Unfolding the genetic map of monogenic liver diseases in Egypt

Monogenic liver disorders constitute a major disease burden in pediatric patients presenting with manifestations of liver disease. This is particularly significant in countries with high rates of consanguinity as in Egypt. We recruited 228 infants and children suffering from various forms of liver disease with suspected monogenic background and no conclusive biochemical diagnosis. They presented to the Pediatric Hepatology Unit at Cairo-University-Children’s-Hospital, Egypt, over the period April 2017-June 2023 and were referred for genetic diagnosis by various next-generation-sequencing technologies. One-hundred and eighty-five children (81.1%) had a significant genetic finding. Those included 88 children with a main presentation of organomegaly, 83 with cholestasis, 8 with acute liver failure and 6 with hyperbilirubinemic syndromes. One-hundred seventy-five disease-causing variants (51 pathogenic, 86 likely-pathogenic and 38 of uncertain-significance) in 72 different genes were detected in our cohort, including 85 novel variants in 49 different genes. Variants in AGL (Glycogen storage disease type-III; GSD3), ABCB4 (Progressive familial intrahepatic cholestasis type-III; PFIC3) and ABCB11 (PFIC2) genes were the most common affecting 19, 14 and 13 children, respectively. This study is the first to provide the landscape of pediatric monogenic liver diseases in a homogenous population from the Middle East and Africa, an area notoriously known to be poorly represented in genetic database and literature. Furthermore, our presented data are extremely important for genetic counseling and prenatal diagnosis and will further guide national health care policy makers to prevent or mitigate the effects of such disorders in the future.