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

• Published in: Frontiers in genetics Vol. 13; p. 796759
• Main Authors: Linhares, Natália Duarte, Fagundes, Eleonora Druve Tavares, Ferreira, Alexandre Rodrigues, Queiroz, Thaís Costa Nascentes, da Silva, Luiz Roberto, Pena, Sergio D J
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 25-02-2022
• Subjects: arthrogryposis; cholestasis; Genetics; renal dysfunction; VPS33B gene; whole exome sequencing; arthrogryposis; VPS33B gene; renal dysfunction; cholestasis; whole exome sequencing
• ISSN: 1664-8021; 1664-8021
• DOI: 10.3389/fgene.2022.796759

The arthrogryposis, renal dysfunction, and cholestasis syndrome (ARCS) is an autosomal recessive multisystem disease caused by variants in
or
. 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
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
and
should be considered in patients with normal gamma-glutamyl transferase cholestasis.