HNRNPK – Au-Kline Syndrome

Au-Kline syndrome is a severe multisystem developmental disorder most notably presenting with intellectual disability and various congenital anomalies. Multiple independent studies have implicated de novo variants in HNRNPK as causative for this syndrome (PMID:35422839), establishing a clear genotype–phenotype correlation. This association is supported by comprehensive clinical evaluations that consistently document similar dysmorphic features and neurodevelopmental deficits in affected individuals.

Genetic evidence derives from several case reports and multi‐patient studies where de novo missense and loss‑of‑function variants were identified. For instance, a de novo missense variant, formatted as c.143T>A (p.Leu48Val), was reported in a Chinese patient with Au‑Kline syndrome (PMID:35422839). In one multi‐patient study, 32 individuals with Au‑Kline syndrome were reported, including 13 with de novo missense variants (PMID:36130591); another study expanded the spectrum with six additional cases (PMID:29904177). Such observations reinforce the pathogenic role of HNRNPK variants in this disorder.

The inheritance pattern for Au-Kline syndrome is autosomal dominant, as the vast majority of reported cases are attributable to de novo heterozygous variants. The lack of parental history further underscores the sporadic nature of these mutations. In the described studies, no additional affected relatives exhibiting segregating variants were noted, aligning with expectations for a dominantly inherited, de novo condition.

In detail, the mutation spectrum includes both missense and loss‑of‑function changes that perturb the normal function of the HNRNPK protein. The recurrent identification of variants affecting critical domains—such as the K‑homology (KH) domain—supports a mechanism of pathogenicity likely related to disruption of RNA binding and regulatory functions. The reported variant c.143T>A (p.Leu48Val) exemplifies this, given its predicted deleterious impact on a conserved residue (PMID:35422839).

Functional studies further support the association, with in silico analyses and transcript studies indicating that the altered HNRNPK protein exhibits diminished RNA binding and aberrant splicing profiles. In one multi‐patient report, a unique DNA methylation signature consistent with HNRNPK disruption was identified, bolstering the functional relevance of these variants (PMID:36130591). Although functional experiments remain somewhat limited compared to the robust genetic evidence, the experimental data available are concordant with the clinical phenotype.

Integrating both the genetic and functional evidence, it is clear that de novo variants in HNRNPK are strongly implicated in Au‑Kline syndrome. The consistency across several unrelated probands, the recurrence of variants affecting crucial domains, and the supportive molecular studies all converge to affirm this gene–disease relationship. This association not only aids in diagnostic decision‑making but also holds promise for commercial assay development and future scientific publication.

Key Take‑home: HNRNPK variants serve as a robust diagnostic marker for Au‑Kline syndrome, offering critical insights for clinical management and guiding future research directions.

References

• Frontiers in Genetics • 2022 • Case Report: Exome and RNA Sequencing Identify a Novel de novo Missense Variant in HNRNPK in a Chinese Patient With Au‑Kline Syndrome PMID:35422839
• European Journal of Human Genetics : EJHG • 2018 • Phenotypic Spectrum of Au‑Kline Syndrome: A Report of Six New Cases and Review of the Literature PMID:29904177
• American Journal of Medical Genetics. Part A • 2019 • Okamoto Syndrome has Features Overlapping with Au‑Kline Syndrome and is Caused by HNRNPK Mutation PMID:30793470

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