Patients With Hereditary Hemorrhagic Telangiectasia Diagnosed by Nanopore Long Read Sequencer

ABSTRACT Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by excessive and frequent epistaxis, telangiectasia, and visceral involvement, with a strong positive family history. The genes responsible for HHT are endoglin ( ENG ), activin A receptor‐like kinase 1 ( ACVRL1 or ALK‐1 ), and SMAD4 are known. As opposed to epistaxis and telangiectasia, whether or not the disease is prone to any visceral lesions depends on the causative gene. Arteriovenous malformations (AVMs) of the brain and lung are common in ENG , hepatic AVMs and cutaneous telangiectasia are common in ACVRL1 , and juvenile polyposis (JP‐HHT) is characteristic in SMAD4 . Therefore, the diagnosis of HHT and its subclasses in patients with recurrent epistaxis is clinically important for predicting cerebral and visceral complications and for prophylactic medical or surgical treatment. Genomic techniques for the molecular diagnosis of HHT have advanced remarkably in recent years. Long‐read sequencing using nanopore technology is now recognized as a new and effective approach for the detection of structural aberrations, such as large deletions, that cannot be detected by conventional short‐read analysis. In particular, a new technique called adaptive long‐read sequencing can selectively sequence only pre‐defined target regions. Here we report two patients with HHT in whom no variants were found by short‐read targeted sequencing, but structural variants were detected by adaptive nanopore sequencing. These molecular diagnostic results were used in their clinical management.