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

## TL;DR

A new genetic variant in the FOCAD gene causes infantile liver cirrhosis and neutropenia, with successful treatment through liver transplantation.

## Contribution

Identification of a novel homozygous splice-site variant in FOCAD and demonstration of successful liver transplantation as a treatment.

## Key findings

- A novel homozygous FOCAD splice-site variant causes progressive liver cirrhosis and neutropenia in a 3-year-old patient.
- RNA and protein analysis confirmed the variant leads to an in-frame deletion and impaired protein stability.
- Living-donor liver transplantation resulted in a favorable clinical outcome for the patient.

## Abstract

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.

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.

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.

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.