A New Aberration in the VPS33B Gene Leads to Full-Symptom ARCS1

Patient: Male, newborn Final Diagnosis: ARCS1 Symptoms: Cholestasis and/or gallbladder dysfunction Medication: — Clinical Procedure: — Specialty: Pediatrics and Neonatology OBJECTIVE: Rare disease BACKGROUND: ARCS1 is an acronym for arthrogryposis, renal dysfunction, and cholestasis. It is a congenital malfunction with autosomal recessive inheritance, and, unfortunately, its prognosis is still poor. It is believed that VPS33B is altered in 75% of cases and that the VIPAR gene is altered in approximately 25% of them. CASE REPORT: An affected child was born from the first pregnancy of 26-year-old mother and a 30-year-old father with no previous medical history and no genetic conditions. The first clinical symptoms were observed at the end of the child’s second week of life. The mother reported the child has decreasing body weight and loss of appetite. After admission to the ward, the child was apathetic and sleepy. Symptoms of conjunctivitis, pale and dry skin, and mild face and mild body dysmorphia were observed. CONCLUSIONS: Laboratory tests revealed proteinuria of up to 1.36 g/l and glycosuria of up to 28 mmol/l, as well as fluctuating metabolic acidosis. The bilirubin level reached 6.62 mg/dl, along with alkaline phosphatase at 470 U/l. Moreover, hypothyroidism with TSH at 16.71 uU/ml was observed. Because of the co-occurrence of cholestasis and renal dysfunction, molecular testing was done. The 17(th) exon of VPS33B was sequenced by Sanger DNA sequencing method. To the best of our knowledge, this is the first report of homozygotic mutation c.1235_1236delinsG (p.Pro412ArgfsTer7) in the VPS33B gene. The risk of transfer of the mutation to future descendants was calculated as 25%. Due to the wide landscape of molecular alternation in the 17(th) exon of the VPS33B gene, we propose using Sanger whole-exon sequencing as a first-choice diagnostic test.