Titel: Deep intronic de novo germline EHMT1 variant in a patient with syndromic developmental delay
ID: P-ClinG-089
Art: Postertalk
Redezeit: 2 min
Session: Poster Session

Referent: Sophia Peters (Bonn/DE)

Abstract - Text


Pathogenic heterozygous germline variants in the EHMT1-gene cause Kleefstra syndrome 1 (OMIM # 610253), which is characterized by intellectual disability with severe expressive language delay (often without active speech), distinctive facial features and additional abnormalities, including organ malformations, seizures, and psychiatric disorders.

We present a six year old girl with developmental delay with prominent speech involvement and dysmorphic facial features (hypertelorism, hypoplastic midface, broad nasal root, short nose, anteverted nares, thin lips) that correlate well with Kleefstra syndrome. Chromosome analysis, FraX diagnostics, Angelman syndrome gene panel and MLPA, as well as chromosomal microarray were unremarkable.

Diagnostic trio whole exome sequencing and variant prioritization using phenotype data revealed a heterozygous deep intronic variant (NG_011776.1:c.2712+1866G>A) in EHMT1 in the patient; no other (likely) pathogenic variant was identified. The variant was present in 45 of 90 reads in the index; however, the variant position was covered by only two sequencing reads in the father and not covered at all in the mother. In subsequent Sanger sequencing, the variant was not found in either parent but confirmed in the patient. Hence, it is highly likely that this variant occurred de novo in the patient. In silico tools predict that this variant generates a new splice donor site. To analyze the possible splice effect of this variant, a transcript analysis using the patient"s cDNA is currently in progress.

Our findings once again stress the importance of deep intronic variants and highlight this pitfall of whole exome sequencing which can only be overcome systematically by e.g. diagnostic whole genome sequencing.