Maternal mutations of<i>FOXF1</i>cause alveolar capillary dysplasia despite not being imprinted

Alsina, Miguel; Monteagudo-Sánchez, Ana; Guerineau, Luciana Rodiguez; Court, Franck; Serrano, Isabel; Martorell, Loreto; Zurriaga, Carlota Rovira; Moore, Gudrun E.; Ishida, Miho; Castañón, M; Calderón, Elisenda Moliner; Monk, David; Hernando, J. Moreno

doi:10.1002/humu.23213

Cited by 13 publications

(4 citation statements)

References 27 publications

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“…Recently, based on qRT-PCR and bisulfite-PCR, Alsina Casanova et al [42] concluded that there was no evidence of imprinting at the 16q24.1 locus in lung tissue. However, due to a lack of informative SNVs, allelic expression of LINC01082 was not assessed.…”

Section: Discussionmentioning

confidence: 99%

Novel parent-of-origin-specific differentially methylated loci on chromosome 16

et al. 2019

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Background Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise almost exclusively on the maternally inherited chromosome 16. Given the phenotypic similarities between upd(16)mat and ACDMPV, together with parental allelic bias in ACDMPV, we hypothesized that there may be unknown imprinted loci mapping to chromosome 16 that become functionally unmasked by chromosomal structural variants. Results To identify parent-of-origin biased DNA methylation, we performed high-resolution bisulfite sequencing of chromosome 16 on peripheral blood and cultured skin fibroblasts from individuals with maternal or paternal upd(16) as well as lung tissue from patients with ACDMPV-causative 16q24.1 deletions and a normal control. We identified 22 differentially methylated regions (DMRs) with ≥ 5 consecutive CpG methylation sites and varying tissue-specificity, including the known DMRs associated with the established imprinted gene ZNF597 and DMRs supporting maternal methylation of PRR25 , thought to be paternally expressed in lymphoblastoid cells. Lastly, we found evidence of paternal methylation on 16q24.1 near LINC01082 mapping to the FOXF1 enhancer. Conclusions Using high-resolution bisulfite sequencing to evaluate DNA methylation across chromosome 16, we found evidence for novel candidate imprinted loci on chromosome 16 that would not be evident in array-based assays and could contribute to the birth defects observed in patients with upd(16)mat or in ACDMPV. Electronic supplementary material The online version of this article (10.1186/s13148-019-0655-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Novel parent-of-origin-specific differentially methylated loci on chromosome 16

et al. 2019

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“… 49 Unfortunately, detailed studies on imprinting of the FOXF1 locus in fetal, neonatal, and adult lung tissue have not been able to confirm this idea. 50 , 64 …”

Section: Imprinting Of Foxf1mentioning

confidence: 99%

“…Still, this might implicate parental imprinting of the regulatory region instead of the transcription region itself 49 . Unfortunately, detailed studies on imprinting of the FOXF1 locus in fetal, neonatal, and adult lung tissue have not been able to confirm this idea 50 , 64 …”

Section: Imprinting Of Foxf1mentioning

confidence: 99%

Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects

et al. 2018

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Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and lethal disorder mainly involving the vascular development of the lungs. Since its first description, significant achievements in research have led to a better understanding of the underlying molecular mechanism of ACD/MPV and genetic studies have identified associations with genomic alterations in the locus of the transcription factor FOXF1. This in turn has increased the awareness among clinicians resulting in over 200 cases reported so far, including genotyping of patients in most recent reports. Collectively, this promoted a better stratification of the patient group, leading to new perspectives in research on the pathogenesis. Here, we provide an overview of the clinical aspects of ACD/MPV, including guidance for clinicians, and review the ongoing research into the complex molecular mechanism causing this severe lung disorder.

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“…Of these, five parents were subsequently recognized as clinically affected ( FGFR3 , SCN5A X2, BAG3 and ENG ), with important implications for further cascade testing within the family; one parent was found to be mosaic ( SHH , 20% mosaicism). Parental transmission of FOXF1 and RANBP2 variants on the other hand, are thought to be explained by a parent-of-origin effect 16 and incomplete penetrance 17 , respectively. Eight individuals received a partial diagnosis, whereas another five had a dual diagnosis (Supplementary Tables 1 – 3 ).…”

Section: Resultsmentioning

confidence: 99%

Integrated multi-omics for rapid rare disease diagnosis on a national scale

Lunke,

Bouffler,

Patel

et al. 2023

Nat Med

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Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9 d and diagnostic yield was 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). This included major impacts, such as informing precision treatments, surgical and transplant decisions and palliation, in 94 patients (60%). Our results provide preliminary evidence of the clinical utility of integrating multi-omic approaches into mainstream diagnostic practice to fully realize the potential of rare disease genomic testing in a timely manner.

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Maternal mutations ofFOXF1cause alveolar capillary dysplasia despite not being imprinted

Cited by 13 publications

References 27 publications

Novel parent-of-origin-specific differentially methylated loci on chromosome 16

Novel parent-of-origin-specific differentially methylated loci on chromosome 16

Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects

Integrated multi-omics for rapid rare disease diagnosis on a national scale

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