# Biochemical, Clinical, and Functional Characterization of a Rare c.‐106C>A Promoter Region Variant in Late‐Onset Ornithine Transcarbamylase Deficiency: A Multifamily Case Series

## TL;DR

This study examines a rare genetic variant in the OTC gene linked to late-onset ornithine transcarbamylase deficiency, showing varied symptoms and enzyme activity in affected males.

## Contribution

The study provides the first biochemical and clinical characterization of the c.-106C>A promoter variant in late-onset OTC deficiency across multiple families.

## Key findings

- Affected males showed a wide range of symptoms, from asymptomatic to fatal hyperammonemic crises.
- Liver biopsy data revealed severely reduced or absent OTC enzyme activity in some cases.
- Ammonia scavenger therapy helped prevent recurrent decompensation in most affected males.

## Abstract

Ornithine transcarbamylase (OTC) deficiency can present during the neonatal period, infancy, or adulthood. Late‐onset phenotypes are influenced by residual enzyme activity and OTC gene expression. The objective of this study was to assess the pathogenicity of a rare promoter region variant, c.‐106C>A. We reviewed three independent pedigrees harboring the c.‐106C>A variant. Retrospective chart reviews were conducted for 16 affected males to evaluate biochemical and clinical features. Functional OTC enzyme data were obtained from the liver biopsy of three affected males. The median age of diagnosis for symptomatic males was 15 years (range: 0.08–55). All 21 heterozygous females have been asymptomatic to date. Of the 16 hemizygous males, seven have experienced at least one episode of hyperammonemia, and eight have remained asymptomatic. The proband from Family A presented at age 55, with a peak ammonia level of 694 μmol/L. His OTC activity was 8.2 μmol/g liver/min (control: 94.9 μmol/g liver/min). The proband from Family B presented at age 15 with an ammonia level of 1568 μmol/L and later died from cerebral edema. His OTC activity was 2.2 μmol/g liver/min (control: 73.2 μmol/g liver/min). The proband from Family C presented at age 24 with hyperammonemia and later died following withdrawal of care. His liver punch biopsy OTC enzyme activity was measured to be 0 μmol/g liver/min (control range: 25–31.7 μmol/g liver/min). For most affected males, ammonia scavenger therapy has successfully prevented recurrent decompensation. The combined biochemical, clinical, and enzymatic data strongly support the pathogenicity of the c.‐106C>A OTC promoter region variant in late‐onset OTC deficiency.

This study highlights a rare promoter region variant in the OTC gene (c.‐106C>A) that is associated with late‐onset ornithine transcarbamylase deficiency across three independent pedigrees.Affected hemizygous males demonstrated marked clinical and biochemical heterogeneity, ranging from asymptomatic status to fatal hyperammonemic crises.Liver biopsy data showed severely reduced or absent OTC enzyme activity, supporting a functional impact of the c.‐106C>A promoter variant on gene expression.Our findings emphasize the importance of sequencing regulatory regions of the OTC gene in suspected cases when coding‐region analysis is initially unrevealing.

This study highlights a rare promoter region variant in the OTC gene (c.‐106C>A) that is associated with late‐onset ornithine transcarbamylase deficiency across three independent pedigrees.

Affected hemizygous males demonstrated marked clinical and biochemical heterogeneity, ranging from asymptomatic status to fatal hyperammonemic crises.

Liver biopsy data showed severely reduced or absent OTC enzyme activity, supporting a functional impact of the c.‐106C>A promoter variant on gene expression.

Our findings emphasize the importance of sequencing regulatory regions of the OTC gene in suspected cases when coding‐region analysis is initially unrevealing.