Intellectual disabilityGene: CWF19L1
Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Created: 25 Feb 2019, 5:42 p.m.
Comment on publications: Added PMID:30167849 Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability Santos-Cortez et.el, (2018)
Created: 25 Feb 2019, 5:38 p.m.
Biallelic pathogenic variants in CWF19L1 cause Spinocerebellar ataxia, autosomal recessive 17 (MIM 616127).
Burns et al. (2014 - PMID: 25361784) report on 2 sibs born to consanguineous parents, homozygous for a splice site variant (NM_018294.5:c.964+1G>A). Congenital ataxia with hypoplasia of vermis and cerebellar hemispheres and ID were features reported in both in this study.
Clinical details on this family were published previously (Yapici and Eraksoy - PMID: 15981765) where ID appeared to be a feature for one of the sibs (FSIQ of 68) but not the other (IQ of 90) [the sibs seem to correspond to patients 5 and 6 from the third family of the original report].
Expression in patient lymphoblastoid cell lines was reduced using expression micro-arrays and quantitative reverse-transcription PCR.
The variant was shown to lead to skipping of exon 9. Introduction of an out-of-frame stop codon (thus NMD) may explain mRNA levels.
Western blot using epitope spanning exons 5-7 demonstrated absence (in patient but not in control LCLs) of the 2 protein bands expected based on this epitope. [A shorter isoform due to downstream alternative start site would not be detectable].
Using commercial normal tissue brain lysates revealed only the canonical protein band suggesting that this is the isoform present in brain.
Morpholino knockdown of cwf91l1 in zebrafish resulted in altered cerebellar staining (/structure) and abnormal motor behavior.
Nguyen et al. (2016 - PMID: 26197978) report on a further individual with ID, ataxia and abnormal cerebellum (extensive discussions whether this represents hypoplasia/atrophy) compound heterozygous for a missense (NM_018294.4:c.37G>C / p.Asp13His) and a nonsense variant (c.946A>T / p.Lys316*).
mRNA expression in patient fibroblasts was similar to control while cDNA sequence analysis was suggestive of lower levels for the r.946A>U transcript (compared to r.37G>C) possibly due to NMD.
Evers et al. (2016 - PMID: 27016154) report on a further individual, born to consanguineous parents, homozygous a frameshift variant (NM_018294.5:c.467delC or p.Pro156Hisfs). This individual presented with ID, ataxia and similar cerebellar anomalies.
cDNA of 3 different regions of CWF19L1 suggested tht mRNA was not entirely degraded by NMD. Western blot demonstrated absence of a band corresponding to the longest isoform in patient LCL cells. [All isoforms discussed in Fig3].
A subsequent pregnancy of the same couple was terminated due to presence of additional fetal anomalies possibly not explained by homozygosity (only) for this variant which was confirmed (cerebellar measurements were in the the low-normal range and morphology reportedly normal).
In ClinVar additional variants have been submitted as pathogenic/likely pathogenic (although a phenotype is not specified for all).
CWF19L1 is not associated with any phenotype in G2P.
This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).
As a result CWF19L1 can be considered for inclusion in this panel probably as green (rather than amber).
Created: 31 Dec 2018, 12:29 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Spinocerebellar ataxia, autosomal recessive 17 (MIM 616127)
Variants in this GENE are reported as part of current diagnostic practice
Gene: cwf19l1 has been classified as Green List (High Evidence).
Phenotypes for gene: CWF19L1 were changed from Spinocerebellar ataxia, autosomal recessive 17, 616127; intellectual disability to Spinocerebellar ataxia, autosomal recessive 17, 616127; intellectual disability, developmental delay
Publications for gene: CWF19L1 were set to 25361784; 15981765; 26197978; 27016154
Phenotypes for gene: CWF19L1 were changed from Spinocerebellar ataxia, autosomal recessive 17, 616127 to Spinocerebellar ataxia, autosomal recessive 17, 616127; intellectual disability
Publications for gene: CWF19L1 were set to 25361784
Phenotypes for gene: CWF19L1 were changed from Spinocerebellar ataxia, autosomal recessive 17 (MIM 616127) to Spinocerebellar ataxia, autosomal recessive 17, 616127
gene: CWF19L1 was added gene: CWF19L1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: CWF19L1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CWF19L1 were set to 25361784 Phenotypes for gene: CWF19L1 were set to Spinocerebellar ataxia, autosomal recessive 17 (MIM 616127) Penetrance for gene: CWF19L1 were set to Complete Review for gene: CWF19L1 was set to GREEN gene: CWF19L1 was marked as current diagnostic