Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability

Duan, Ruizhi; Hijazi, Hadia; Güleç, Elif Yılmaz; Eker, Hatice Koçak; Costa, Silvia R.; Şahin, Yavuz; Ocak, Zeynep; Işıkay, Sedat; Ozalp, Özge; Bozdoğan, Sevcan Tuğ; Aslan, Hüseyin; Elçioğlu, Nursel; Bertola, Débora Romeo; Gezdırıcı, Alper; Du, Haowei; Fatih, Jawid M.; Grochowski, Christopher M.; Akay, Gülsen; Genomics, Shalini N. Jhangiani Baylor-Hopkins Center for Mendelian; Karaca, Ender; Gu, Shen; Coban‐Akdemir, Zeynep; Posey, Jennifer E.; Bayram, Yavuz; Sutton, V. Reid; Carvalho, Claudia M.B.; Pehlivan, Davut; Gibbs, Richard A.; Lupski, James R.

doi:10.1016/j.xhgg.2022.100132

Cited by 4 publications

(2 citation statements)

References 98 publications

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“…Moreover, whole genome studies in the remaining “unsolved” MRKH probands may elucidate other genes and noncoding variants that may contribute to MRKH. Such studies may also further elucidate developmental genomics and inheritance models, such as the CIGD and Allele specific Gene Dosage (AsGD) models, 70 , 71 that underlie birth defects and enable more informative genetic counseling for families with children having rare birth defects.…”

Section: Discussionmentioning

confidence: 99%

Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome

Jolly¹,

Du²,

Borel³

et al. 2023

Human Genetics and Genomics Advances

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Section: Discussionmentioning

confidence: 99%

Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome

Jolly¹,

Du²,

Borel³

et al. 2023

Human Genetics and Genomics Advances

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“…Learning such dose-response relationships from ‘experiments of nature’ has confirmed the role of PCSK9 in familial hypercholesterolaemia, LDL cholesterol, and coronary artery disease (as reviewed in [3]). More recently, Duan et al [4] described a naturally occurring allelic series in the BHLHA9 locus associated with the clinical severity and penetrance of congenital limb malformations. Allelic series can also be generated experimentally, as was done recently by Mohajeri et al [5], who used CRISPR to engineer an allelic series of MEF2C mutations in vitro , providing a cellular model for human neurodevelopmental disorders.…”

Section: Introductionmentioning

confidence: 99%

An allelic series rare variant association test for candidate gene discovery

McCaw

Kugathasan

Bereket

et al. 2022

Preprint

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Allelic series are of candidate therapeutic interest due to the existence of a dose-response relationship between the functionality of a gene and the degree or severity of a phenotype. We define an allelic series as a gene in which increasingly deleterious mutations lead to increasingly large phenotypic effects, and develop a gene-based rare variant association test specifically targeted for the identification of allelic series. Building on the well-known burden and sequence kernel association tests (SKAT), we specify a variety of association models, covering different genetic architectures, and integrate these into a COding-variant Allelic Series Test (COAST). Through extensive simulations, we confirm that COAST maintains the type I error and improves power when the pattern of coding-variant effect sizes increases monotonically with mutational severity. We applied COAST to identify allelic series for 4 circulating lipid traits and 5 cell count traits among 145,735 subjects with available whole exome sequencing data from the UK Biobank. Compared with optimal SKAT (SKAT-O), COAST identified 29% more Bonferroni significant associations with circulating lipid traits, on average, and 82% more with cell count traits. All of the gene-trait associations identified by COAST have corroborating evidence either from rare-variant results in the full cohort (Genebass, N=400K), or from common variant results in the GWAS catalog. In addition to detecting many gene-trait associations present in Genebass using only a fraction (36.9%) of the sample, COAST detects associations, such as ANGPTL4 with triglycerides, that are absent from Genebass but which have clear common variant support.

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The impact of the Turkish (TK) population variome on the genomic architecture of rare disease traits

Akdemir

Song

Pehlivan

et al. 2020

Preprint

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We investigated the influences of admixture and consanguinity on the genetic architecture of disease by generating a database of variants derived from exome sequencing (ES) of 853 unrelated Turkish (TK) individuals with different disease phenotypes. We observed that TK genomes are more similar to Europeans with 69.3% of the unique variants (N = 356,613) not present in the Greater Middle Eastern variome.We found higher inbreeding coefficient values in the TK cohort correlating with a larger median span of long-sized (>1.606 Mb) runs of homozygosity (ROH). We show that long-sized ROHs arose from recently configured haplotypes and are enriched for rare homozygous deleterious variants. Such haplotypes, and the combinatorial effect of their embedded ultra-rare variants, provide the most explanatory molecular diagnoses for the TK individuals' observed disease traits. Such haplotype evolution results in homozygosity of disease associated haplotypes due to identity-by-descent in a family or extended clan.Genomics hypothesis (Lupski et al., 2011), the notion that novel rare variant alleles arising within a patient, or the recent past generations of a family or more extended clan, significantly contribute to disease in populations. These data underscore the value of studying alternative population substructures that present with high levels of both admixture and consanguinity to elucidate the molecular mechanisms and genetic and genomic architecture underlying disease in populations. Results The Turkish (TK) variomeAfter removing related individuals from the Baylor Hopkins Center for Mendelian Genomics (BHCMG) database, exomes from 4,933 unrelated individuals remained for further analyses. From this data set, we used principal component analysis (PCA) to investigate the population structure between our TK and non-TK cohorts in comparison to the African, Asian, and European population samples from the 1000 Genomes Project. The first main principal component axis (PC1) separated the African samples from the Asian, the European populations and the TK and non-TK cohorts of the BHCMG samples ( Figure 1A). The second main principal component axis (PC2) further separated the Asian samples from the European and the TK and non-TK groups of the BHCMG cohort. These studies showed that the TK genomes were distinct from the African and Asian populations, and more similar to the variomes of European samples compared to the non-TK samples that spread out across different populations ( Figure 1A and Supplementary Figure 1).

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Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability

Cited by 4 publications

References 98 publications

Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome

Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome

An allelic series rare variant association test for candidate gene discovery

The impact of the Turkish (TK) population variome on the genomic architecture of rare disease traits

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