Oligogenic inheritance of a human heart disease involving a genetic modifier

Gifford, Casey A.; Ranade, Sanjeev S.; Samarakoon, Ryan; Salunga, Hazel T.; Soysa, T. Yvanka de; Huang, Yu; Zhou, Ping; Elfenbein, Aryé; Wyman, Stacia K.; Bui, Yen; Metzler, Kimberly R. Cordes; Ursell, Philip C.; Ivey, Kathryn N.; Srivastava, Deepak

doi:10.1126/science.aat5056

Cited by 151 publications

(134 citation statements)

References 58 publications

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“…This heterogeneous behavior in the same mutation mentioned above, however, suggests that FOXH1 variants may act as susceptibility elements affected by other genetic or environmental factors. A recent study performed by Casey et al confirmed that a combination of rare inherited heterozygous mutations is sufficient to mimic the CHD phenotype . But no rare pathogenic mutations were identified in genes related to heart development other than FOXH1 in our study.…”

Section: Discussionmentioning

confidence: 99%

Identification of FOXH1 mutations in patients with sporadic conotruncal heart defect

Wei

et al. 2020

Clinical Genetics

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Conotruncal heart defects (CTD) are an important subtype of congenital heart disease that occur due to abnormality in the development of the cardiac outflow tract (OFT). FOXH1 is a transcription factor that participates in the morphogenesis of the right ventricle and OFT. In this study, we confirmed the expression of FOXH1 in mouse and human embryos during OFT development. We also scanned the coding exons and splicing regions of the FOXH1 gene in 605 patients with sporadic CTD and 300 unaffected controls, from which we identified seven heterozygous FOXH1 gene mutations. According to bioinformatics analysis results, they were predicted potentially deleterious at conserved amino acid sites. Western blot was used to show that all the variants decreased the expression of FOXH1 protein, while dual‐luciferase reporter assay showed that six of them, with an exception of p.P35R, had enhanced abilities to modulate the expression of MEF2C, which interacts with NKX2.5 and is involved in cardiac growth. The electrophoretic mobility shift assays result showed that two mutations altered DNA‐binding abilities of mutant FOXH1 proteins. Phenotype heterogeneity was found in patients with the same mutation. These results indicate that FOXH1 mutations lead to disease‐causing functional changes that contribute to the occurrence of CTD.

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Section: Discussionmentioning

confidence: 99%

Identification of FOXH1 mutations in patients with sporadic conotruncal heart defect

Wei

et al. 2020

Clinical Genetics

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“…A potential application of the approach is to produce mice carrying multiple modifications in candidate loci that have been identified in high-throughput studies or genetic screenings to mimic clinical manifestations of multigenic diseases. 78 In summary, we have established novel DM1 mouse models by one-step injection of haploid cells carrying three or four mutant genes into oocytes, providing suitable models to investigate the molecular mechanisms underlying complex manifestations and perform drug screening (Fig. 6d).…”

Section: Discussionmentioning

confidence: 99%

Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1

Yin

Wang

et al. 2019

Cell Res

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Multisystem manifestations in myotonic dystrophy type 1 (DM1) may be due to dosage reduction in multiple genes induced by aberrant expansion of CTG repeats in DMPK, including DMPK, its neighboring genes (SIX5 or DMWD) and downstream MBNL1. However, direct evidence is lacking. Here, we develop a new strategy to generate mice carrying multigene heterozygous mutations to mimic dosage reduction in one step by injection of haploid embryonic stem cells with mutant Dmpk, Six5 and Mbnl1 into oocytes. The triple heterozygous mutant mice exhibit adult-onset DM1 phenotypes. With the additional mutation in Dmwd, the quadruple heterozygous mutant mice recapitulate many major manifestations in congenital DM1. Moreover, muscle stem cells in both models display reduced stemness, providing a unique model for screening small molecules for treatment of DM1. Our results suggest that the complex symptoms of DM1 result from the reduced dosage of multiple genes.

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“…In the human population, CHD is more likely mediated by complex genetics involving oligogenic interactions (Akhirome, Walton, Nogee, & Jay, 2017;Gifford et al, 2019). This could also explain the observation of complex CHD in patients with SIT, which is seldom seen in inbred mice.…”

Section: Clinical Implications For Patients With Chd Associated Witmentioning

confidence: 98%

“…However, differing from the human population, our mice are entirely inbred and the screen was designed to recover only recessive mutations. In the human population, CHD is more likely mediated by complex genetics involving oligogenic interactions (Akhirome, Walton, Nogee, & Jay, ; Gifford et al, ). This could also explain the observation of complex CHD in patients with SIT, which is seldom seen in inbred mice.…”

Section: Role Of Left–right Patterning In Congenital Heart Diseasementioning

confidence: 99%

Left–right patterning in congenital heart disease beyond heterotaxy

Gabriel

2020

American J of Med Genetics Pt C

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Congenital heart defect is one of the most common structural birth defects in the human population. It is highly associated with heterotaxy, a birth defect involving randomized left–right patterning of visceral organ situs. Large scale mouse forward genetics have led to the finding of a central role for cilia in CHD pathogenesis, with some cilia and non‐cilia mutations causing CHD with heterotaxy. Interestingly, many of the mutations causing CHD with heterotaxy can give rise to three laterality outcomes comprising normal situs solitus, mirror symmetric situs inversus totalis, or randomized situs with heterotaxy. Given CHD is largely observed only with heterotaxy, this suggests a new paradigm is needed for investigating the genetics of CHD associated with heterotaxy. Furthermore, analysis of data from multiple large birth cohorts have independently confirmed a broader involvement of laterality disturbance in CHD. This was demonstrated by the common cooccurrence of rare laterality defects with CHD lesions of a wide spectrum. These findings suggest left–right patterning is tightly intertwined with the developmental processes that regulate cardiac morphogenesis and its disturbance may contribute to all types of CHD even in the absence of laterality defects.

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Oligogenic inheritance of a human heart disease involving a genetic modifier

Cited by 151 publications

References 58 publications

Identification of FOXH1 mutations in patients with sporadic conotruncal heart defect

Identification of FOXH1 mutations in patients with sporadic conotruncal heart defect

Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1

Left–right patterning in congenital heart disease beyond heterotaxy

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