A locus for bilateral perisylvian polymicrogyria maps to Xq28

Abstract

Polymicrogyria (PMG) is one of a large group of human cortical malformations that collectively account for a significant percentage of patients with epilepsy, congenital neurological deficits, and intellectual disability. PMG is characterized by an excess of small gyri and abnormal cortical lamination. The most common distribution is bilateral, symmetrical, and maximal, in the region surrounding the sylvian fissures, and is known as "bilateral perisylvian polymicrogyria" (BPP). Most cases are sporadic, although several families have been observed with multiple affected members, usually following an X-linked inheritance pattern. Here we report the first genetic locus for BPP mapped by linkage analysis in five families. Linkage places the critical region for BPP at Xq28 (LOD score 3.08 in Xq28, distal to DXS8103 by multipoint analysis). We suggest that this region contains a gene that is necessary for correct neuronal organization and that the identification of this gene will both enhance our understanding of normal cortical development and accelerate the identification of other genes responsible for PMG.

Figure 1

Pedigrees of families included in analysis. All affected children (black symbols) have definite or probable BPP. In family LP97-096, individual LP97-096a1 (gray symbol) has a milder form of BPP as compared to her affected brother (i.e., individual LP97-096a2). MRI scans were not performed on the patients denoted by an asterisk (*).

Figure 2

MRI scans of patients LP98-002a1 and LP99-146a1, showing sagittal T1 (top) and axial T2 (bottom) images for both patients. The images show bilateral extended sylvian fissures lined by polymicrogyric cortex, showing characteristic stippling of the gray-white junction and an irregular, overfolded cortical ribbon (arrows).

Figure 3

X-chromosome haplotypes in family LP98-002. Only informative individuals are indicated. The crossovers in the affected children are labeled by an “X.” The critical region (DXS8103–Xqter) is the only region on the X chromosome that the three affected boys share.

Figure 4

Result of multipoint linkage analysis in set of five families with BPP. Real genetic distances between the markers were used to perform the calculations. For clarity purposes, only one of every five markers is indicated on the genetic distance axis. The maximum LOD score is 3.08 in the region distal to DXS8103.