Mild Phenotype of Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome 1 Caused by a Novel VPS33B Variant.

Natália Duarte Linhares,Eleonora Druve Tavares Fagundes,Thaís Costa Nascentes Queiroz,Alexandre Rodrigues Ferreira,Sergio D J Pena,Luiz Roberto Da Silva

doi:10.3389/fgene.2022.796759

Abstract

The arthrogryposis, renal dysfunction, and cholestasis syndrome (ARCS) is an autosomal recessive multisystem disease caused by variants in VPS33B or VIPAS39. The classical presentation includes congenital joint contractures, renal tubular dysfunction, cholestasis, and early death. Additional features include ichthyosis, central nervous system malformations, platelet dysfunction, and severe failure to thrive. We studied three patients with cholestasis, increased aminotransferases, normal gamma-glutamyl transferase, and developmental and language delay. Whole exome sequencing analysis identified VPS33B variants in all patients: patients 1 and 2 presented a novel homozygous variant at position c.1148T>A. p.(Ile383Asn), and patient 3 was compound heterozygous for the same c.1148T>A. variant, in addition to the c.940-2A>G. variant. ARCS is compatible with the symptomatology presented by the studied patients. However, most patients that have been described in the literature with ARCS had severe failure to thrive and died in the first 6 months of life. The three patients studied here have a mild ARCS phenotype with prolonged survival. Consequently, we believe that the molecular analysis of the VPS33B and VIPAS39 should be considered in patients with normal gamma-glutamyl transferase cholestasis.

Highlights

Arthrogryposis, renal dysfunction, and cholestasis syndrome (ARCS) is a rare autosomal recessive multisystem disorder that has been named because of its three cardinal features (Nezelof et al, 1979; Horslen et al, 1994)
Consistent with the widespread organ dysfunction in ARCS, VPS33B has a role in the regulation of intracellular protein trafficking, with abnormal organelle biogenesis on the liver and on the kidney that may result in cholestasis and tubular disfunction (Gissen et al, 2004)
We report three patients with the same novel c.1148T>A. variant, and we believe that this variant could be associated with a mild phenotype

Summary

Introduction

Arthrogryposis, renal dysfunction, and cholestasis syndrome (ARCS) is a rare autosomal recessive multisystem disorder that has been named because of its three cardinal features (Nezelof et al, 1979; Horslen et al, 1994). Consistent with the widespread organ dysfunction in ARCS, VPS33B has a role in the regulation of intracellular protein trafficking, with abnormal organelle biogenesis on the liver and on the kidney that may result in cholestasis and tubular disfunction (Gissen et al, 2004). VPS33B interacts with soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs), which are involved in synaptic vesicle fusion, vesicular exocytosis, and neurosecretion (Lobingier and Merz, 2012; Han et al, 2017). Mouse knockout studies have shown that VPS33B and VIPAS39 are essential for epidermal lamellar body biogenesis and function (Rogerson and Gissen, 2018)

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