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Methylation signatures in clinically variable syndromic disorders: a familial DNMT3A variant in two adults with Tatton-Brown–Rahman syndrome

European Journal of Human Genetics volume 31, pages 1350–1354 (2023)Cite this article

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Tatton-Brown–Rahman syndrome (TBRS; OMIM #615879) is a rare overgrowth and intellectual disability (ID) syndrome caused by heterozygous loss-of-function variants in the DNMT3A gene. Other characteristic features include obesity and a distinctive facial appearance, including a round or long face, thick, horizontal eyebrows, narrow palpebral fissures and prominent upper incisors. Furthermore, psychiatric and behavioral problems, joint hypermobility, kyphoscoliosis, urogenital, cardiovascular issues and seizures have been reported [1,2,3]. Heterozygous pathogenic DNMT3A variants have been reported in about 100 TBRS cases, the vast majority being children. They include pathogenic missense, frameshift, splice site and nonsense variants as well as microdeletions. Most of the variants were found to be de novo, although rare cases of transmission from a less affected or mosaic parent were reported and showed autosomal dominant inheritance [1,2,3,4,5]. On the other hand, germline gain-of-function variants in this gene have been implicated in microcephalic dwarfism (OMIM #618724). The DNMT3A gene encodes for DNA methyltransferase 3 alpha. It is a key player in epigenetic programming by de novo methylation maintenance, essential for genome regulation and development. Pathogenic loss-of-function variants in DNMT3A have also been described as prevalent drivers in clonal hematopoiesis and adult hematological malignancies such as acute myeloid leukemia (AML) and are suggested to have a proliferative advantage in hematopoietic progenitor cells by epigenetic changes. Thus, aberrant methylation, amongst others caused by DNMT3A variants, appears to be an important contributing factor in cancer development [6, 7]. Overgrowth syndromes involve a heterogeneous group of disorders in which height, head circumference and/or weight are more than 2 standard deviations above the mean (>+2.0 SD). Often such syndromes, like other syndromic or neurodevelopmental disorders, present with overlapping clinical characteristics and sometimes molecular findings remain inconclusive, hampering a straightforward clinical diagnosis and management. Extensive clinical phenotyping and the use of additional diagnostic tools, including those for functional validation of genetic variants, are therefore crucial. An increasing number of genetic syndromes have unique peripheral blood methylation patterns, called episignatures, which can be used for diagnostic testing and for the interpretation of ambiguous genetic results [8, 9].

To date, about 100 TBRS patients with pathogenic loss-of-function variants in the DNMT3A gene have been reported. The syndrome is characterized by postnatal overgrowth (83%) and ID (18% mild, 65% moderate and 16% severe; few cases with borderline low intelligence) and clear developmental delay. In addition, the most commonly reported features are joint hypermobility (74%), obesity (67%) and hypotonia (54%). Furthermore, behavioral and psychiatric issues have been reported in about half of cases, kyphoscoliosis in 33% and seizures in 22%. Several publications report on individuals presenting with urogenital abnormalities including cryptorchidism (11%), vesicoureteral reflux and hypospadias, brain abnormalities such as ventriculomegaly (7%) and Chiari malformation (5%) and hematological (4%) and other malignancies (5%). Finally, cardiovascular problems (10%) were reported including congenital heart defects (ASD, VSD), aortic root enlargement (3%), mitral valve prolapse and cardiomyopathy (3%). These latter were initially thought to be incidental co-occurring findings [1,2,3,4,5,6]; however, Cecchi et al. suggest an association of TBRS with aortic disease and cardiomyopathy [5].

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Fig. 1: Clinical pictures and pedigree of the two TBRS patients.
Fig. 2: EpiSign (DNA methylation) analysis of peripheral blood from the proband and his father with the p.(Arg736Cys) DNTM3A variant.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

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Acknowledgements

We thank the patients and their families for participating in this study.

Funding

No funding or financial assistance was received in support of the study.

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Authors and Affiliations

  1. Center for Medical Genetics, Ghent University Hospital, Gent, Belgium

    Candy Kumps, Erika D’haenens & Olivier M. Vanakker

  2. Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada

    Jennifer Kerkhof, Haley McConkey, Marielle Alders & Bekim Sadikovic

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  1. Candy Kumps
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  7. Olivier M. Vanakker
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Contributions

CK saw the patients, contributed to variant interpretation, and wrote the manuscript. ED contributed to data analysis and exome-based analysis. OMV saw the patients, contributed to variant interpretation, and assisted in manuscript preparation. ED was involved in exome data analysis. JK, HM, MA, and BS performed methylation studies and the EpiSign analysis.

Corresponding author

Correspondence to Candy Kumps.

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The authors declare no competing interests.

Ethical approval

Informed consent for trio-based whole exome sequencing and for the publication of clinical data and photographs were obtained from the patients. Ethical approval was not required by our ethics committee, given the fact that this research concerns a case report.

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Kumps, C., D’haenens, E., Kerkhof, J. et al. Methylation signatures in clinically variable syndromic disorders: a familial DNMT3A variant in two adults with Tatton-Brown–Rahman syndrome. Eur J Hum Genet 31, 1350–1354 (2023). https://doi.org/10.1038/s41431-023-01459-w

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