Background information about genetics

A person’s genotype is their unique sequence of DNA. More specifically, this term is used to refer to the two forms a person has inherited from their mother and father, for a particular gene. Their phenotype is the observable expression of their genotype and results from the interaction between the genotype and their environment.

Haploinsufficiency is the situation that occurs when one copy of a gene is inactivated or deleted and the remaining functional copy of the gene is not adequate to produce the needed gene product to preserve normal function

A person has two copies of each gene, one inherited from their mother and one from their father. If a condition is described as dominant a person will show signs of a condition if they have one faulty and one normal gene. If the condition is described as recessive someone with one faulty and one normal gene will appear normal. A person needs to have 2 faulty copies of the gene (one from each parent) to show signs of a recessive condition. A person with one faulty gene for a recessive condition is called a carrier – they are normal but have a 50% risk of passing on the faulty gene in each pregnancy.

A null variant of a gene is one which does not perform the expected function.

A truncating variant of a gene is one which results in a shortened version of a protein being produced.

A presence-absence variation (PAV) is an extreme form of structural variation in a genomic segment containing one or more genes is present in some individual but absent in others.

A domain is a segment of DNA that is associated with a particular function.

A proband is the first person in a family to be identified as having a particular genetic disorder.

A variant of unknown significance (VAS) is a genetic variant that has been identified on genetic testing but whose significance to the functioning or health of a person is not known. i.e. is not clear whether the variation seen is responsible for the differences seen in the individual or whether it is just a chance finding

A pathogenic variant is one which causes disease

What causes Kleefstra Syndrome

EHMT1 is a gene found on chromosome 9. A mutation in this gene or a deletion of a specific region of chromosome 9 that includes EHMT1 leads to Kleefstra Syndrome.

EHMT1 produces Histone Methyltransferase 1. This is an enzyme which controls the activity of other genes involved in the development and function of organs and tissues throughout the body.

An enzyme is a biological catalyst, almost always a protein, which speeds up a chemical reaction within a cell.

Kleefstra syndrome (KLEFS1) is a rare, autosomal dominant neurodevelopmental disorder caused by pathological EHMT1 variants affecting multiple organ systems.

KLEFS1 is caused by EHMT1 Haploinsufficiency.

Most cases of KLEFS 1 are sporadic. This means that the mutation or deletion is new to the affected person and not passed on from a parent. However a person with KS has a 50% chance of passing the condition on with each pregnancy.

RESEARCH

Rots et al., Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome, The American Journal of Human Genetics (2024) https://doi.org/10.1016/j.ajhg.2024.06.008

After nearly 20 years of research this paper summarises the current knowledge of Kleefstra syndrome.

Summary

They assessed 209 individuals with a rare EHMT1 variant, did detailed laboratory tests and computer modelling. As result they classified 191 of the individuals as having, or being likely to have, Kleefstra syndrome. This has enabled the authors to update the clinical spectrum of Kleefstra Syndrome, including some individuals with normal intelligence and some familial cases.

They describe several variants of EHMT1 which have differing functional consequences and so lead to a broad clinical spectrum for KLEFS 1.

Introduction to the paper

They describe the key features of Kleefstra Syndrome. These are moderate to severe intellectual disability and/or global developmental delay, autistic spectrum disorder (ASD), characteristic facial features and multisystem involvement

The most common facial features are:
Microcephaly (small head)
Synophrys (eyebrows meeting in the centre of the face)
Mildly upslanting palpebral fissures (the outer corner of the eye is higher than the inner corner)
Midface hypoplasia (relative underdevelopment of the centre of the face)
Coarse facies (loss of the fine features of mouth, nose, lips chin and brows)
Protruding tongue
Relative prognathism (prominent lower jaw – like Jimmy Hill)

Other associated clinical conditions and congenital anomalies include:
Hypothyroidism
Feeding difficulties in infancy
Obesity
Cardiac defects
Skeletal anomalies including scoliosis (abnormal sideways bend to spine)

What they did

To get details on molecular structure in KLEFS1 they collected samples from individuals with likely or confirmed KLEFS1, including rare variants. They also assessed material from other individuals with other neurodevelopmental disorders, and individuals with genetic defects whose significance was not known. Almost half of the patients came from their extensive local database, the rest from collaborators in other countries.

