A novel pathogenic synonymous DHCR7 variant unveiled by aberrant splicing in Smith-Lemli-Opitz syndrome.
Y, Z., Q, Z., Q, H., G, Y., H, L., & Y, A. (2026). A novel pathogenic synonymous DHCR7 variant unveiled by aberrant splicing in Smith-Lemli-Opitz syndrome.. Human genetics. https://doi.org/10.1007/s00439-026-02853-2
Y Z, Q Z, Q H, G Y, H L, Y A. A novel pathogenic synonymous DHCR7 variant unveiled by aberrant splicing in Smith-Lemli-Opitz syndrome.. Human genetics. 2026; doi: 10.1007/s00439-026-02853-2
Y Z, Q Z, Q H, et al. A novel pathogenic synonymous DHCR7 variant unveiled by aberrant splicing in Smith-Lemli-Opitz syndrome.[J]. Human genetics. 2026. DOI: 10.1007/s00439-026-02853-2.
@article{y2026,
author = {Zhou Y and Zhang Q and He Q and Yang G and Li H and An Y},
title = {A novel pathogenic synonymous DHCR7 variant unveiled by aberrant splicing in Smith-Lemli-Opitz syndrome.},
journal = {Human genetics},
year = {2026},
doi = {10.1007/s00439-026-02853-2},
note = {PMID: 42406129},
}
TY - JOUR AU - Zhou Y AU - Zhang Q AU - He Q AU - Yang G AU - Li H AU - An Y TI - A novel pathogenic synonymous DHCR7 variant unveiled by aberrant splicing in Smith-Lemli-Opitz syndrome. T2 - Human genetics PY - 2026 DO - 10.1007/s00439-026-02853-2 AN - PMID:42406129 ER -
Synonymous mutations, once regarded as silent, are increasingly recognized as pathogenic through disruption of mRNA splicing. Here, we report a prenatal case with classic features of Smith-Lemli-Opitz syndrome (SLOS), including increased nuchal translucency, enlarged kidneys, and fetal growth restriction. Whole-exome sequencing identified compound heterozygous DHCR7 variants: a previously reported missense variant, NM_001360.3:c.1220A > G (p.Asn407Ser), and a novel synonymous variant, NM_001360.3:c.963G > A (p.Gln321 =). Functional validation using minigene assays and patient-derived cDNA demonstrated that c.963G > A causes aberrant splicing, resulting in a premature termination codon and production of a truncated protein lacking the sterol-sensing domain, which contains multiple recurrent pathogenic missense sites. These findings establish the deleterious effect of this synonymous change, analogous to the well-characterized splice-site variant NM_001360.3:c.964 - 1G > C (historically referred to as IVS8 - 1G > C). In sum, this study provides the first definitive evidence that a synonymous DHCR7 variant can act as a likely pathogenic allele through splicing disruption. Moreover, it offers critical molecular insight and a refined framework for interpreting synonymous variants-particularly variants of uncertain significance-with important implications for clinical diagnosis, genetic counseling, and prenatal care.