New clinical study from Boston Children’s Hospital expands the picture of Kleefstra Syndrome

An important study from Kleefstra Syndrome Clinic at Boston Children’s Hospital offers one of the most detailed clinical pictures of Kleefstra Syndrome to date and attempts to answer a question that has concerned families and researchers for years. Can the type of genetic variation be related to how the syndrome manifests?;

The work titled Novel Phenotypes and Genotype–Phenotype Correlations in a Large Clinical Cohort of Patients With Kleefstra Syndrome published in the scientific journal Clinical Genetics and was based on the retrospective review of medical records of 65 individuals with genetically confirmed Kleefstra syndrome, which had been evaluated at the specialized Kleefstra Clinic of Boston Children’s Hospital.

The mean age of the participants was 9.3 years, with ages ranging from about 10 months to 35 years. The study included 40 women and girls and 25 men and boys. About two-thirds of the sample were aged 11 years or younger.

Three different genetic groups

The researchers divided the participants into three groups based on the genetic cause of the syndrome.

The 54%, meaning 35 individuals, had a pathogenic or likely pathogenic sequence variant in EHMT1 (genetic alteration within the EHMT1 gene itself)*.

The 29%, meaning 19 individuals, had a small deletion in the 9q34 region, smaller than 1 Mb.

The 17%, that is, 11 individuals, had a larger 9q34 deletion, equal to or greater than 1 Mb.

This separation allowed researchers to examine not only which features appear in Kleefstra, but also whether some of them are more frequent depending on the genotype.

*The 54%, meaning 35 individuals, had a pathogenic or likely pathogenic genetic variant within the EHMT1 gene itself. Simply put, the gene was present, but its DNA sequence had changed in a way that could disrupt its normal function. This differs from cases involving 9q34 deletion, where a large portion of chromosome 9 is missing, including the EHMT1 gene and possibly other neighboring genes.

What was recorded in the 65 patients

As expected, neurodevelopmental manifestations constituted a significant part of the clinical picture.

A developmental delay or intellectual disability had been documented in the 77% of the participants, while an autism spectrum disorder in the 38%.

He had epilepsy 15%, while a smaller but significant percentage, approximately 9%, had drug-resistant epilepsy.

Aside from the neurodevelopmental characteristics, problems from other systems were also frequently recorded. Structural heart defects were present in 40%, hearing loss in 32% and constipation at 31%. The hyperechoicity was observed at 78% in the entire sample.

These percentages are very useful for better describing the syndrome, but they require careful interpretation. These data come from the medical records of 65 individuals who were followed at a specialized center and do not represent a prevalence study of the general population of individuals with Kleefstra syndrome.

A subgroup with the most significant mobility difficulties

One of the characteristics highlighted by the study was the existence of a subgroup of individuals with significant motor dysfunction.

The researchers defined a significant motor dysfunction as a case in which a child at least two years old had not yet learned to walk independently or had begun walking independently at the age of three or later.

With this definition, 15 of the 62 individuals for whom suitable data were available—approximately 24%—belonged to this group.

Seven children aged two years or older were not yet walking independently, while eight others had achieved independent walking after the age of three. In this second group, the average age at which children began walking independently was approximately 4.4 years, and in one case, it was as late as 9 years.

This finding is important because it highlights greater diversity in motor development than can be perceived when Kleefstra syndrome is described solely in terms of its most common characteristics.

The largest deletions appear to be associated with a heavier motor presentation

When the researchers examined the three genetic groups separately, the group of large deletions, equal to or greater than 1 Mb, presented some particularly stark differences.

In this small group of 11 individuals, significant motor dysfunction had been recorded in 75%, epilepsy in 36% and cortical visual impairment in 55%.

Only the 30% had achieved independent walking at the time of the evaluation, compared with the 100% in the group with sequence variants.

The researchers also examined the relationship between the size of the deletion and the age of independent walking.

In individuals with a deletion for whom the necessary data were available, the more known genes included in the deleted region, the later independent walking tended to be achieved.

