Early post-zygotic mutations contribute to congenital heart disease

Hsieh, Alexander; Su, M.; Ja, Willcox; Jm, Gorham; Ac, Tai; Hu, Qi; DePalma, Steven R.; McKean, David; Griffin, Emily; Kb, Manheimer; Bernstein, Daniel; Rw, Kim; Newburger, JW; Ga, Porter; Srivastava, Deepak; Tristani‐Firouzi, Martin; Brueckner, Martina; Rp, Lifton; Goldmuntz, Elizabeth; Bd, Gelb; Wk, Chung; Seidman, C E; Jg, Seidman; Shen, Yufeng

doi:10.1101/733105

Cited by 3 publications

(3 citation statements)

References 62 publications

(85 reference statements)

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“…Our cohort, with three proband-derived tissue samples, allows us to explicitly test this alternative hypothesis. We found that an average of 1.5% of the de novo variants in the proband's blood were not germline in origin (not present in all three proband tissues) and is a similar rate as found in other recent papers [58,99]. In fact, in proband 411 a blood-specific somatic variant in MIR4717 would have been classified as a germline variant.…”

Section: Discussionsupporting

confidence: 86%

Deep whole genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias

Bogenschutz

Fox

Farrell

et al. 2020

Preprint

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The diaphragm is a mammalian muscle critical for respiration and separation of the thoracic and abdominal cavities. Defects in the development of the diaphragm are the cause of congenital diaphragmatic hernia (CDH), a common birth defect. In CDH, weaknesses in the developing diaphragm allow abdominal contents to herniate into the thoracic cavity and impair lung development, leading to a high neonatal mortality. The genetic etiology of CDH is complex. Single nucleotide variants (SNVs), insertion/deletions (indels), and structural/copy number variants in more than 150 genes have been associated with CDH, although few genes are recurrently mutated in multiple patients and recurrently mutated genes can be incompletely penetrant. This suggests that multiple genetic variants in combination, other not yet investigated classes of variants, and/or nongenetic factors contribute to CDH susceptibility. However, to date no studies have comprehensively investigated the contribution of all possible classes of variants throughout the genome to the etiology of CDH. In our study, we used a unique cohort of four patients with isolated CDH with samples from blood, skin, and diaphragm connective tissue and parental blood samples and deep whole genome sequencing to assess germline and somatic de novo and inherited variants of various sizes (SNVs, indels, and structural variants) in exons, introns, UTRs, and intergenic regions. In each patient we found a different mutational landscape that included germline de novo, and inherited SNVs and indels in multiple genes. We also found in two patients an inherited 343 bp deletion interrupting an annotated enhancer of the CDH associated gene, GATA4, and we hypothesize that this common deletion (found in 1-2% of the population) acts as a sensitizing allele for CDH. Overall, our comprehensive reconstruction of the genetic architecture of four CDH individuals demonstrates that the etiology of CDH is heterogeneous and multifactorial.Bogenschutz et al. AUTHOR SUMMARYDeep whole genome sequencing of family trios shows that etiology of congenital diaphragmatic hernias is heterogeneous and multifactorial.

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Section: Discussionsupporting

confidence: 86%

Deep whole genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias

Bogenschutz

Fox

Farrell

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…We found that an average of 1.5% of the de novo variants in the probands’ blood were not germline in origin (not present in all three proband tissues) and is a similar rate as found in other recent papers. 93 , 123 In fact, in proband 411, a blood-specific somatic variant in MIR4717 would have been classified as a germline variant. Thus, researchers should be cautious about inferring that all de novo variants in the blood are germline in origin.…”

Section: Discussionmentioning

confidence: 99%

Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias

Bogenschutz

Fox

Farrell

et al. 2020

Human Genetics and Genomics Advances

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Summary The diaphragm is critical for respiration and separation of the thoracic and abdominal cavities, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDH), a common and often lethal birth defect. The genetic etiology of CDH is complex. Single-nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs) in more than 150 genes have been associated with CDH, although few genes are recurrently mutated in multiple individuals and mutated genes are incompletely penetrant. This suggests that multiple genetic variants in combination, other not-yet-investigated classes of variants, and/or nongenetic factors contribute to CDH etiology. However, no studies have comprehensively investigated in affected individuals the contribution of all possible classes of variants throughout the genome to CDH etiology. In our study, we used a unique cohort of four individuals with isolated CDH with samples from blood, skin, and diaphragm connective tissue and parental blood and deep whole-genome sequencing to assess germline and somatic de novo and inherited SNVs, indels, and SVs. In each individual we found a different mutational landscape that included germline de novo and inherited SNVs and indels in multiple genes. We also found in two individuals a 343 bp deletion interrupting an annotated enhancer of the CDH-associated gene GATA4 , and we hypothesize that this common SV (found in 1%–2% of the population) acts as a sensitizing allele for CDH. Overall, our comprehensive reconstruction of the genetic architecture of four CDH individuals demonstrates that the etiology of CDH is heterogeneous and multifactorial.

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“…In this study, we developed a computational method, EM-mosaic (Expectation-Maximization-based detection of Mosaicism) [35], to detect mosaic single-nucleotide variants (SNVs) using WES of proband and parent DNA. To optimize this method, we measured mosaic detection power as a function of sequencing depth.…”

Section: Introductionmentioning

confidence: 99%

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease

et al. 2020

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Background: The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. Methods: We developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD probandparent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available. Results: EM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.

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Early post-zygotic mutations contribute to congenital heart disease

Cited by 3 publications

References 62 publications

Deep whole genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias

Deep whole genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias

Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease

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