A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human

Abstract

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare developmental lung disorder that is uniformly lethal. Affected infants die within the first few weeks of their life despite aggressive treatment, although a few cases of late manifestation and longer survival have been reported. We have shown previously that mutations and deletions in FOXF1 are a cause of this disorder. Although most of the cases of ACD/MPV are sporadic, there have been infrequent reports of familial cases. We present a family with five out of six children affected with ACD/MPV. DNA analysis identified a missense mutation (c.416G4T; p.Arg139Leu) in the FOXF1 gene that segregated in the three affected siblings tested. The same variant is also present as a de novo mutation in the mother and arose on her paternally derived chromosome 16. The two tested affected siblings share the same chromosome 16 haplotype inherited from their maternal grandfather. Their single healthy sibling has a different chromosome 16 haplotype inherited from the maternal grandmother. The results are consistent with paternal imprinting of FOXF1 in human.

Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder

“…Six published de novo microdeletions that included FOXF1 (D1, D3, D4, and D8) or mapped upstream of FOXF1 (D9 and D10) also arose de novo on the maternal chromosome (Stankiewicz et al 2009). Moreover, in a recently published unique familial case of ACD/MPV, with missense mutations in FOXF1 affecting five subjects, the mutation was inherited from a heterozygous healthy mother, in whom the mutation arose de novo on her paternal chromosome (Sen et al 2012). In aggregate, these findings strongly suggest a parental-origin bias of FOXF1-associated CNVs (P < 0.001, n = 14).…”

“…Also, deletions upstream of FOXF1, leaving FOXF1 intact, have been described in two patients with ACD/MPV, suggesting the presence of distant regulatory elements for FOXF1 (Stankiewicz et al 2009). In addition, FOXF1 has been bioinformatically predicted to be paternally imprinted (Luedi et al 2007), and other studies have supported this prediction (Stankiewicz et al 2009;Sen et al 2012).…”

“…A few familial ACD/MPV cases have been described (Sen et al 2004(Sen et al , 2012Eulmesekian et al 2005). During the last 10 years, we ascertained ACD/MPV samples (mainly formalin-fixed paraffin-embedded lung tissues) from more than 90 families.…”

A novel missense mutation in the transcription factor FOXF1 cosegregating with infantile hypertrophic pyloric stenosis in the extended pedigree linked to IHPS5 on chromosome 16q24

“…This may be because this family only has a missense mutation in FOXF1 which does not lead to complete inactivation of the protein. However, recently a missense mutation at the same site (R139L) was identified in three siblings with ACDMPV, the segregation of which appeared to be consistent with paternal imprinting of FOXF1 38 . Our results are not consistent with this but differential patterns of imprinting have been reported between different tissues 39 which could partly explain the contrasting results with regards to severity of disease and mode of inheritance.…”

A Novel Mutation in <b><i>FOXF1</i></b> Gene Associated with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins, Intestinal Malrotation and Annular Pancreas

“…DNA from the patient was amplified with appropriate primers applying the protocol described by Sen et al [11.] DNA sequencing was performed using an ABI 3130XL instrument following the manufacturer’s instruction.…”