Programmpunkt

11:54–11:56

Titel: How DeepGestalt triggered WES re-analysis and led to the identification of a KANSL1 intragenic deletion causing Koolen-de Vries syndrome
ID: P-ClinG-088
Art: Postertalk
Redezeit: 2 min
Session: Poster Session
ClinG 1

Referent: Claudia Perne (Bonn/DE)


Abstract - Text

Abstract-Text

We present a fifteen-year-old girl with global developmental delay and moderate intellectual disability. She has had muscular hypotonia ­since early childhood. Brain MRI showed two heterotopic foci as well as symmetrically clumped hippocampi. The patient has a long face, slightly upslanting palpebral fissures, ptosis of the left eye, a prominent, bulbous nasal tip and low-hanging columella, pale skin with many moles and thick curly hair and a missing left upper canine tooth. Her family described her as extremely friendly, but anxious in contact with other children. Chromosome analysis, FraX diagnostics and chromosomal microarray (CMA) performed at the age of eight years were unremarkable.


The Gestalt Score in Face2Gene using DeepGestalt scored remarkably high for Koolen-de Vries syndrome. Nevertheless, Sanger sequencing and MLPA of the KANSL1-gene gave normal results. We then performed trio Whole Exome Sequencing (WES) and subsequent variant calling according to the GATK best practice pipeline. Again, no pathogenic variant was detected in KANSL1 or any other gene. Only after targeted re-analysis of KANSL1 sequencing data in Integrative Genomics Viewer (IGV), we were able to detect a 4708 bp intragenic deletion comprising parts of intron 6 and exon 7 (c.1849-4611_1895del;r.spl). The deletion was verified by qPCR and could be confirmed by Sanger sequencing using adjusted primers. The variant was absent in the parents; hence, it is highly likely that this variant occurred de novo in the patient.


Koolen-De Vries syndrome (OMIM # 610443) is caused either by recurrent heterozygous 500- to 650-kb deletions at chromosome 17q21.31 that include KANSL1 or by heterozygous intragenic pathogenic variants in KANSL1. The above-mentioned recurrent CNV usually is detected by CMA and identified in approximately 95% of patients. CMA can additionally detect smaller atypical partial deletions of KANSL1 (Koolen et al 2012, Dubourg et al. 2011, Cooper et al. 2011). However, CMA, MLPA as well as WES may miss small intragenic CNVs depending e.g. on deletion size or deletion localization as demonstrated here.


This case demonstrates the utility of Face2Gene and DeepGestalt in facilitating the diagnosis of genetic syndromes with typical facial dysmorphism and stresses the importance of accurate CNV analysis of WES and WGS data.