# Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG

## TL;DR

This study expands the known clinical features of autosomal-dominant STT3A-CDG, a rare genetic disorder affecting glycosylation, and highlights new symptoms and biochemical patterns.

## Contribution

The paper reports new clinical features and biochemical variability in autosomal-dominant STT3A-CDG, including previously unreported symptoms like anorectal malformation and bleeding diathesis.

## Key findings

- Abnormal transferrin glycosylation was present in nearly all individuals (20/21).
- Newly reported features include anorectal malformation, morbid obesity, and bleeding diathesis.
- Variants clustered in conserved catalytic regions, with p.Arg405 as a recurrent hotspot.

## Abstract

STT3A encodes the catalytic subunit of the oligosaccharyltransferase A (OST-A) complex and is classically linked to severe autosomal-recessive congenital disorder of glycosylation (CDG). To define the distinct autosomal-dominant disorder, we reviewed all published cases and integrated three previously unpublished individuals from the CDG natural history study. Across 21 individuals, abnormal transferrin glycosylation was present in nearly all individuals (20/21), and subtle facial dysmorphism was common (18/21). Neurodevelopmental involvement was frequent, including motor delay (13/21), learning difficulties (13/21), speech delay (12/21), and intellectual disability (10/21). Musculoskeletal manifestations were also common, including skeletal abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset osteoarthritis in adults (6/21). Less frequent features included congenital heart defects (5/21) and coagulation factor deficiency (5/21). Importantly, the newly reported individuals expand dominant STT3A-CDG with previously unreported features, including anorectal malformation, morbid obesity, and clinically significant bleeding diathesis with von Willebrand factor and factor VIII deficiency. Biochemical signatures ranged from classic type I transferrin patterns to subtle or atypical abnormalities, emphasizing that near-normal transferrin testing does not exclude the diagnosis. Variants clustered in conserved catalytic regions, with recurrent p.Arg405 across de novo, inherited, and mosaic cases supporting a mutational hotspot and likely dominant-negative mechanism.