NRK – Sotos syndrome

In a single case study of a patient with Sotos syndrome (PMID:21834033), comprehensive genomic analysis revealed an 862 kb deletion at Xq22.3 that encompasses NRK along with several other genes. This patient exhibited an atypical Sotos syndrome presentation marked by severe developmental delay, joint hypermobility, and hyperextensible skin. Although classical Sotos syndrome is most commonly linked to NSD1 anomalies, the additional deletion suggests that NRK may contribute to a marfanoid-hypermobility phenotype in select cases. The deletion was inherited from a healthy mother, which is consistent with an X‑linked mode of inheritance and may indicate a reduced penetrance in females. As only this single proband has been reported, and the segregation evidence is limited to this case, the overall gene–disease association for NRK in the context of Sotos syndrome is considered to be of limited strength.

Functional evidence for NRK’s involvement is also minimal. While NRK is known to belong to the glucokinase subfamily and is implicated in activating the JNK pathway—important for skeletal muscle development—there are no direct functional studies confirming its pathogenicity in Sotos syndrome. The experimental data thus far are preliminary and underscore the need for replication and further functional assays. Taken together, the limited genetic and experimental data suggest a cautious clinical interpretation. Key take‑home: Although the involvement of NRK in Sotos syndrome is supported by mechanistic clues, further studies are needed before this association can be broadly applied in the clinic.

References

• American journal of medical genetics. Part A • 2011 • Marfanoid hypermobility caused by an 862 kb deletion of Xq22.3 in a patient with Sotos syndrome PMID:21834033

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