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

Ornithine transcarbamylase deficiency (OTCD, MIM#311250) is a rare X-linked urea cycle disorder causing hyperammonemia. While around 600 pathogenic OTC variants have been reported, cryptic changes like synonymous or in-frame variants remain poorly characterized and are easily overlooked in routine screening.

We analyzed the clinical and genetic profiles of two unrelated Chinese male patients clinically diagnosed with OTCD. Whole-exome sequencing (WES) was performed to identify the genetic etiology. A minigene assay was then used to assess the splicing effect of the detected synonymous variant.

WES revealed two rare OTC variants: a synonymous variant (NM_000531.6: c.663G>A, p.Lys221Lys) and a novel de novo inframe variant (c.756_761dupAGCAGC, p.Ala253_Ala254dup). Minigene assay confirmed that the c.663G>A variant causes exon 6 skipping, leading to the deletion of 41 amino acids (c.541_663del, p.Glu181_Lys221del). Both variants were classified as clinically pathogenic, and the genotype-phenotype relationships were potentially established.

Our study expands the mutation spectrum of OTC and emphasizes the importance of cryptic variants interpretation and the need for additional functional studies to verify the pathogenicity of these variants.