De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

Homsy, Jason; Zaidi, Samir; Shen, Yufeng; Ware, James S.; Samocha, Kaitlin E.; Karczewski, Konrad J.; DePalma, Steven R.; McKean, David; Wakimoto, Hiroko; Gorham, Josh; Jin, Sheng Chih; Deanfield, John; Giardini, Alessandro; Porter, George A.; Kim, Richard; Bilgüvar, Kaya; López-Giráldez, Francesc; Tikhonova, Irina; Mane, Shrikant; Romano-Adesman, Angela; Qi, Hongjian; Vardarajan, Badri N.; Ma, Lijiang; Daly, Mark J.; Roberts, Amy; Russell, Mark W.; Mital, Seema; Newburger, Jane W.; Gaynor, J. William; Breitbart, Roger E.; Iossifov, Ivan; Ronemus, Michael; Sanders, Stephan; Kaltman, Jonathan R.; Seidman, Jonathan G.; Brueckner, Martina; Gelb, Bruce D.; Goldmuntz, Elizabeth; Lifton, Richard P.; Seidman, Christine E.; Chung, Wendy K.

doi:10.1126/science.aac9396

Cited by 697 publications

(928 citation statements)

References 27 publications

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“…The etiology of these deficits remains enigmatic to date. Precise regulation of BMP, Wnt, and Ras/ERK signaling is crucial to normal brain development (39)(40)(41)(42), raising the possibility that genotype might influence neurocognitive outcome, as appears to be the case for congenital heart disease (22,23). The results provide a means of stratifying non-syndromic patients to assess the extent to which specific genotypes contribute to neurocognitive outcome.…”

Section: Discussionmentioning

confidence: 99%

“…Two probands with metopic NSC had de novo LOFs in chromatin modifiers (SUV420H1 and SMARCD2); de novo LOFs in these two genes, as well as other chromatin modifiers, have previously been implicated in the pathogenesis of other congenital disorders, including autism and congenital heart disease (22)(23)(24), and de novo LOFs in other chromatin modifiers, including ASXL1, KAT6A, and KMT2D have been reported in rare cases of syndromic craniosynostosis (5), suggesting that this gene set plays a role in a smaller fraction of NSC cases. Additional interesting mutations include a de novo D-mis variant in THBS1, a gene with very high expression in midline sutures that regulates the bioavailability of FGF signaling substrates at the plasma membrane (25), and a de novo D-mis variant in MAPK7, a nuclear effector of several RTK signaling pathways (Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…We followed a previously described method to estimate the number of genes in which damaging de novo mutations contribute risk to craniosynostosis (23). In summary, the number of observed damaging mutations in 291 craniosynostosis cases (K), the number of those genes mutated twice (R1), and number of those genes mutated at least three times (R2) was tabulated.…”

Section: Methodsmentioning

confidence: 99%

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De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Timberlake

Furey

Choi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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100

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Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10 −11 ). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

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Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Timberlake

Furey

Choi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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100

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“…Eine große Problematik ergibt sich jedoch aus der Tatsache, dass viele der Gene nur eine unzureichende Assoziation mit den zugrunde liegenden Herzfehlern zeigen und zum aktuellen Zeitpunkt nicht als kausal betrachtet werden können. Im Gegensatz zu den syndromalen Herzfehlern lassen sich bei isolierten Herzfehlern zu einem weitaus geringeren Prozentsatz De-novo-Mutationen nachweisen [6,14]. Außerdem zeigt sich eine Anhäufung von seltenen proteintrunkierenden Varianten, welche von einem gesunden Elternteil vererbt worden sind.…”

Section: Nicht-syndromale Strukturelle Herzfehlerunclassified

Genetik der angeborenen Herzfehler

Kahlert

Hoff

Hitz

2017

Medizinische Genetik

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“…Therefore, the etiology underlying CTD requires elucidation. Previous studies have established the important role genetic risk factors serve in the pathogenesis of CTD (10)(11)(12)(13)(14)(15). The 22q11 deletion syndrome (22q11DS), also known as DiGeorge syndrome, is a chromosomal abnormality responsible for ~12% of conotruncal malformations (16)(17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

Zhang

Liu

et al. 2017

Exp Ther Med

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Abstract. Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the TBX1 gene that codes for a T-box transcription factor essential for normal cardiovascular development, may contribute to the development of CTD. CTDs are genetically heterogeneous and the genetic defects responsible for CTDs in the majority of patients remain unknown. The present study sequenced the coding regions and splicing junction boundaries of TBX1 in 136 patients with CTDs and 300 matched healthy individuals. The disease-causing potential of the identified TBX1 sequence variation was evaluated using MutationTaster, PolyPhen-2, SIFT and PROVEN software. The functional characteristics of the mutant TBX1 gene were defined using a dual-luciferase reporter assay system. A novel heterozygous TBX1 mutation, p.S233Y, was identified in a patient with transposition of the great arteries (TGA) and a ventricular septal defect. This mutation was absent in the 300 controls and altered the amino acid produced, serine, which is evolutionarily conserved across several species, and was predicted to be pathogenic in silico. Luciferase assays conducted in COS-7 cells demonstrated that the newly identified TBX1 mutation was associated with significantly diminished transcriptional activation of the ANF promoter compared with the wild-type TBX1. To the best of our knowledge, the present study is the first to associate a TBX1 loss-of-function mutation with enhanced susceptibility to TGA, which adds significant insight to the molecular mechanism of TGA.

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De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

Cited by 697 publications

References 27 publications

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Genetik der angeborenen Herzfehler

TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

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