title: ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension.
abstract: Germline mutations in genes encoding members of the transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curaçao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.
authors.affiliation: Oncogenetics and Angiogenetics Laboratory, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Eyries
authors.forename: F
authors.initials: F
authors.lastname: Coulet
authors.forename: B
authors.initials: B
authors.lastname: Girerd
authors.forename: D
authors.initials: D
authors.lastname: Montani
authors.forename: M
authors.initials: M
authors.lastname: Humbert
authors.forename: P
authors.initials: P
authors.lastname: Lacombe
authors.forename: T
authors.initials: T
authors.lastname: Chinet
authors.forename: L
authors.initials: L
authors.lastname: Gouya
authors.forename: J
authors.initials: J
authors.lastname: Roume
authors.forename: M M
authors.initials: MM
authors.lastname: Axford
authors.forename: C E
authors.initials: CE
authors.lastname: Pearson
authors.forename: F
authors.initials: F
authors.lastname: Soubrier
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics*; D000328:Adult; D000483:Alleles; D001483:Base Sequence; D005091:Exons; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000235:genetics*; D009030:Mosaicism; D010375:Pedigree; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications / Q000235:genetics*
chemical_list: C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II