Pedigree and Functional Analysis of Two Cryptic OTC Variants Causing Ornithine Transcarbamylase Deficiency in Two Unrelated Families

OTC (2 independent cryptic variants, X-linked)

Cryptic variants (synonymous or in-frame) in OTC → pseudo-exon activation or aberrant splicing → loss of function; undetected by standard screening (WES), require RNA-seq or dedicated functional analysis

Identification and functional characterization of two cryptic variants (synonymous/in-frame) in OTC in two unrelated boys with ornithine transcarbamylase deficiency (OTCD) and hyperammonemia diagnosed by WES. Cryptic variants, poorly characterized by routine screening, affect splicing or mRNA stability. Functional analysis by pedigree, RNA-seq and enzymatic activity confirms their pathogenicity. Approximately 600 pathogenic OTC variants are listed; cryptic variants remain the most poorly detected fraction.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

OTCD is the most common urea cycle disorder (X-linked). Cryptic variants represent a blind spot for classical WES diagnosis. Systematic RNA-seq in suspected OTCD cases without identified WES variant would significantly improve diagnostic yield.

non-canonical cryptic variants + functional analysis +3; pedigree 2 independent families +2; diagnostic impact (WES insufficient) +2