Background Dandy-Walker malformation features agenesis/hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of posterior fossa. Although Dandy-Walker malformation is relatively common and several genes were linked to the syndrome, the genetic cause in the majority of cases is unknown.
Objective To identify the mutated gene responsible for Dandy-Walker malformation, kidney disease and bone marrow failure in four patients from two unrelated families.
Methods Medical assessment, sonographic, MRI and pathological studies were used to define phenotype. Chromosomal microarray analysis and whole-exome sequence were performed to unravel the genotype.
Results We report four subjects from two unrelated families with homozygous mutations in the Exocyst Complex Component 3-Like-2 gene (EXOC3L2).EXOC3L2 functions in trafficking of post-Golgi vesicles to the plasma membrane. In the first family a missense mutation in a highly conserved amino acid, p.Leu41Gln, was found in three fetuses; all had severe forms of Dandy-Walker malformation that was detectable by prenatal ultrasonography and confirmed by autopsy. In the second family, the affected child carried a nonsense mutation, p.Arg72*, and no detected protein. He had peritrigonal and cerebellar white matter abnormalities with enlargement of the ventricular trigones, developmental delay, pituitary hypoplasia, severe renal dysplasia and bone marrow failure.
Conclusion We propose that biallelic EXOC3L2 mutations lead to a novel syndrome that affects hindbrain development, kidney and possibly the bone marrow.
- dandy walker malformation
- bone marrow failure
- renal failure
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AS and SL are co-primary authors.
AS and SL contributed equally.
Contributors AS and SL performed research, analysed data and wrote the paper. ZL, HB, AA, YH, MM, DH, SE, BJ, SH and NS contributed and analysed data, reviewed the manuscript. SD and HM performed research and analysed data, reviewed the manuscript. SSS provided critical control data, reviewed and edited the manuscript. SZ: contributed and analysed data, reviewed and edited the manuscript. YD: designed research, oversaw the project, analysed data and wrote the paper.
Funding The study was supported by grants from the Canadian Institutes of Health Research, funding references 286737(YD) and by the Adler Chair For Pediatric Cardiology, Sackler School of Medicine (MS).
Competing interests None declared.
Patient consent Not required.
Ethics approval Research Ethics Board, The Hospital for Sick Children, Toronto, Canada.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it was published online first. The name of author Stephen W Scherer has been corrected.
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