The first molecularly confirmed diagnosis of Kleefstra syndrome in Rwanda

A 15-month-old child with developmental delay and hypotonia becomes the first person in Rwanda in whom Kleefstra syndrome is molecularly confirmed. By itself, an isolated case does not change what we know about the natural history or treatment of the syndrome. The significance of this publication lies elsewhere, as it highlights the gap that still exists in access to genetic diagnosis and serves as a reminder that the geographical distribution of recorded cases of a rare condition is not necessarily its true geographical distribution.

The work titled The First Case of Kleefstra Syndrome in a Rwandan Patient with Global Developmental Delay published on April 7, 2026 in the scientific journal Genes. This is a collaboration between researchers and clinicians from University of Rwanda, the University Teaching Hospital of Kigali and the University of Liège in Belgium. According to the authors, this is the first molecularly confirmed case of Kleefstra syndrome in Rwanda and, according to their review, no such confirmed case had been previously published from East Africa.

From developmental delay to genetic diagnosis

What exome sequencing revealed

For the investigation, it was carried out trio whole-exome sequencing, meaning sequencing of the child's exome in parallel with that of both parents.

The analysis detected a heterozygous variant in the gene EHMT1:

NM_024757.5: c.2871dup; p.(Phe958Leufs*219).

This specific change adds an extra nucleotide to the sequence and shifts the reading frame of the gene, meaning it is a frameshift variant. The shift leads to the generation of a premature termination signal and, consequently, to the loss of the normal function of one copy of the EHMT1. This exact mechanism, the insufficient amount of functional EHMT1, constitutes the known molecular mechanism of Kleefstra syndrome type 1.

The variant was not detected in general population databases and, because both parents were tested simultaneously, the researchers were able to confirm that it was again, meaning it had appeared for the first time in the child and had not been inherited from either parent. Based on the ACMG criteria applied by the research team, it was classified as pathogen, molecularly confirming the diagnosis of Kleefstra syndrome. This is of particular importance because Kleefstra is not only caused by large deletions in the 9q34.3 region. About half of the molecular diagnoses involve intragenic pathogenic variants of the EHMT1, which require appropriate molecular methods to be detected. A simple karyotype, for example, cannot identify most such changes.

Why a single incident is interesting

A case report cannot tell us how common Kleefstra syndrome is in Rwanda or in Africa in general. Nor can it be used to argue that children of African descent have a different clinical presentation. The fact that this is the first published molecularly confirmed case in Rwanda it does not mean that he is also the first person with Kleefstra born or living in the country. It much more likely reflects how difficult access to specialized genetic testing is for many families.

The authors themselves note that the molecularly confirmed Kleefstra cases published from Africa are extremely few. Prior to this work, cases or data had been reported from South Africa, Egypt, and Morocco, while no confirmed case had been reported from Rwanda.

This fact does not constitute proof that the syndrome is rarer in Africa. It is rather an indication that where there is no access to genetic diagnosis, rare genetic diseases remain largely invisible.

The problem of access to genetic diagnosis

The work itself provides a particularly characteristic element. The authors state that in Rwanda there were only three geneticists for a population of about 14 million people, while a significant part of the available genetic diagnosis was based on conventional cytogenetic techniques such as the karyotype.

For Kleefstra syndrome, this constitutes a real diagnostic limitation.

The karyotype can detect large chromosomal changes, but is not suitable for detecting a small pathogenic variant such as c.2871dup found in the specific child. Even certain small deletions may require more sensitive methods. For the diagnosis of Kleefstra, techniques such as chromosomal microarray, sequencing of EHMT1, gene panels or broader sequencing approaches such as exome sequencing, depending on the clinical case.

Without access to such tests, a child may receive the general diagnosis of «developmental delay» or «intellectual disability» without the underlying genetic cause ever being identified.

And the difference is not just nominal.

The correct genetic diagnosis can guide clinical follow-up, help the family better understand the child's condition, allow for genetic counseling, and pave the way for connection with specialized centers, patient organizations, registries, and research studies.

What does the incident tell us about the syndrome itself

The clinical profile of the child was largely consistent with the already known picture of the syndrome, which includes hypotonia from infancy, significant developmental delay, motor and speech delay, and facial features. These belong to the well-documented characteristics of KLEFS1. The authors pay special attention to short stature, bilateral clinodactyly of the fifth toes, and the fact that the child did not present with obesity. These findings are of interest as part of the clinical record, but require caution in their interpretation. A single two-year-old child cannot determine whether a feature is more or less frequent in Kleefstra. Especially the absence of obesity at this age should not be considered unusual or protective, as the weight gain described in part of the Kleefstra population often concerns later stages of childhood.

Therefore, the specific case adds yet another well-documented observation to the spectrum of the syndrome, but does not redefine its phenotype.

Why does geographic diversity matter in research

There is also a second reason why such publications are valuable.

Our knowledge of rare genetic diseases is generated by people who manage to reach a diagnosis, in specialized hospitals, and ultimately in research teams. If specific countries and populations are underrepresented in genetic research, then the picture we have of a disease may disproportionately reflect populations with better access to genetic services.

In Kleefstra, where we are still trying to better understand the range of its pathogenic variants EHMT1, genotype-phenotype relationships, and the natural history at different ages, recording people from more geographic and population groups can improve the overall picture of the disease. This is also one of the reasons why the authors call for more data from different populations.