Patterns and distribution of de novo mutations in multiplex Middle Eastern families

Kohailan, Muhammad; Aamer, Waleed; Syed, Najeeb; Padmajeya, Sujitha Subash; Hussein, Sura; Sayed, Asmaa; Janardhanan, Jyothi; Palaniswamy, Sasirekha; Hajj, Nady El; Akil, Ammira Al‐Shabeeb; Fakhro, Khalid

doi:10.1038/s10038-022-01054-9

Cited by 5 publications

(2 citation statements)

References 55 publications

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“…52 Sperm SNV MF was in the same order of magnitude as DNM rates measured by whole genome sequencing of pedigrees (around 1.2 x 10 -8 ). 8,41,53,54 There was no correlation in the individual-specific SNV MF between blood and sperm across the men. We caution that this is a very small sample size for this analysis.…”

Section: Discussionmentioning

confidence: 86%

Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-basedde novomutation analyses

Axelsson,

LeBlanc,

Shojaeisaadi

et al. 2024

Preprint

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De novo mutations (DNMs) are drivers of genetic disorders. However, the study of DNMs is hampered by technological limitations preventing accurate quantification of ultra-rare mutations. Duplex Sequencing (DS) theoretically has < 1 error/billion base-pairs (bp). To determine the utility of DS to quantify and characterize DNMs, we analyzed DNA from blood and spermatozoa from six healthy, 18-year-old Swedish men using the TwinStrand DS mutagenesis panel (48 kb spanning 20 genic and intergenic loci). The mean single nucleotide variant mutation frequency (MF) was 1.2 x 10-7 per bp in blood and 2.5 x 10-8 per bp in sperm, with the most common base substitution being C>T. Blood MF and substitution spectrum were similar to those reported in blood cells with an orthogonal method. The sperm MF was in the same order of magnitude and had a strikingly similar spectrum to DNMs from publicly available whole genome sequencing data from human pedigrees (1.2 x 10-8 per bp). DS revealed much larger numbers of insertions and deletions in sperm over blood, driven by an abundance of putative extra-chromosomal circular DNAs. The study indicates the strong potential of DS to characterize human DNMs to inform factors that contribute to disease susceptibility and heritable genetic risks.

show abstract

Section: Discussionmentioning

confidence: 86%

Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-basedde novomutation analyses

Axelsson,

LeBlanc,

Shojaeisaadi

et al. 2024

Preprint

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show abstract

“…VCF files were annotated using the SnpEff/SnpSift tool [ 24 ] by adding allele frequencies from variant databases (1000 Genomes Project [ 25 ], gnomAD [ 26 ], and ExAC [ 27 ], and Qatar-genome project (QGP)). De novo variants were detected in complete trios ( n = 79) using a combination of three tools (VarScan [ 28 ], RUFUS [ 29 ], and FreeBayes [ 30 ]) as previously described [ 31 ]. All variants reported in this study were lifted over to GRCh38/hg38 using Broad Institute liftover tool ( https://liftover.broadinstitute.org ) [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

Genomic architecture of autism spectrum disorder in Qatar: The BARAKA-Qatar Study

Abdi,

Aliyev,

Trost

et al. 2023

Genome Med

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Background Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social and communication skills, restricted interests, and repetitive behaviors. The prevalence of ASD among children in Qatar was recently estimated to be 1.1%, though the genetic architecture underlying ASD both in Qatar and the greater Middle East has been largely unexplored. Here, we describe the first genomic data release from the BARAKA-Qatar Study—a nationwide program building a broadly consented biorepository of individuals with ASD and their families available for sample and data sharing and multi-omics research. Methods In this first release, we present a comprehensive analysis of whole-genome sequencing (WGS) data of the first 100 families (372 individuals), investigating the genetic architecture, including single-nucleotide variants (SNVs), copy number variants (CNVs), tandem repeat expansions (TREs), as well as mitochondrial DNA variants (mtDNA) segregating with ASD in local families. Results Overall, we identify potentially pathogenic variants in known genes or regions in 27 out of 100 families (27%), of which 11 variants (40.7%) were classified as pathogenic or likely-pathogenic based on American College of Medical Genetics (ACMG) guidelines. Dominant variants, including de novo and inherited, contributed to 15 (55.6%) of these families, consisting of SNVs/indels (66.7%), CNVs (13.3%), TREs (13.3%), and mtDNA variants (6.7%). Moreover, homozygous variants were found in 7 families (25.9%), with a sixfold increase in homozygous burden in consanguineous versus non-consanguineous families (13.6% and 1.8%, respectively). Furthermore, 28 novel ASD candidate genes were identified in 20 families, 23 of which had recurrent hits in MSSNG and SSC cohorts. Conclusions This study illustrates the value of ASD studies in under-represented populations and the importance of WGS as a comprehensive tool for establishing a molecular diagnosis for families with ASD. Moreover, it uncovers a significant role for recessive variation in ASD architecture in consanguineous settings and provides a unique resource of Middle Eastern genomes for future research to the global ASD community.

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Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses

Axelsson,

LeBlanc,

Shojaeisaadi

et al. 2024

Sci Rep

View full text Add to dashboard Cite

De novo mutations (DNMs) are drivers of genetic disorders. However, the study of DNMs is hampered by technological limitations preventing accurate quantification of ultra-rare mutations. Duplex Sequencing (DS) theoretically has < 1 error/billion base-pairs (bp). To determine the DS utility to quantify and characterize DNMs, we analyzed DNA from blood and spermatozoa from six healthy, 18-year-old Swedish men using the TwinStrand DS mutagenesis panel (48 kb spanning 20 genic and intergenic loci). The mean single nucleotide variant mutation frequency (MF) was 1.2 × 10− 7 per bp in blood and 2.5 × 10− 8 per bp in sperm, with the most common base substitution being C > T. Blood MF and substitution spectrum were similar to those reported in blood cells with an orthogonal method. The sperm MF was in the same order of magnitude and had a strikingly similar spectrum to DNMs from publicly available whole genome sequencing data from human pedigrees (1.2 × 10− 8 per bp). DS revealed much larger numbers of insertions and deletions in sperm over blood, driven by an abundance of putative extra-chromosomal circular DNAs. The study indicates the strong potential of DS to characterize human DNMs to inform factors that contribute to disease susceptibility and heritable genetic risks.

show abstract

Patterns and distribution of de novo mutations in multiplex Middle Eastern families

Cited by 5 publications

References 55 publications

Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-basedde novomutation analyses

Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-basedde novomutation analyses

Genomic architecture of autism spectrum disorder in Qatar: The BARAKA-Qatar Study

Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses

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