What they found

209 individuals from 200 independent families with a rare genetic variation involving EHMT1 were studied. The researchers identified 6 different categories of variation of the EHMT 1 gene which resulted in KLEFS1.

Of the 209 individuals identified, 18 were thought to have benign variants or variants of unknown significance leaving 191 for full genetic analysis. After exclusion of individuals for whom no detailed phenotype data was available and those with a second diagnosis that was thought to contribute to their phenotype a detailed comparison of phenotype and genotype was performed on the remaining 125 individuals. 58/125 of these patients came from The Netherlands.

The genetic variants in the 125 individuals included in the detailed genotype-phenotype were:

The researchers provide a detailed analysis of the phenotype associated with each group of genetic variants. They assessed differences in prevalence of the more common (present in >25% of individuals) clinical features between the different genetic variations and found that for some (intellectual disability, Global developmental delay, constipation and abnormal heart structure) this was statistically significant.

Individuals with multi-gene deletions had a higher prevalence of most of the features associated with KLEFS1. In particular they were more likely to show severe intellectual disability, be constipated and have short stature, but for the majority of features this did not reach statistical significance.

Those with PAVs had a lower prevalence of learning disability, feeding difficulties and structural heart problems than those with isolated EHMT1 null variants

Individuals with N-terminal truncating variant had a milder phenotype with a significantly higher IQ and lower prevalence of intellectual disability. Also constipation and feeding difficulties were not noted in this group.

The study identified families in whom a variant of EHMT1 which causes KLEFS1 was found to be inherited from a parent. In each case the parent was diagnosed after the diagnosis of the offspring. All but one of the affected parents had mild intellectual disability or global developmental delay.

The table below is copied from the paper. It summaries the clinical features associated with each of the genetic variants of KLEFS1:

They have also

GDD = global developmental delay

What this paper adds to what we know already

To date this is the largest group of individuals with Kleefstra syndrome (KLEFS1) be studied. The researchers used clinical analysis, laboratory testing and computer modelling. By identifying the study population initially from genetic data rather than from clinical features they have shown that the features of KLEFS1 are more varied than had previously been thought. Whilst most of the individuals have moderate to severe intellectual disability some individuals with normal intellectual ability were identified. In contrast to a previously published study this paper shows that some behavioural and psychiatric disorders previously described in adolescents do also occur in childhood. Constipation has been shown to be more prevalent than previously thought.

They have classified several different genetic variants which cause the syndrome and described the clinical features associated with each variant. The authors discuss the how the genetic variants identified may affect the production or function of EHMT1 and thus lead to the clinical features of KLEFS1

A number of inherited cases of KEFS1 have also been identified.

They have used their new data to re-calculate the prevalence (number of existing cases) of KLEFS1 to be approximately 1:36,000.

This paper provides up to date clinical and molecular information about KLEFS1 almost 20 years after its discovery.

Rots et al., Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes, The American Journal of Human Genetics (2024) https://doi.org/10.1016/j.ajhg.2024.06.009

This is a technically complicated paper which looks at Kleefstra Syndrome Type 2.

Haploinsufficiency of the gene KMT2D has recently been recognised as a cause of neurodevelopmental disorder (NDD) which has been designated Kleefstra Syndrome Type 2. As yet little is known about the clinical and molecular spectrums of this disorder. This study investigated 98 individuals with rare KMT2C variants. They used data from 81 individuals with pathogenic/likely pathogenic variants to describe the clinical problems associated with KMT2D-related NDD. Photographs of 34 of these individuals were used for a detailed analysis of the associated facial features. This work enabled to researchers to conclude that KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes thus highlighting tee ed to rename this condition.

The table below is copied from the paper. It summarises the clinical features of KMT2C-related NDD (Kleefstra Syndrome Type 2).