A number sign (#) is used with this entry because of evidence that severe congenital liver disease (SCOLIV) is caused by homozygous or compound heterozygous mutation in the FOCAD gene (614606) on chromosome 9p21.

Severe congenital liver disease (SCOLIV) is an autosomal recessive disorder characterized by the onset of progressive hepatic dysfunction usually in the first years of life. Affected individuals show feeding difficulties with failure to thrive and features such as jaundice, hepatomegaly, and abdominal distension. Laboratory workup is consistent with hepatic insufficiency and may also show coagulation defects, anemia, or metabolic disturbances. Cirrhosis and hypernodularity are commonly observed on liver biopsy. Many patients die of liver failure in early childhood (Moreno Traspas et al., 2022).

Moreno Traspas et al. (2022) reported 14 children from 10 unrelated families with severe congenital liver disease. The patients, who were all under 15 years of age, were ascertained through international collaborative efforts after genetic analysis identified biallelic mutations in the FOCAD gene. The families were from India, France, the United States, Pakistan, Saudi Arabia, Portugal, and Brazil; 6 of the families were consanguineous. Many of the pregnancies were complicated by intrauterine growth retardation, and all but one of the patients presented in infancy with vomiting, diarrhea, feeding difficulties, poor overall growth, and failure to thrive with signs of malnutrition. Some had gastritis and cow's milk allergies, and a few needed supplemental nutrition. Physical examination showed jaundice, abdominal distension, hepatomegaly or hepatosplenomegaly, and ascites in most patients. Additional features included a compromised respiratory system in about 50%, congenital cardiac defects (usually patent foramen ovale or patent ductus arteriosus) in 42.9%, and variable genitourinary abnormalities, such as hydronephrosis, in 42.9%. Almost half of the patients had inguinal or umbilical hernia. Laboratory studies showed variable abnormalities, including elevated liver function tests, hyperbilirubinemia, coagulation defects, increased ammonia levels, hypoalbuminemia, increased alpha-fetoprotein (AFP; 104150), anemia, thrombocytopenia, increased ferritin, and metabolic abnormalities, such as hypoglycemia and metabolic acidosis. Liver imaging and biopsy mainly showed cirrhosis (in 71.4%), with multinodularity (57.1%), intrahepatic cholestasis (35.7%), biliary hyperplasia (28.6%), microvesicular steatosis, portal fibrosis, and portal and septal inflammation; increased glycogen content and iron overload were observed in some. Of the 14 children, 6 died due to hepatic or multiorgan failure, 5 of them before 1 year of age.

The transmission pattern of SCOLIV in the families reported by Moreno Traspas et al. (2022) was consistent with autosomal recessive inheritance.

In 14 patients from 10 unrelated families of various ethnic origins with SCOLIV, Moreno Traspas et al. (2022) identified biallelic mutations in the FOCAD gene (see, e.g., 614606.0001-614606.0006). Most of the mutations were nonsense, frameshift, or splice site alterations, predicted to result in a loss of function, but there were also 3 missense variants at highly conserved residues. Western blot analysis of dermal fibroblasts derived from 2 patients showed near absent FOCAD expression in cellular extracts. There were also decreased levels of the SKIC2 protein (600478), suggesting that FOCAD may contribute to the stability of this RNA helicase. Similar results were obtained in FOCAD-null human hepatocytes in vitro, with the addition of decreased SKIC3 (614589). There was also increased secretion of the inflammatory marker CCL2 (158105). These findings and altered gene expression patterns suggested that loss of FOCAD disrupts hepatocyte homeostasis, which the authors postulated is the cell of origin responsible for the liver cirrhosis phenotype.

Moreno Traspas et al. (2022) found that CRISPR/Cas9-mediated knockdown of the focad gene in zebrafish embryos resulted in decreased overall survival, growth retardation, and liver abnormalities, including swollen hepatocytes, steatosis, fibrosis, and hepatocyte apoptosis. Metabolic analysis showed dysregulation of multiple lipid species, and transcriptome analysis demonstrated differential expression of multiple genes involved in liver metabolism, inflammation, and RNA biology compared to wildtype.