Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy

Abstract

Autosomal recessive cerebellar ataxia (ARCA) is a group of neurological disorders characterized by degeneration or abnormal development of the cerebellum and spinal cord. ARCA is clinically and genetically highly heterogeneous, with over 20 genes involved. Exome sequencing of a girl with ARCA from non-consanguineous Dutch parents revealed two pathogenic variants c.37G4C; p.D13H and c.946A4T; p.K316* in CWF19L1, a gene with an unknown function, recently reported to cause ARCA in a Turkish family. Sanger sequencing showed that the c.37G4C variant was inherited from the father and the c.946A4T variant from the mother. Pathogenicity was based on the damaging effect on protein function as the c.37G4C variant changed the highly conserved, negatively charged aspartic acid to the positively charged histidine and the c.946A4T variant introduced a premature stop codon. In addition, 27 patients with ARCA were tested for pathogenic variants in CWF19L1, however, no pathogenic variants were identified. Our data confirm CWF19L1 as a novel but rare gene causing ARCA. European Journal of Human Genetics (2016) 24, 619-622; doi:10.1038/ejhg.2015.158; published online 22 July 2015 INTRODUCTIONAutosomal recessive cerebellar ataxia (ARCA) is a group of rare, genetically and clinically heterogeneous neurological disorders affecting both the peripheral and central nervous systems, mainly occurring in children and young adults. 1 Clinical manifestations range from progressive cerebellar syndromes, as a key feature, to spinocerebellar symptoms with spasticity, ophthalmoplegia, sensory/motor neuropathy, involuntary movements, seizures, cognitive impairment, skeletal abnormalities and cutaneous disorders. To date, more than 20 genes have been reported to cause ARCA, however, explaining only 40% of cases. 2 Recently, pathogenic variants were described in a novel gene (CWF19L1) in two siblings with autosomal recessive ataxia syndrome. 3 Here, we report a second case, a girl from non-consanguineous Dutch parents, with cerebellar ataxia and atrophy, who was compound heterozygous for pathogenic variants in the CWF19L1 gene. Our results confirm the suggested role of CWF19L1 in rare cases of autosomal recessive cerebellar ataxia.

Exome sequencing reveals a novel CWF19L1 mutation associated with intellectual disability and cerebellar atrophy

“…The novel mutation c.467delC leads to a frameshift starting at amino acid 156 (shown by a red arrow) which results in a putative premature stop codon at amino acid 189 (marked by an red asterisk). The location of the mutations reported by Burns et al [] and Nguyen et al [] is indicated by black arrows. The c‐terminal parts of C19L1 against which the antibodies are raised are indicated by a blue or grey box (antibodies HPA036890 and PA5‐31646, respectively).…”

“…The advent of next‐generation sequencing technologies has facilitated the discovery of novel genes. Very recently, biallelic mutations in CWF19L1 (complexed with cdc5 protein 19‐like 1) were reported in two families with early onset cerebellar ataxia and cognitive impairment [Burns et al, ; Nguyen et al, ]. CWF19L1 knockdown in a zebrafish model leads to abnormal cerebellar morphology and function [Burns et al, ].…”

A comprehensive strategy for exome-based preconception carrier screening

“…11,12 Standard filter steps were location (exonic and canonical splice, the latter defined as ≤2 nucleotides intronic), sequencing depth/reads (≥8), and zygosity (homozygous variants removed). Variably applied filter steps were amino acid alteration (synonymous variants removed), annotation in databases (HGMD and/or ClinVar), allele frequency (dbSNP <5% versus <1%), mutation type (frameshift, nonsense, splice site, missense), presence of identical variants in both partners of the couple, presence of variants in the same genes in both partners of the couple, and presence of variants in genes included in gene panels.…”

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

“…For family MR106 with a CWF19L1 homozygous variant and family MR90 with a TUSC3 homozygous variant, seizures were observed in some family members. Seizure has not been previously reported as a feature of CWF19L1- and TUSC3- related ARID (Burns et al 2014; Nguyen et al 2016; Evers et al 2016; Garshasbi et al 2008, 2011; Khan et al 2011; Loddo et al 2013; Al-Amri et al 2016). Interestingly TUSC3 belongs to the same gene family as ALG3 , which is associated with congenital disorders of N-linked glycosylation that commonly include seizures as a feature (Table 1; Garshasbi et al.…”

“…Unless indicated, these variants were absent in 194 unrelated Pakistani exomes with non-cognitive Mendelian phenotypes and in ~ 1000 unrelated individuals in the GME Variome Project. References per known gene: ALG3 (Riess et al 2013); ASPM (Kousar et al 2010); BCKDK (Novarino et al 2012); CRADD (Di Donato et al 2016; Harel et al 2017); CWF19L1 (Burns et al 2014; Nguyen et al 2016; Evers et al 2016); CYB5R3 (Ewenczyk et al 2008); GAN (Kuhlenbäumer et al 2002; Tazir et al 2009); LRP2 (Vasli et al 2016); MBOAT7 (Johansen et al 2016); MLYCD (Salomons et al 2007); PNKP (Shen et al 2010); SPTBN2 (Lise et al 2012); TUSC3 (Garshasbi et al 2008, 2011; Khan et al 2011; Loddo et al 2013; Al-Amri et al 2016); WDR62 (Wang et al 2017). …”