Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia.

Subcortical band heterotopia (SBH) comprises part of a spectrum of phenotypes associated with classical lissencephaly (LIS). LIS and SBH are caused by alterations in at least two genes: LIS1 (PAFAH1B1) at 17p13.3 and DCX (doublecortin) at Xq22.3-q23. DCX mutations predominantly cause LIS in hemizygous males and SBH in heterozygous females, and we have evaluated several families with LIS male and SBH female siblings. In this study, we performed detailed DCX mutation analysis and genotype-phenotype correlation in a large cohort with typical SBH. We screened 26 sporadic SBH females and 11 LIS/SBH families for DCX mutations by direct sequencing. We found 29 mutations in 22 sporadic patients and 11 pedigrees, including five deletions, four nonsense mutations, 19 missense mutations and one splice donor site mutation. The DCX mutation prevalence was 84.6% (22 of 26) in sporadic SBH patients and 100% (11 of 11) in SBH pedigrees. Maternal germline mosaicism was found in one family. Significant differences in genotype were found in relation to band thickness and familial vs sporadic status.

Incomplete penetrance with normal MRI in a woman with germline mutation of the DCX gene.

X-linked isolated lissencephaly sequence (ILS) and subcortical band heterotopia are allelic human disorders associated with mutations of the DCX gene in both familial and sporadic forms. The authors describe a large Sardinian family in which three brothers with ILS have a missense mutation of the DCX gene. Their mother, a nonmosaic carrier, has a normal phenotype and cranial MRI. Skewed X-inactivation in the lymphocytes was also ruled out. This is the first report of an asymptomatic carrier of a DCX mutation likely due to apparent nonpenetrance.

The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene.

Lissencephaly is a cortical malformation secondary to impaired neuronal migration resulting in mental retardation, epilepsy and motor impairment. It shows a severity spectrum from agyria with a severely thickened cortex to posterior band heterotopia only. The LIS1 gene on 17p13.3 encodes a 45 kDa protein named PAFAH1B1 containing seven WD40 repeats. This protein is required for optimal neuronal migration by two proposed mechanisms: as a microtubule-associated protein and as one subunit of the enzyme platelet-activating factor acetylhydrolase. Approximately 65% of patients with isolated lissencephaly sequence (ILS) show intragenic mutations or deletions of the LIS1 gene. We analyzed 29 non-deletion ILS patients carrying a mutation of LIS1 and we report 15 novel mutations. Patients with missense mutations had a milder lissencephaly grade compared with those with mutations leading to a shortened or truncated protein (P = 0.022). Early truncation/deletion mutations in the putative microtubule-binding domain resulted in a more severe lissencephaly than later truncation/deletion mutations (P < 0.001). Our results suggest that the lissencephaly severity in ILS caused by LIS1 mutations may be predicted by the type and location of the mutation. Using a spectrum of ILS patients, we confirm the importance of specific WD40 repeats and a putative microtubule-binding domain for PAFAH1B1 function. We suggest that the small number of missense mutations identified may be due to underdiagnosis of milder phenotypes and hypothesize that the greater lissencephaly severity seen in Miller-Dieker syndrome may be secondary to the loss of another cortical development gene in the deletion of 17p13.3.