Linkage to chromosome 2q36.1 in autosomal dominant Dandy-Walker malformation with occipital cephalocele and evidence for genetic heterogeneity

Abstract

We previously reported a Vietnamese-American family with isolated autosomal dominant occipital cephalocele. Upon further neuroimaging studies, we have recharacterized this condition as autosomal dominant Dandy-Walker with occipital cephalocele (ADDWOC). A similar ADDWOC family from Brazil was also recently described. To determine the genetic etiology of ADDWOC, we performed genome-wide linkage analysis on members of the Vietnamese-American and Brazilian pedigrees. Linkage analysis of the Vietnamese-American family identified the ADDWOC causative locus on chromosome 2q36.1 with a multipoint parametric LOD score of 3.3, while haplotype analysis refined the locus to 1.1 Mb. Sequencing of the five known genes in this locus did not identify any protein-altering mutations. However, a terminal deletion of chromosome 2 in a patient with an isolated case of Dandy-Walker malformation also encompassed the 2q36.1 chromosomal region. The Brazilian pedigree did not show linkage to this 2q36.1 region. Taken together, these results demonstrate a locus for ADDWOC on 2q36.1 and also suggest locus heterogeneity for ADDWOC.

Fig. 1

Representative occipital cephalocele (a) and MRI abnormalities (b–f) from the Vietnamese-American ADDWOC family. a Photograph of occipital cephalocele from individual II-8. b T1 post-contrast sagittal MRI of individual III-3. Note small and upwardly rotated cerebellar vermis and markedly enlarged fourth ventricle and posterior fossa. c Parasagittal T1 MRI of individual II-4, who was originally identified as an obligate carrier. Note skull defect and occult occipital cephalocele (arrow). d Mid-sagittal T1 MRI of individual II-4. Note cerebellar vermal hypoplasia and mildly enlarge fourth ventricle. e T1 sagittal MRI of individual I-2, who was originally identified as an obligate carrier. Note cerebellar vermal hypoplasia and mildly enlarged cisterna magna. f T1 sagittal MRI of individual II-2. Note mild cerebellar vermal hypoplasia. Arrowheads in b, c, d, and f point to the protrusion of occipital lobe through the tentorial notch

Fig. 2

Pedigree of the Vietnamese-American ADDWOC family. Generation number is listed along the left margin, and individuals are numbered underneath each symbol. Thus, the proband (indicated by an asterisk) corresponds to individual III-8. Solid-shaded large symbols correspond to affected members. The smaller shaded symbol represents a spontaneously aborted fetus. Only the affected individuals (except I-3, I-4, and III-7) were included in the linkage analysis

Fig. 3

Genome-wide linkage analysis of the Vietnamese-American ADDWOC family. a Plot of multipoint parametric LOD scores across the autosomes demonstrates a single ADDWOC-linked locus on chromosome 2 with a significant LOD score of 3.30. b Higher magnification of the locus on chromosome 2 depicts the markers with significant LOD scores. Closed triangles are one or two nearby SNP markers with dbSNP rs numbers given next to them. S1 and A1 markers are novel SNPs in SGPP2 and ACSL3

Fig. 4

Haplotype analysis of the ADDWOC locus in the Vietnamese-American pedigree. SNP markers are listed along the left margin, and under each individual the corresponding alleles are listed. The two alleles for each SNP are represented by numbers 1 and 2. A1 allele 2 and S1 allele 2 are the newly discovered variants. The ancestral haplotype containing the ADDWOC affection locus is noted by the closed box. Chromosomal recombinations during meioses leading to individuals II-3, III-3, and III-8 narrowed the ADD-WOC haplotype, as noted by the smaller box in those individuals

Fig. 5

Features of the ADDWOC locus. Chromosome 2 idiogram is depicted on the left and the 2q36.1 region is magnified to its right. Positions of SNP markers and genes are marked along this region. There ADDWOC locus is limited by rs724149 proximally and rs1371552 distally. There are 5 identified genes and 2 pseudogenes (NANOGP2 and LOC653773) in the ADDWOC locus, and PAX3 is located 107 kb outside the locus. Positive and negative strand genes are depicted on the right and left, respectively

Fig. 6

MRI of isolated Dandy-Walker patient with deletion overlapping ADDWOC locus. a T1 sagittal MRI demonstrates enlarged cisterna magna and cerebellar vermal hypoplasia. b G-banded partial karyotype of chromosome 2 homologs in this patient shows the normal homolog (left) and the deleted homolog (right) next to a chromosome 2 ideogram. The double arrow points to the deletion breakpoint in band 2q36.1 on both the idiogram and deleted chromosome 2. The formal karyotype is: 46,XY,del(2)(q36.1→qter) [12]/46,XY[18]