A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring

Abstract

The euchromatic histone-lysine N-methyltransferase 1 (EHMT1) gene was examined in a 3-year-old boy with characteristic clinical features of Kleefstra syndrome. Sequencing of all 27 EHMT1 exons revealed a novel mutation, NM_024757.4:c.2712 þ 1G4A, which affects the splice donor of intron 18. Whereas the index patient is heterozygous for that mutation, his phenotypically normal mother shows tissue-specific mosaicism. Sequencing of EHMT1 RT-PCR products revealed two aberrant transcript variants: in one variant, exon 18 was skipped; in the other, a near-by GT motif was used as splice donor and intronic sequence was inserted between exons 18 and 19. Both transcript variants were found in the patient and his mother. The latter had lower amounts of these transcripts consistent with mosaic status. This is the first description of an EHMT1 point mutation being inherited from a parent with verified mosaicism. The constitutive c.2712 þ 1G4A splice site mutation in EHMT1 is fully pathogenic, and the transcript variants produced do not attenuate the severity of the disease.

A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors

“…One previous report identified a splice variant that was present as a mosaic in the mother (Rump et al. ). Within limits of our PCR sensitivity, we saw no evidence of mosaic genotypes in AH's mother or father, although we did not test multiple tissues.…”

“…In all other reports, the EHMT1 mutations appear de novo (Rump et al. ). Here, we report a distinct de novo splice site mutation in a 27‐year‐old patient with the characteristic features of Kleefstra syndrome, as well as the previously reported regression that began in this patient about age 23.…”

New Insights into Kleefstra Syndrome: Report of Two Novel Cases with Previously Unreported Features and Literature Review

“…EHMT1 mutations are responsible for 20-25% of KS diagnoses [Kleefstra et al, 2015]. Missense, nonsense, frameshift, and splicing mutations have all been described [Kleefstra et al, 2006;Rump et al, 2013]. Intragenic deletions, detected by multiplex ligation-dependent probe amplification, have been estimated as the causes of approximately 4% of KS diagnoses in children with a pathognomonic phenotype but no observable cytogenetic anomalies [Kleefstra et al, 2006].…”

Hypogonadotropic Hypogonadism and Kleefstra Syndrome due to a Pathogenic Variant in the EHMT1 Gene: An Underrecognized Association

“…The variant destroys a canonical splice donor site and likely leads to a truncated protein [8]. EHMT1 is expressed in multiple tissues including the brain, eyes, male embryonic germ cells, epididymis, ovary, heart, and aorta [9].…”