Severe early-onset Wilson disease caused by a common pathogenic variant in the Bukharan Jewish population in Israel

• Published in: Gene Vol. 887; p. 147728
• Main Authors: Orenstein, Naama, Glassberg, Yael Mozer, Shkalim-Zemer, Vered, Basel-Salmon, Lina, Averbuch, Noa Shefer, Lagovsky, Irina, Mark, Anat Guz, Amir, Achiya Z., Bazak, Lily, Cooper, Shiri, Goldberg, Yael
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.12.2023
• Subjects: ATP7B; Early diagnosis; Founder pathogenic variant; P.(Val1262Phe); P.(Val1262Phe); Early diagnosis; ATP7B; PV; ALF; WD; Founder pathogenic variant
• DOI: 10.1016/j.gene.2023.147728
• ISSN: 0378-1119

•p.(Val1262Phe) is a unique pathogenic variant in ATP7B in Bukharan Jewish descent.•In our cohort, patients had a severe phenotype of WD with early onset.•A high carrier rate was discovered in Bukharan Jewish controls.•Early diagnosis is the most important factor influencing long-term prognosis in WD.•We suggest including this variant in neonatal preclinical screening programs. Wilson disease is caused by pathogenic variants in the ATP7B gene which encodes a copper-transporting ATPase. Describe a common founder pathogenic variant among Bukharan Jews and to assess its prevalence, clinical features, and outcome. The cohort consisted of patients of Bukharan Jewish descent diagnosed with Wilson disease at a tertiary pediatric medical center in 2013–2018. Clinical and genetic data were collected and analyzed. Six patients from 4 unrelated families who were homozygous for the c.3784G > T p.(Val1262Phe) pathogenic variant in ATP7B were identified. Five presented with elevated aminotransferase levels, and one, with acute liver failure. Mean age at diagnosis was 8.7 years (5–12.5). Serum ceruloplasmin level was extremely low in all patients (1.9–7 mg/dL; mean 3.2(. The variant was identified in a heterozygous state in 5/153 Bukharan Jews; 2/33 from our local exome database and 3/120 healthy unrelated Bukharan Jews in another cohort, for an estimated carrier frequency of ∼1:30. We report a common founder pathogenic variant in the ATP7B gene among Bukharan Jews associated with severe early-onset Wilson disease. Given the clinical severity, high frequency of the variant, and being a treatable disease, its inclusion in pre-symptomatic screening in the Bukharan Jewish community should be considered. Furthermore, WD should be part of future genetic newborn screening programs in Israel and worldwide, to enable early treatment and prevention of future life-threatening complications.