncharacterized alleles. Here, we present a novel strategy of new allele and gene discovery for recessive/biallelic disease traits. In this approach, patients with large recurrent genomic deletions mediated by nonallelic homologous recombination (NAHR) are sequenced, and new discoveries are revealed in the hemizygous chromosomal regions in trans to the large deletion, essentially enabling haploid genomic segment genetics. We demonstrate through computational analyses that a collection of 30 large recurrent genomic deletions scattered in the human genome contribute to more than 10% of individual disease load for 2.13% of all known "recessive disease genes". We performed meta-analyses for all literature reported patients affected with the 13 genes whose carrier burden are predicted to be almost exclusively from large recurrent genomic deletions. The results suggest that current sequencing efforts for personal genomes with large recurrent deletions is under-appreciated. By retrospective analyses of previously undiagnostic exome sequencing (ES) data on 69 subjects harboring 26 types of recurrent deletions, probable diagnostic variants were uncovered in genes including COX10, ERCC6, PRRT2 and OTUD7A, demonstrating new disease allele/gene/mechanism characterization. Findings from this study support the contention that more whole genome sequencing (WGS) may further resolve molecular diagnoses and provide evidence for multi-locus pathogenic variation (MPV). Such analyses benefit all stakeholders in both research development and patient clinical care.

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Whole-exome sequence analysis highlights the role of unmasked recessive mutations in copy number variants with incomplete penetrance

Cited by 9 publications

References 23 publications

Pathogenic Variants in NUP214 Cause “Plugged” Nuclear Pore Channels and Acute Febrile Encephalopathy

Pathogenic Variants in NUP214 Cause “Plugged” Nuclear Pore Channels and Acute Febrile Encephalopathy

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

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