Variable phenotypic presentation of a novel<i>FOXF1</i>missense mutation in a single family

Reiter, Joel; Szafrański, Przemysław; Breuer, Oded; Perles, Zeev; Dagan, Tamir; Stankiewicz, Paweł; Kerem, Eitan

doi:10.1002/ppul.23425

Cited by 19 publications

(23 citation statements)

References 23 publications

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“…4c) with four children, one of them affected by ACDMPV, that was inherited from the healthy father who was approximately 70% mosaic for the mutation in the peripheral blood nucleated cells (Reiter et al 2016). …”

Section: Resultsmentioning

confidence: 99%

“…Family 138 also illustrates variable expressivity of ACDMPV with two siblings presenting with severe pulmonary hypertension after birth, one of whom had hypoxemia, but survived beyond infancy, and the other had partial anomalous pulmonary venous return. The third sibling died in the neonatal period from ACDMPV (Reiter et al 2016). …”

Section: Discussionmentioning

confidence: 99%

“…c Family 138 with the pathogenic missense mutation in the FOXF1 1 st exon transmitted by healthy father, 70% mosaic in peripheral blood. A twin sister (shaded symbol) of the deceased ACDMPV patient has partial anomalous venous return (Reiter et al (2016). d Family 123 with the frameshift mutation transmitted by healthy mother, likely germline mosaic for the mutation.…”

Section: Figmentioning

confidence: 99%

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Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

et al. 2016

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Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in etiology of ACDMPV.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

et al. 2016

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“…Its diagnosis is histological2 and is defined by: immature lobular development, decreased number of pulmonary capillaries, lymphangiectasia, medial hypertrophy of small pulmonary arteries, muscularisation of distal arterioles and dilated bronchial veins in the same adventitial sheath as pulmonary arteries 3. ACD is a pathology with phenotypic variability since many cases of delayed presentation and/or prolonged survival have been described 4–11. In 2009, Stankiewicz et al ascribed ACD to heterozygous loss of function of the FOXF1 gene 12.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic and genetic spectrum of alveolar capillary dysplasia: a retrospective cohort study

Jourdan-Voyen

Touraine

Masutti

et al. 2019

Arch Dis Child Fetal Neonatal Ed

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ObjectiveAlveolar capillary dysplasia (ACD) is one of the causes of pulmonary hypertension. Its diagnosis is histological but new pathogenetic data have emerged. The aim of this study was to describe a French cohort of patients with ACD to improve the comprehension and the diagnosis of this pathology which is probably underdiagnosed.MethodsA retrospective observational study was conducted in French hospitals. Patients born between 2005 and 2017, whose biological samples were sent to the French genetic reference centres, were included. Clinical, histological and genetic data were retrospectively collected.ResultsWe presented a series of 21 patients. The mean of postmenstrual age at birth was 37.6 weeks. The first symptoms appeared on the median of 2.5 hours. Pulmonary hypertension was diagnosed in 20 patients out of 21. Two cases had prolonged survival (3.3 and 14 months). Histological analysis was done on lung tissue from autopsy (57.1% of cases) or from percutaneous biopsy (28.6%). FOXF1 was found abnormal in 15 patients (71.4%): 8 deletions and 7 point mutations. Two deletions were found by chromosomal microarray.ConclusionThis study is one of the largest clinically described series in literature. It seems crucial to integrate genetics early into diagnostic support. We propose a diagnostic algorithm for helping medical teams to improve diagnosis of this pathology.

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“…Our results are consistent with numerous genome‐wide methylation screens for DMRs in which no parent‐of‐origin methylation profiles were reported within the 16q24.1 interval (Court et al., ; Sanchez‐Delgado et al., ). This lack of direct evidence for imprinting is supported by a familial case in which the FOXF1 mutation, a c.90_96del, was inherited from the father (Szafranski et al., ) and an individual case in which a c.C231A mutation was also paternally transmitted (Reiter et al., ). Furthermore, a 4.1‐kb de novo enhancer deletion also arose on the paternal allele (Szafranski et al., ).…”

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Maternal mutations ofFOXF1cause alveolar capillary dysplasia despite not being imprinted

et al. 2017

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Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare cause of pulmonary hypertension in newborns. Maternally inherited point mutations in Forkhead Box F1 gene (FOXF1), deletions of the gene, or its long-range enhancers on the maternal allele are responsible for this neonatal lethal disorder. Here, we describe monozygotic twins and one full-term newborn with ACD and gastrointestinal malformations caused by de novo mutations of FOXF1 on the maternal-inherited alleles. Since this parental transmission is consistent with genomic imprinting, the parent-of-origin specific monoallelic expression of genes, we have undertaken a detailed analysis of both allelic expression and DNA methylation. FOXF1 and its neighboring gene FENDRR were both biallelically expressed in a wide range of fetal tissues, including lung and intestine. Furthermore, detailed methylation screening within the 16q24.1 regions failed to identify regions of allelic methylation, suggesting that disrupted imprinting is not responsible for ACDMPV.

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Variable phenotypic presentation of a novelFOXF1missense mutation in a single family

Cited by 19 publications

References 23 publications

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

Phenotypic and genetic spectrum of alveolar capillary dysplasia: a retrospective cohort study

Maternal mutations ofFOXF1cause alveolar capillary dysplasia despite not being imprinted

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