A novel homozygous splice-site variant in the FOCAD gene causing infantile liver cirrhosis and neutropenia: expanding disease phenotype and successful surgical treatment

Background Progressive liver cirrhosis in pediatric patients characterized by clinical and genetic variability. Infantile cirrhosis caused by biallelic variants in the FOCAD gene is an extremely rare multi-system disorder leading to the progressive liver dysfunction. A small number of patients with limited survival were described so far, and any new clinical observation can provide a new insight for complete phenotypic spectrum and perspectives on available treatment to meet patient’s needs. Methods We performed clinical, instrumental, histological and laboratory evaluation of the family with patient (male, 3 y.o.) with progressive liver cirrhosis and apparently healthy parents. Genetic study was performed using whole-exome sequencing. Validation of the rare variant found on WES and cascade familial screening were performed by capillary Sanger sequencing. Functional validation included RNA analysis from patient-derived fibroblasts and in silico protein modeling. Results The patient exhibited an expanded phenotype including microcephaly, macrotia and neutropenia. Genetic testing revealed a novel homozygous FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T FOCAD (NM_001375570.1):c.1455 + 1G > T affecting RNA splicing with in-frame deletion of 36 nucleotides. Aberrant protein lacks 12 aminoacids (p.Thr475_Val486del) resulting in loss of two conserved α -helices. Structural modeling predicted impaired protein stability. At 25 months, the patient underwent a living-donor liver transplantation with a good clinical result, and favorable outcome in 1 year post-liver transplant. Conclusion Canonic splice site variant NM_001375570.1:c.1455 + 1G > T FOCAD (NM_001375570.1):c.1455 + 1G > T realizes through in-frame deletion of 12 amimoacids (p.Thr475_Val486del) of the FOCAD protein with detectable expression in patient-derived cells. Homozygous carrier of this pathogenic variant exhibits progressive hepatic failure expanded with neutropenia. Liver transplantation had a good long-term result, and can be considered as a promising surgical approach for patients with FOCAD -related infantile cirrhosis.