Likely inborn error of metabolism

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. 86% of patients also had metabolic anomalies (e.g., steatosis, increased glycogen content, iron overload). Hence, this gene should be promoted to Green at the next GMS update. This association is tagged for expert review regarding phenotypic fit for the panel, as the metabolic anomalies are quite variable. Inclusion on this panel would also ensure inclusion on R27 Paediatric disorders, which covers more syndromic presentations.

Created: 16 Jun 2026, 9:31 a.m. | Last Modified: 16 Jun 2026, 9:31 a.m.

Panel Version: 9.10

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% - e.g., steatosis, increased glycogen content, iron overload), 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: 16 Jun 2026, 9:28 a.m. | Last Modified: 16 Jun 2026, 9:29 a.m.

Panel Version: 9.10

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