Reversible white matter lesions associated with mutant EHMT1 and Kleefstra syndrome

Abstract

Kleefstra syndrome (KS; OMIM #610253), formerly known as the 9q subtelomeric deletion syndrome, is an autosomal dominant cause of intellectual disability (ID) characterized by hypotonia and facial dysmorphisms.(1,2) The cause of KS is attributed to haploinsufficiency of the euchromatin histone methyltransferase 1 (EHMT1) gene (OMIM *607001) located at chromosome 9q34.3 (i.e., distal long arm of chromosome 9), either by microdeletion or point mutation. EHMT1 encodes a histone H3 methyltransferase at position Lys-9 (H3K9).(1-3).

Figure. Genetic deletion and MRI changes with EHMT1 deletion

(A) EHMT1 gene is represented (top) with its numbered exon regions (merged into Hg19 assembly). The EHMT1 protein includes 3 important functional domains: (1) ankyrin domain, (2) pre-SET domain, and (3) SET domain. Previously published deletions restricted to the functional domains are identified. (B–I) MRI of the brain of the patient described in this study. (B–D) Axial MRI fluid-attenuated inversion recovery images of the brain with arrows pointing toward anomalies noted at 2 years of age. (E) Coronal T2 image of the brain also showing anomalous white matter signal. (F–I) Similar sequences on MRI at 6 years of age showed marked reduction of the hyperintense T2 signal in the region of the white matter anomalies previously seen at 2 years of age.