Abstract
BackgroundPoint mutations or genomic deletions of FOXF1 result in a lethal developmental lung disease Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. However, the clinical consequences of the constitutively increased dosage of FOXF1 are unknown.MethodsCopy-number variations and their parental origin were identified using a combination of array CGH, long-range PCR, DNA sequencing, and microsatellite analyses. Minisatellite sequences across different species were compared using a gready clustering algorithm and genome-wide analysis of the distribution of minisatellite sequences was performed using R statistical software.ResultsWe report four unrelated families with 16q24.1 duplications encompassing entire FOXF1. In a 4-year-old boy with speech delay and a café-au-lait macule, we identified an ~15 kb 16q24.1 duplication inherited from the reportedly healthy father, in addition to a de novo ~1.09 Mb mosaic 17q11.2 NF1 deletion. In a 13-year-old patient with autism and mood disorder, we found an ~0.3 Mb duplication harboring FOXF1 and an ~0.5 Mb 16q23.3 duplication, both inherited from the father with bipolar disorder. In a 47-year old patient with pyloric stenosis, mesenterium commune, and aplasia of the appendix, we identified an ~0.4 Mb duplication in 16q24.1 encompassing 16 genes including FOXF1. The patient transmitted the duplication to her daughter, who presented with similar symptoms. In a fourth patient with speech and motor delay, and borderline intellectual disability, we identified an ~1.7 Mb FOXF1 duplication adjacent to a large minisatellite. This duplication has a complex structure and arose de novo on the maternal chromosome, likely as a result of a DNA replication error initiated by the adjacent large tandem repeat. Using bioinformatic and array CGH analyses of the minisatellite, we found a large variation of its size in several different species and individuals, demonstrating both its evolutionarily instability and population polymorphism.ConclusionsOur data indicate that constitutional duplication of FOXF1 in humans is not associated with any pediatric lung abnormalities. We propose that patients with gut malrotation, pyloric or duodenal stenosis, and gall bladder agenesis should be tested for FOXF1 alterations. We suggest that instability of minisatellites greater than 1 kb can lead to structural variation due to DNA replication errors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-014-0128-z) contains supplementary material, which is available to authorized users.
Highlights
Point mutations or genomic deletions of FOXF1 result in a lethal developmental lung disease Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins
Neurofibromatosis type 1 (NF1) deletions are classified into type I caused by nonallelic homologous recombination (NAHR) during meiosis and type II arising from NAHR during mitosis and associated with a high frequency of somatic mosaicism [27,28]
Using long-range PCR (LR-PCR) with primers F1 and R1 (Additional file 1: Table S1), the proximal breakpoint of the 16q24.1 duplication was mapped at chr16:86,539,970-86,539,977 and the distal breakpoint was mapped at chr16:86,555, 608-86,555,615, defining a 15,645 bp tandem head-to-tail duplication
Summary
Point mutations or genomic deletions of FOXF1 result in a lethal developmental lung disease Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. Heterozygous point mutations and genomic deletions involving the dosage-sensitive FOXF1 gene on chromosome 16q24.1 have been reported as causative in patients with a rare, neonatally-lethal developmental lung disorder Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV; OMIM 265380) [1,2,3,4,5]. In a number of ACDMPV patients negative for mutation and deletion in FOXF1, we identified overlapping genomic deletions mapping upstream of FOXF1. These deletions enabled us to define an ~60 kb noncoding, evolutionarilyconserved, and differentially-methylated cis-regulatory enhancer region that maps ~272 kb upstream of FOXF1 and harbors lung-specific long non-coding RNA (lncRNA) genes [6,7]. The antisense lncRNA gene, FENDRR, located 5 kb upstream of FOXF1, was found to associate with the polycomb repressive complex (PRC) and negatively regulate FOXF1 expression [9]
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