This finding reinforces the idea that in individuals with larger deletions, the clinical picture may be influenced not only by the loss of EHMT1, but also from the simultaneous loss of neighboring genes.

This does not mean that the genotype predicts a child's future

These results are of great scientific significance, but they should not be used as an individual prognosis.

A child with a deletion is not certain to present with epilepsy, significant motor impairment, or cortical visual impairment. Similarly, a sequence variant does not guarantee a milder clinical picture.

Correlations describe differences between groups and not the course of a specific person.

This is particularly important in a syndrome with such great phenotypic diversity as Kleefstra.

There is also a milder end of the spectrum

Another interesting finding of the study is that the cognitive profile was not the same in all participants.

Four individuals had an IQ in the low average range, and one individual had an IQ within the average normal range.

And the these five individuals had sequence variants in EHMT1 and not 9q34 deletions.

The number is too small to draw definitive conclusions. Nevertheless, the finding is important because it contributes to expanding the known phenotypic spectrum of Kleefstra and indicates that there may also be individuals with a clearly milder cognitive profile.

Drug-resistant epilepsy and specifically epileptic syndromes

Epilepsy was present in a total of 15% of the group, but the researchers also identified a smaller subgroup with a more complex picture.

Six of the 65 individuals, approximately 9%, had drug-resistant epilepsy, meaning the seizures were not controlled despite a trial of at least two appropriately chosen antiepileptic drugs.

Five individuals had a history of infantile spasms and two had a diagnosis Lennox-Gastaut syndrome.

The authors point out that cases of infantile spasms had been reported in Kleefstra in the past, while the presence of Lennox-Gastaut had not been a well-recognized association with the syndrome until then.

And caution is required here, too. Two incidents are not enough to establish Lennox-Gastaut as a feature of Kleefstra, but they raise a question that can now be examined in larger patient series.

New and lesser-known features

The study also recorded some very rare findings that had not been well described in Kleefstra.

Two people presented eye movements similar to opsoclonus. In these specific cases, screening for opsoclonus-myoclonus syndrome was negative, and the movements resolved over time.

Two people had thrombocytopenia.

A person developed progressive cerebral atrophy.

Another person had been diagnosed with adrenocortical carcinoma.

These findings are interesting precisely because they may lead to new research questions. However, they should not be considered newly established features of Kleefstra syndrome.

When a finding appears in one or two individuals, we cannot know whether it is truly related to the syndrome or if it is a coincidental event.

And the heart remains an important part of the picture

Structural heart abnormalities had been recorded in 40% of the study's total sample.

It is interesting to note that in the group with large deletions, the percentage reached 82%, compared to 37% in the group with smaller deletions and 29% in the group with sequence variants. However, when the two deletion groups were combined and compared with the sequence variants, the difference—53% versus 29%—did not reach the threshold for statistical significance. The researchers also identified three individuals with cardiac conduction disorders and refer to the latest data on arrhythmias and atrial fibrillation in Kleefstra syndrome. The picture that emerges, therefore, is that cardiac involvement in Kleefstra syndrome is not necessarily limited to congenital structural abnormalities.

What we should keep from the study

This specific work confirms once again that Kleefstra Syndrome it does not have a single clinical picture.

At the same time, however, it adds something very important. Phenotypic diversity appears to be, at least to some degree, related to the type of genetic change.

In this specific clinical cohort, individuals with 9q34 deletions more frequently presented with developmental delay or intellectual disability, significant motor impairment, epilepsy, and cortical visual impairment compared to individuals with sequence variants in EHMT1.

These data do not yet allow us to accurately predict the trajectory of a specific child from their genetic result.

However, they bring us one step closer to a more personalized understanding of Kleefstra Syndrome, where we do not simply know that there is a loss of EHMT1 function, but we examine what exact genetic variation is present and how it may be connected to the clinical picture.

This is important both for the better monitoring of individuals with Kleefstra today and for the design of future natural history studies, biomarkers, and therapeutic interventions.