Helen Middleton-Price

A gene for FG syndrome maps in the Xq12-q21.31 region

FG syndrome is an X-linked recessive condition in which mental retardation is associated with congenital hypotonia, macrocephaly, characteristic face, and constipation. This syndrome was mapped by Zhu et al. [Cytogenet Cell Genet 1991;58:2091A] to Xq21.31-q22 by linkage analysis with a max lod score of 1.2 for the DXYS1X, DXS178, DXS101, and DXS94 loci and crossovers at DXS16 (Xp22.31) and DXS287 (Xq22.3). However, this mapping was only provisional and needed to be refined. In this paper, we report the results of a new linkage analysis performed on 10 families including that studied by Zhu et al. [1991]. Two-point analysis demonstrated linkage with DXS441 (Zmax = 3.39 at theta = 0.12) at Xq13. In addition, separate analysis of the lod scores obtained for the Xq13 markers suggested linkage exclusion for three families. Genetic heterogeneity was confirmed by analysis of the linkage results with the HOMOG program (max logL = 4.07, theta = 0, alpha = 0.65). Localization of one FG gene between DXS135 and DXS1066 was suggested by analysis of crossovers found in those three families which were assumed to be linked to Xq13 with a probability of 0.95 or more. This region could be reduced to the DXS135-DXS72 interval after combining our data with those from deletions previously described in males in the Xq13-q21 region.

Carrier determination for X-linked agammaglobulinemia using X inactivation analysis of purified B cells

We report the development of a relatively quick and simple method for the assessment of X inactivation status for carrier determination in families affected by X-linked agammaglobulinemia (XLA). This method utilises an immunomagnetic separation technique for B cell purification and a polymerase chain reaction (PCR) based assay for the determination of methylation status at the androgen receptor (AR) gene locus to assess whether X inactivation is random or non-random at this locus. We report the results we have obtained using this assay to investigate females known to be carriers of various X-linked immunodeficiency disorders. In addition, we investigated four females from different families affected by XLA, two of whom were of unknown carrier status, and we discuss the results obtained with this and other X-inactivation assays. A similar assay has recently been described by Allen et al. (1992) and applied to members of one family affected by XLA.

Identification of deletions in the btk gene allows unambiguous assessment of carrier status in families with X-linked agammaglobulinaemia.

Mutations within thebtk gene have recently been shown to cause X-linked agammaglobulinaemia (XLA). Altered patterns of DNA restriction fragments are seen by Southern blot analysis of DNA from affected patients with deletions in thebtk gene. We have identified seven affected families in which altered restriction fragments can be used to diagnose and confirm the carrier status of female relatives of affected boys and in prenatal diagnosis.

Physical mapping identifies DXS265 as a useful genetic marker for carrier detection and prenatal diagnosis of X-linked agammaglobulinemia

The gene responsible for X-linked agammaglobulinemia (XLA) has not been identified; however, in the course of genetic linkage studies designed to map the locus more precisely, a number of closely linked polymorphic loci have been identified. These have proved to be useful in identifying carriers and in pre-natal diagnosis of this disease. The DXS178 locus was found to be closest to the XLA locus and has been the most usefully employed probe to date. Using physical mapping techniques, we have identified a previously cloned genetic marker, DXS265, as being situated within 5kb of DXS178. So far, we have found one family that is not informative for DXS178 but that is informative for DXS265; females in this family can now be offered the possibility of carrier determination and pre-natal diagnosis for this life-threatening disease.

The major cystic fibrosis mutation in a British population

SummaryWe have studied 72 families with at least one child with cystic fibrosis (CF); they were referred because they had requested pre-natal diagnosis in a future pregnancy. The ΔF508 mutation was found in 108/140 CF chromosomes (77%). In 41/72 families (57%), both parents carried a deleted chromosome and the child was doubly deleted. In only 4 families, 2 of them being consanguineous, did neither parent carry a deleted chromosome. Meconium ileus was associated with children who were ΔF508/ΔF508, ΔF508/non-deleted and non-deleted/ non-deleted.