Somatic and Germline Mosaic Mutations in the doublecortin Gene Are Associated with Variable Phenotypes

Abstract

Mutations in the X-linked gene doublecortin lead to "double cortex" syndrome (DC) in females and to X-linked lissencephaly (XLIS) in males. Because most patients with DC and XLIS are sporadic, representing de novo doublecortin mutations, we considered that some of these patients could be somatic or germline mosaics. Among a population of 20 patients and their families, we found evidence for mosaic doublecortin mutations in 6 individuals. Germline mosaicism was identified in two unaffected women, each with two affected children. Additionally, one affected male with DC was found to be a somatic mosaic, which presumably spared him from the more severe phenotype of lissencephaly. The high rate of mosaicism indicates that there may be a significant recurrence risk for DC/XLIS in families at risk, even when the mother is unaffected.

Failed Clearance of Aneuploid Embryonic Neural Progenitor Cells Leads to Excess Aneuploidy in theAtm-Deficient But Not theTrp53-Deficient Adult Cerebral Cortex

“…Although sex chromosome aneuploidy (DeLisi et al, 1994;Samango-Sprouse, 2001) and X chromosome mosaicism (Gleeson et al, 2000;Samango-Sprouse, 2001) have been specifically linked to neurological disease, the mechanism through which XY mosaicism affects normal or pathological brain function is not clear. Altered levels of XY aneuploidy as a reflection of overall aneuploidy can, however, direct further study of the neurodevelopmental parameters that shape overall aneuploidy.…”

Inheritance of most X‐linked traits is not dominant or recessive, just X‐linked

“…Yet muscle fibers are multinucleated syncytia that might be expected to follow different rules than the norm. In our own studies, we X-linked recessive Males are affected almost exclusively Transmission occurs through unaffected or carrier females to their sons Male-to-male transmission is not observed Affected males are at risk of transmitting the disorder to their grandsons through their obligate carrier daughters X-linked dominant Daughters of affected males always inherit the disorder Sons of affected males never inherit the disorder Affected females can transmit the disorder to offspring of both sexes An excess of affected females exists in pedigrees for the disorder found a high frequency of post-zygotic mosaicism in heterozygous mothers of children with mutations of either of the known X-linked lissencephaly genes, DCX [Gleeson et al, 2000;Matsumoto et al, 2001] and ARX (W.B. Dobyns, unpublished data).…”

Genetics and mechanisms leading to human cortical malformations

“…De novo mutations show a higher proportion of nonsense and frameshift changes, and are likely therefore to lead to a more severely perturbed protein [98]. Indeed, maternal germline or somatic mosaicism may explain the difference between sporadic SBH and XLIS in males [39,95,100]. The 10% of SBH patients showing no DCX mutations are likely to have mutations in other genes such as TUBA1A or occasionally LIS1 [101,102].…”