Clin Exp Otorhinolaryngol.  2019 Nov;12(4):405-411. 10.21053/ceo.2019.00304.

Spectrum of Novel Hereditary Hemorrhagic Telangiectasia Variants in an Austrian Patient Cohort

• Koenighofer M
• Parzefall
• Frohne A
• Allen M
• Unterberger U
• Laccone F
• Schoefer C
• Frei K
• Lucas T

• KMID: 2462737
• DOI: http://doi.org/10.21053/ceo.2019.00304

Abstract

OBJECTIVES
Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant genetic disorder characterized by pathogenic blood vessel development and maintenance. HHT type 1 (HHT1) and type 2 (HHT2) are caused by variants in endoglin (ENG) and activin receptor-like kinase-1 (ACVRL1), respectively. The aim of this study was to identify the spectrum of pathogenic variants in ENG and ACVRL1 in Austrian HHT families.
METHODS
In this prospective study, eight Austrian HHT families were screened for variants in ENG and ACVRL1 by polymerase chain reaction amplification and sequencing of DNA isolated from peripheral blood.
RESULTS
Heterozygous variants were identified in all families under study. HHT1 was caused by a novel c.816+1G>A splice donor variant, a novel c.1479C>A nonsense (p.Cys493X) variant and a published c.1306C>T nonsense (p.Gln436X) variant in ENG. Variants found in ACVRL1 were novel c.200G>C (p.Arg67Pro) and known c.772G>A (p.Gly258Ser) missense variants in highly conserved residues, a known heterozygous c.100dupT frameshift (p.Cys34Leufs*4) and the known c.1204G>A missense (p.Gly402Ser) and c.1435C>T nonsense (p.Arg479X) variants as causes of HHT2.
CONCLUSION
Novel and published variants in ENG (37.5%) and ACVRL1 (62.5%) were exclusively identified as the cause of HHT in an Austrian patient cohort. Identification of novel causative genetics variants should facilitate the development of tailored therapeutical applications in the future treatment of autosomal dominant HHT.

Keyword

Telangiectasia; Hereditary Hemorrhagic; Endoglin; Activin Receptor-Like Kinase-1

MeSH Terms

Activins
Blood Vessels
Cohort Studies*
DNA
Genetics
Humans
Polymerase Chain Reaction
Prospective Studies
Telangiectasia, Hereditary Hemorrhagic*
Telangiectasis
Tissue Donors
Activins
DNA

Figure

• 

  Fig. 1. Schematic diagram of variants identified in relation to exon and protein domains of endoglin (ENG) and activin receptor-like kinase-1 (ACVRL1). Signal peptides (SP), transmembrane domains (TM), ENG N- and C-terminal zona pellucida (ZP) domains, the juxtamembrane metalloproteinase-14 (MMP-14) cleavage site to produce soluble ENG, generation of short (S) and long (L) membrane bound forms by differential splicing within exon 14 in the cytoplasmic (CY) domain, the zona pellucida binding motif in L-ENG together with the region of the ACVRL1 extracellular domain (ECD) determining specificity for bone morphogenetic protein (BMP) and cytoplasmic glycine- and serine-rich (GS) region (dotted exons not drawn to scale) are illustrated. ATP, adenosine triphosphate.

• 

  Fig. 2. Endoglin (ENG) mutations identified in families suffering from hereditary hemorrhagic telangiectasia. (A) A heterozygous ENG c.816+1G> A splice site variant (B) and a c.1479C>A nonsense (p.C493X) mutation were identified in the proband analyzed (+/–) by Sanger sequencing.

• 

  Fig. 3. Novel activin receptor-like kinase-1 (ACVRL1) mutation identified in families suffering from hereditary hemorrhagic telangiectasia. (A) A c.200G>C missense (p.R67P) mutation were identified in the proband analyzed (+/–) by Sanger sequencing. (B) Cross species sequence alignments show the arginine residue at p.67 is highly conserved in mammals.

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