Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension

Abstract

Despite advances in the diagnosis and management of idiopathic non-cirrhotic portal hypertension (INCPH), its pathogenesis remains elusive. Insight may be gained from study of early onset familial INCPH, in which Mendelian mutations may account for disease. We performed exome sequencing of 8 subjects from 6 kindreds with onset of portal hypertension of indeterminate etiology during infancy or childhood. Three subjects from two consanguineous families shared the identical rare homozygous p.N46S mutation in DGUOK, a deoxyguanosine kinase required for mitochondrial DNA replication; haplotype sharing demonstrated the mutation in the two families was inherited from a remote common ancestor. All three affected subjects had stable portal hypertension with non-cirrhotic liver disease for 6–16 years of follow-up. This mutation impairs ATP binding and reduces catalytic activity. Loss-of-function mutations in DGUOK have previously been implicated in cirrhosis and liver failure but not in isolated portal hypertension. Interestingly, treatment of patients with HIV infection with the nucleoside analog didanosine is known to cause portal hypertension in a subset of patients and lowers deoxyguanosine kinase levels in vitro; the current findings implicate these effects on deoxyguanosine kinase in the causal mechanism. CONCLUSION: Our findings provide new insight into the mechanisms mediating inherited and acquired non-cirrhotic portal hypertension, expand the phenotypic spectrum of DGUOK deficiency, and provide a new genetic test for a specific cause of INCPH.

Idiopathic Portal Hypertension

“…Human leukocyte antigen DR3 + was identified in 7 out of 8 patients with IPH belonging to four different families with more than one member affected . Other gene mutations are present in other patients with IPH and familiar aggregation such as mutations in the telomerase complex gene, autosomal dominantly inherited mutations in the potassium/calcium‐activated channel subfamily N member 3 gene, and recessively inherited mutations in the deoxyguanosine kinase gene …”

ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment

“…One example of an unmet medical need is idiopathic liver disease, which remains a challenge in both pediatric and adult hepatology. We and others have shown the utility of whole-exome sequencing in the diagnosis of such patients (2)(3)(4)(5)(6). Children with unexplained liver disease who are the offspring of a consanguineous union are excellent candidates for recessive disease-causing mutations.…”

Exome Sequencing in Clinical Hepatology

“…Other independent studies have consistently reported WES diagnostic rates of 20% or higher . Furthermore, we and others have successfully combined WES with deep phenotyping (i.e., detailed characterization of each patient's phenotypic features) to identify the underlying genetic defects in infants and children with idiopathic liver diseases, including children with liver failure of indeterminate etiology . Astute clinical annotation (i.e., comprehensive phenotype description of the patient) is central to harnessing the maximal potential of genomic data .…”