Description of the smallest critical region for Dandy–Walker malformation in chromosome 13 in a girl with a cryptic deletion related to t(6;13)(q23;q32)

Abstract

We report on a girl with mild dysmorphic facial features, Dandy-Walker malformation (DWM), iris coloboma, profound hearing loss, and hyperlaxity of skin and joints, whose karyotype is 46,XX,t(6;13)(q23;q32)dn and who has a cryptic imbalance at the 13q32 translocation breakpoint assessed by array-CGH. Our patient has many clinical manifestations in common with those of the previously reported cases of 13q32 deletions, which suggests that at least part of the abnormal phenotype is probably due to the imbalance. The recurrent finding of DWM among patients with 13q deletions has led to the suggestions that candidate gene/s for its development are on chromosome 13. We describe the smallest 13q deletion associated to DWM, which allows further narrowing of the previously established critical region for this brain malformation to 13q32.2-32.3. Among the few genes of the deleted region, ZIC2 and ZIC5 seem the most plausible candidates, which is in keeping with some previous reports. This work also illustrates the usefulness of array-CGH platforms in the identification of cryptic imbalances in carriers of apparently balanced rearrangements with abnormal phenotypes.

Holoprosencephaly with cerebellar vermis hypoplasia in 13q deletion syndrome: Critical region for cerebellar dysgenesis within 13q32.2q34

“…Using aCGH analysis, they narrowed down the region responsible for DWM to 13q32.2.q33.2, suggesting the involvement of ZIC2 as well as ZIC5, which is also located within this interval. Kirchhoff et al further refined the DWM-associated region to 13q32.2q33.1 [6] and Mademont-Soler et al reported a patient with the de novo interstitial deletion del(13)(q32.2q32.3) also presenting with DWM, again consistent with the hypothesis that loss of both ZIC2 and ZIC5 are required for DWM [10].…”

Postnatal diagnosis of constitutive ring chromosome 13 using both conventional and molecular cytogenetic approaches

“…Mutations of ZIC2 are frequently de novo and 70% of cases are due to deletions (Ribeiro et al, 2012), a finding that also support our results. Additional studies have indicated that ZIC2 has a pleiotropic effect and variable penetrance that may be the result of a loss of contiguous genes that in turn may influence gene expression (Mademont-Soler et al, 2010).…”

Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2

“…Heterozygous loss of both ZIC1 and ZIC2 function in humans and mice is one cause of DWM identified to date, and while cerebellar abnormalities are completely penetrant in the mouse model, DWM is variably expressed [Grinberg et al, 2004]. Of note, heterozygous deletion of both the ZIC2 and ZIC5 genes in the 13q32 deletion critical region also has been associated with DWM [Mademont-Soler et al, 2010]. …”