Research Explained: Clinical and molecular results in 15 Turkish patients with Wiedemann‑Steiner syndrome

Research Explained: Clinical and molecular results in 15 Turkish patients with Wiedemann‑Steiner syndrome: identification of eight novel KMT2A variants and a case of dual molecular diagnosis in the CSNK2A1 gene

Authors: Maahin Manzoor Khan, MBBS, CSNK2A1 Foundation Intern

Written by: Gabrielle Rushing, PhD, CSNK2A1 Foundation Chief Scientific Officer

Research Explained Summary

Wiedemann-Steiner syndrome (WSS) is a rare genetic disorder that affects multiple systems of the body, primarily characterized by its impact on development and growth. It is inherited in an autosomal dominant pattern, which means that a single altered copy of the responsible gene is sufficient to cause the condition. However, it is crucial for families to understand that the vast majority of individuals diagnosed with WSS are the first and only members of their family to have the condition (called a de novo genetic change). This is the same inheritance pattern observed in OCNDS. Changes in the KMT2A gene were discovered to be disease-causing in 2012, just 4 years prior to the discovery of OCNDS.

In this study, the clinical and molecular characteristics of 15 unrelated Turkish WSS patients with 8 novel KMT2A variants were evaluated, expanding on the molecular spectrum of the syndrome with new clinical diversity. Additionally, in one patient they found a de novo pathogenic variant in the CSNK2A1 gene associated with Okur-Chung Neurodevelopmental Syndrome (OCNDS) in an individual with WSS.

The individual with OCNDS had a novel frameshift variant in the KMT2A gene, confirming a diagnosis of WSS as well as a pathogenic splice site variant (c.510+1G>A) in the CSNK2A1 gene, confirming a second diagnosis of OCNDS.

The diagnostic challenge emerges due to significant symptom overlap between WSS and OCNDS as many neurodevelopmental disorders have overlapping clinical presentations. The dual diagnosis patient exhibited a mosaic of features characteristic of both conditions, including developmental delay, microcephaly, hypotonia, and many shared facial traits like hypertelorism, ptosis, and a broad nasal bridge. This makes a distinction based on physical examination alone nearly impossible.

This case emphasizes the power of modern genetic diagnostics in determining two diagnoses for a patient that would not be feasible based on symptom presentation alone. 

Given the broad phenotypic variability in such genetic disorders, making a diagnosis based solely on clinical features is often challenging. In this context, whole exome sequencing (WES) significantly facilitates the diagnostic process. Serving as the ultimate testament to the indispensable role of comprehensive genetic testing in modern medicine.