Exclusion mapping of the gene for X-linked neural tube defects in an Icelandic family

Abstract

Various polymorphic markers with a random distribution along the X chromosome were used in a linkage analysis performed on a family with apparently X-linked recessive inheritance of neural tube defects (NTD). The lod score values were used to generate an exclusion map of the X chromosome; this showed that the responsible gene was probably not located in the middle part of Xp or in the distal region of Xq. A further refining of these results was achieved by haplotype analysis, which indicated that the gene for X-linked NTD was located either within Xp21.1-pter, distal from the DMD locus, or in the region Xq12-q24 between DXS106 and DXS424. Multipoint linkage analysis revealed that the likelihood for gene location is highest for the region on Xp. The region Xq26-q28, which has syntenic homology with the segment of the murine X chromosome carrying the locus for 'bent tail' (Bn), a mouse model for X-linked NTD, is excluded as the location for the gene underlying X-linked NTD in the present family. Thus, the human homologue of the Bn gene and the present defective gene are not identical, suggesting that more than one gene on the X chromosome plays a role in the development of the neural tube.

Lack of mutations in ZIC3 in three families with neural tube defects

“…Pedigrees for two families, which have not been published previously, are shown in Figure 1. Although linkage studies and haplotype analysis in a third family from Iceland appear to exclude the region containing the ZIC3 gene (Xq26) [Hol et al, 1994], they were included in our studies because of the ease of sequencing the gene to provide definitive exclusion of ZIC3 as a candidate.…”

SNPs in the CpG island of NAP1L2: A possible link between DNA methylation and neural tube defects?

“…The largest of these families originated from Iceland [Jensson et al, 1988] and has been the subject of several linkage studies. One study setting a penetrance for the disorder at 70% suggested that Xq12‐q24, which coincides with the localization of NAP1L2 , was one of two regions that cosegregates in the family [Hol et al, 1994]. However, the other study, in which exclusively 100% penetrance for expression of the phenotype was considered, failed to detect linkage—possibly due to the small number of available carriers/affected individuals and a lack of informative markers [Newton et al, 1994].…”

Non‐multifactorial neural tube defects

“…There have been a number of reports describing anencephaly in families with an X‐linked pattern of inheritance [Baraitser and Burn, 1984; Toriello, 1984; Jensson et al, 1988]. Some of the families studied did not show linkage to 62 markers on the X chromosome suggesting that the susceptibility gene maps elsewhere on one of the autosomes [Hol et al, 1994; Newton et al, 1994]. The other syndromic causes are either sporadic conditions or those with unknown inheritance, and include Axelrod syndrome, Diprosopus, hemihypertrophy‐hemihypaesthesia‐hemiareflexia‐scoliosis, Medeira syndrome, meroanencephaly, schisis association, and XK‐aprosencephaly.…”