Quantitative dissection of multilocus pathogenic variation in an Egyptian infant with severe neurodevelopmental disorder resulting from multiple molecular diagnoses

Herman, Isabella; Jolly, Angad; Du, Haowei; Dawood, Moez; Abdel-Salam, Ghada M H; Marafi, Dana; Mitani, Tadahiro; Calame, Daniel G.; Coban‐Akdemir, Zeynep; Fatih, Jawid M.; Hegazy, Ibrahim; Jhangiani, Shalini N.; Gibbs, Richard A.; Pehlivan, Davut; Posey, Jennifer E.; Lupski, James R.

doi:10.1002/ajmg.a.62565

Cited by 16 publications

(17 citation statements)

References 56 publications

(109 reference statements)

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“…We then tested the extent to which mutational burden caused by rare homozygous deleterious variants in long-sized ROH regions explains clinical phenotypic features of the individuals in the TK cohort. To achieve this, we performed an unbiased genotype-phenotype correlation analysis based on the HPO terms (Herman et al, 2022; Zhang et al, 2022). In this analysis, we first linked the disease genes present with rare coding homozygous and deleterious variation in an individual genome to their related HPO terms for the trait, as defined in the OMIM (https://www.omim.org) clinical synopsis, according to HPO annotation resource databases.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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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“…Further study of the phenotypic effect of SMARCC2 and SPEN duplication in more patients, rather than deletion, is necessary to understand dosage sensitivity (i.e., triplosensitivity) at these loci; however, these data in aggregate support the contention that the phenotype of the proband is a blended overlapping phenotype driven by multilocus pathogenic variation (MPV) [ 21 , 61 ], i.e., duplication of the NSD1 and SMARCC2 loci, and their associated traits. Our understanding of emerging concepts, such as which genes or loci are dosage-sensitive, whether haploinsufficiency and triplosensitivity traits will be observed for a given dosage-sensitive gene, and the correlation between dosage-sensitive genes and mirror traits is continuing to evolve with human genetics and genomics studies.…”

Section: Discussionmentioning

confidence: 99%

“…To perform quantitative phenotype analysis, we used a similar method to that previously published [ 21 – 23 ] with modification; a detailed description follows. The patient’s clinical description was translated to HPO terms using Doc2Hpo [ 24 ] and manually verified.…”

Section: Methodsmentioning

confidence: 99%

The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation

Jolly

Grochowski

et al. 2022

Genome Med

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Background The multiple de novo copy number variant (MdnCNV) phenotype is described by having four or more constitutional de novo CNVs (dnCNVs) arising independently throughout the human genome within one generation. It is a rare peri-zygotic mutational event, previously reported to be seen once in every 12,000 individuals referred for genome-wide chromosomal microarray analysis due to congenital abnormalities. These rare families provide a unique opportunity to understand the genetic factors of peri-zygotic genome instability and the impact of dnCNV on human diseases. Methods Chromosomal microarray analysis (CMA), array-based comparative genomic hybridization, short- and long-read genome sequencing (GS) were performed on the newly identified MdnCNV family to identify de novo mutations including dnCNVs, de novo single-nucleotide variants (dnSNVs), and indels. Short-read GS was performed on four previously published MdnCNV families for dnSNV analysis. Trio-based rare variant analysis was performed on the newly identified individual and four previously published MdnCNV families to identify potential genetic etiologies contributing to the peri-zygotic genomic instability. Lin semantic similarity scores informed quantitative human phenotype ontology analysis on three MdnCNV families to identify gene(s) driving or contributing to the clinical phenotype. Results In the newly identified MdnCNV case, we revealed eight de novo tandem duplications, each ~ 1 Mb, with microhomology at 6/8 breakpoint junctions. Enrichment of de novo single-nucleotide variants (SNV; 6/79) and de novo indels (1/12) was found within 4 Mb of the dnCNV genomic regions. An elevated post-zygotic SNV mutation rate was observed in MdnCNV families. Maternal rare variant analyses identified three genes in distinct families that may contribute to the MdnCNV phenomenon. Phenotype analysis suggests that gene(s) within dnCNV regions contribute to the observed proband phenotype in 3/3 cases. CNVs in two cases, a contiguous gene duplication encompassing PMP22 and RAI1 and another duplication affecting NSD1 and SMARCC2, contribute to the clinically observed phenotypic manifestations. Conclusions Characteristic features of dnCNVs reported here are consistent with a microhomology-mediated break-induced replication (MMBIR)-driven mechanism during the peri-zygotic period. Maternal genetic variants in DNA repair genes potentially contribute to peri-zygotic genomic instability. Variable phenotypic features were observed across a cohort of three MdnCNV probands, and computational quantitative phenotyping revealed that two out of three had evidence for the contribution of more than one genetic locus to the proband’s phenotype supporting the hypothesis of de novo multilocus pathogenic variation (MPV) in those families.

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“…Concerning overall phenotypic heterogeneity, human phenotype ontology (HPO)-based quantitative phenotypic analysis will be adapted in the future to quantify the limb anomaly trait and investigate the allele-specific differences (or to uncover novel allelic series) in similar CLM spectrums as well as to dissect MPV in AR or AD blended traits. 74 , 97 Autozygosity mapping and AOH/ROH analyses from unphased exome data in consanguineous families could assist with additional novel disease gene/locus discovery in consanguineous families. 98 These strategies extend the effort to test the hypothesis proposed by Coban-Akdemir et al.…”

Section: Discussionmentioning

confidence: 99%

“…Future explorations will compare the allelic-specific gene dosage (AsGD) model proposed in this study with the established compound inheritance gene dosage model (CIGD) model to test this hypothesis and provide evidence as to whether such gene dosage expression models significantly contribute to limb anomalies and other developmental malformations. 95 , 97 …”

Section: Discussionmentioning

confidence: 99%

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

Duan¹,

Hijazi²,

Güleç³

et al. 2022

Human Genetics and Genomics Advances

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Quantitative dissection of multilocus pathogenic variation in an Egyptian infant with severe neurodevelopmental disorder resulting from multiple molecular diagnoses

Cited by 16 publications

References 56 publications

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

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

The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation

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

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