Electroclinical Features of Epilepsy in Kleefstra Syndrome

Abstract

Background Kleefstra syndrome (KS) or 9q34.3 microdeletion syndrome (OMIM #610253) is a rare genetic condition featuring intellectual disability, hypotonia, and dysmorphic facial features. Autism spectrum disorder, severe language impairment, and sleep disorders have also been described. The syndrome can be either caused by a microdeletion in 9q34.3 or by pathogenic variants in the euchromatin histone methyltransferase 1 gene (EHMT1, *607001). Although epilepsy has been reported in 20 to 30% of subjects, a detailed description of epileptic features and underlying etiology is still lacking. The purpose of this study is to investigate epilepsy features in a cohort of epileptic patients with KS.

Methods This multicenter study investigated eight patients with KS and epilepsy. Our findings were compared with literature data.

Results We included five patients with 9q or 9q34.33 deletions, a subject with a complex translocation involving EHMT1, and two with pathogenic EHMT1 variants. All patients presented with moderate to severe developmental delay, language impairment, microcephaly, and infantile hypotonia. Although the epileptic manifestations were heterogeneous, most patients experienced focal seizures. The seizure frequency differs according to the age of epilepsy onset, with patients with early-onset epilepsy (before 36 months of age) presenting more frequent seizures. An overtime reduction in seizure frequency, as well as in antiseizure drug number, was observed in all patients. Developmental delay degree did not correlate with seizure onset and frequency or drug resistance.

Conclusion Epilepsy is a frequent finding in KS, but the underlying pathogenetic mechanism and specific features remain elusive.

Keywords

Kleefstra syndrome - epilepsy - seizures - electroencephalogram - neurodevelopmental disorder - EHMT1

Note

This work was developed within the framework of the DINOGMI Department of Excellence of MIUR 2018–2022 (law 232/2016). IRCCS Istituto Giannina Gaslini is a full member of ERN EpiCARE.

Data Availability Statement

The data that support the findings of this study are reported in the manuscript.

^* T.G. and R.C. contributed equally to this work.

Publikationsverlauf

Eingereicht: 11. Juni 2023

Angenommen: 12. September 2023

Artikel online veröffentlicht:
06. Oktober 2023

• References

• 1 Kleefstra T, Smidt M, Banning MJ. et al. Disruption of the gene euchromatin histone methyl transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome. J Med Genet 2005; 42 (04) 299-306
• 2 Kleefstra T, Brunner HG, Amiel J. et al. Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am J Hum Genet 2006; 79 (02) 370-377
• 3 Stewart DR, Kleefstra T. The chromosome 9q subtelomere deletion syndrome. Am J Med Genet C Semin Med Genet 2007; 145C [phone]
• 4 Aydin H, Bucak IH, Bagis H. Kleefstra syndrome. J Coll Physicians Surg Pak 2022; 32 (04) S76-S78
• 5 Kleefstra T, van Zelst-Stams WA, Nillesen WM. et al. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet 2009; 46 (09) 598-606
• 6 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 7 Ciaccio C, Scuvera G, Tucci A. et al. New insights into Kleefstra syndrome: report of two novel cases with previously unreported features and literature review. Cytogenet Genome Res 2018; 156 (03) 127-133
• 8 Anderlid BM, Schoumans J, Annerén G. et al. Subtelomeric rearrangements detected in patients with idiopathic mental retardation. Am J Med Genet 2002; 107 (04) 275-284
• 9 Dawson AJ, Putnam S, Schultz J. et al. Cryptic chromosome rearrangements detected by subtelomere assay in patients with mental retardation and dysmorphic features. Clin Genet 2002; 62 (06) 488-494
• 10 Okur V, Nees S, Chung WK, Krishnan U. Pulmonary hypertension in patients with 9q34.3 microdeletion-associated Kleefstra syndrome. Am J Med Genet A 2018; 176 (08) 1773-1777
• 11 Noruzinia M, Ahmadvand M, Bashti O, Salehi Chaleshtori AR. Kleefstra syndrome: the first case report from Iran. Acta Med Iran 2017; 55 (10) 650-654
• 12 Quigley DI, Kaiser-Rogers K, Aylsworth AS, Rao KW. Submicroscopic deletion 9(q34.3) and duplication 19(p13.3): identified by subtelomere specific FISH probes. Am J Med Genet A 2004; 125A (01) 67-72
• 13 Iwakoshi M, Okamoto N, Harada N. et al. 9q34.3 deletion syndrome in three unrelated children. Am J Med Genet A 2004; 126A [phone]
• 14 Frega M, Linda K, Keller JM. et al. Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling. Nat Commun 2019; 10 (01) 4928
• 15 Willemsen MH, Beunders G, Callaghan M. et al. Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions. Clin Genet 2011; 80 (01) 31-38