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CASE REPORT article

Front. Genet.

Sec. Human and Medical Genomics

Volume 16 - 2025 | doi: 10.3389/fgene.2025.1661743

Prenatal diagnosis of a de novo pathogenic HNRNPK variant in a Chinese fetus with abnormal ultrasound soft markers: A case report

Provisionally accepted
Yuying  ZhuYuying Zhu1Zhen  YangZhen Yang2Qiumin  ZhuQiumin Zhu1Ke  WuKe Wu1Junying  HeJunying He1Hongmei  ZhouHongmei Zhou1*
  • 1Quzhou Maternal & Child Health Care Hospital, Quzhou, China
  • 2BGI Group, Shenzhen, China

The final, formatted version of the article will be published soon.

Background: Heterozygous pathogenic variants in HNRNPK cause Au-Kline syndrome (AUKS), a neurodevelopmental disorder characterized by congenital anomalies and developmental delay. Prenatal diagnosis of AUKS remains challenging due to nonspecific ultrasound findings, such as increased nuchal translucency (NT) and nuchal fold (NF), which overlap with other genetic conditions. Methods: Whole-exome sequencing (WES) was performed on a fetus exhibiting increased NT and NF thickening, alongside parental samples. Identified variants were validated by Sanger sequencing, with structural and functional impacts predicted using bioinformatic tools. Results: WES revealed a de novo heterozygous frameshift variant in HNRNPK (NM_031263.4: c.504_507del) in exon 9 of 17, which has been deposited in the ClinVar database with accession number VCV003899365 and classified as pathogenic (P). This variant results in a truncated protein (p.Lys168AsnfsTer35): bioinformatic predictions indicate the resulting mRNA is likely subject to nonsense-mediated mRNA decay (NMD), and any escaping mRNA would produce a severely truncated protein lacking critical functional domains, rendering it nonfunctional. Sanger sequencing confirmed the variant was absent in both parental genomes. Ultrasound findings aligned with AUKS-associated nonspecific prenatal anomalies, and post-induction gross examination confirmed subtle AUKS-related craniofacial features, expanding the known prenatal phenotype of AUKS and providing phenotypic severity context. Conclusion: Structural and functional analyses provide mechanistic insights into the variant's pathogenicity, highlighting HNRNPK's role in fetal development. These findings advocate for integrating genomic and phenotypic data to improve prenatal diagnosis of rare genetic syndromes.

Keywords: Nuchal translucency, Prenatal Diagnosis, Whole-exome sequencing, de novo variant, hnRNPK

Received: 08 Jul 2025; Accepted: 30 Sep 2025.

Copyright: © 2025 Zhu, Yang, Zhu, Wu, He and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Hongmei Zhou, 15067022676@163.com

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