Cholestasis

Gene: FOCAD

Green List (high evidence)

Comment on list classification: There are now numerous individuals reported with biallelic FOCAD variants and severe congenital liver disease. Liver cirrhosis in the neonatal period was a consistent finding, with several individuals needing a liver transplant before age 3 years. Hence, this gene should be promoted to Green at the next GMS update.

Created: 11 May 2026, 3:37 p.m. | Last Modified: 11 May 2026, 3:37 p.m.

Panel Version: 4.3

PMID: 35864190 Traspas et al., 2022
Report of 14 children from ten unrelated families (various ancestries, 6/10 families were consanguineous) presenting with a syndromic form of pediatric liver cirrhosis. WGS/WES detected biallelic FOCAD variants which segregate with disease. FOCAD variants detected: 3 missense, 3 stop-gain, 2 frameshift, 5 splicing, and 1 large deletion. LOF is the mechanism of disease. Absence of FOCAD protein shown in F1 and F2 individuals.

The liver phenotype was marked by cirrhosis (71.4%) with multinodularity (57.1%). Intrahepatic cholestasis was diagnosed in 35.7% of the patients, with associated jaundice (35.7%) and biliary hyperplasia (28.6%). Splenomegaly and hepatomegaly also deteced in 71% of patients. In one case, liver transplant was necessary at 6 months of age. Additional non-liver related phenotypes: abdominal distension (78.6%), diarrhea (57.1%), as well as metabolic anomalies (85.7%), hernias, IUGR. Congenital cardiac and genitourinary anomalies present in 42% of patients. 6 children passed away due to hepatic or multiorgan failure (5 before age 1 year).

Moreover, focad-/- knockout zebrafish phenocopied the human disease, revealing altered mRNA degradation processes in the liver.

Further reports (articles not curated in detail):
PMID: 40662096 - Tarrell et al., 2025 - Hispanic male infant with neonatal liver disease - comp het for FOCAD c.1532A > G; p.Tyr511Cys and c.5137C > A; p.Pro1713Thr - both variants VUS, may explain milder disease progression (no liver failure or cirrhosis)
PMID: 41189834 Raja et al., 2025 - neonatal case with liver cirrhosis, required liver transplant at 3 months of age - comp het for FOCAD c.4435del p.Lys1475Asnfs* and exon 6-7 deletion
PMID: 41608453 Nuzhnaya et al., 2026 - 3yo male patient with infantile liver cirrhosis and neutropenia, homozygous for a novel FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T, p.Thr475_Val486del; liver transplant performed at 25 months

This gene is associated with AR Liver disease, severe congenital, OMIM:619991 in OMIM (Accessed 11th May 2026). Not yet curated in ClinGen or G2P.
Sources: Literature

Created: 11 May 2026, 3:34 p.m. | Last Modified: 11 May 2026, 3:43 p.m.

Panel Version: 4.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Liver disease, severe congenital, OMIM:619991; liver disease, severe congenital, MONDO:0859273

Publications

• 35864190
• 40662096
• 41189834
• 41608453