Biomedical subjects
Publications and source records attributed to J Goodship.
We report five children from three families who presented with bilateral choanal atresia associated with a spectrum of additional malformations including cardiac defects, deafness, defects of the external ear, eyes and eye lids and a characteristic dysmorphic appearance. The children were of normal intelligence. This syndrome is distinct from CHARGE association.
It is well established that DiGeorge syndrome (DGS) may be associated with monosomy of 22q11-pter. More recently, DNA probes have been used to detect hemizygosity for this region in patients with no visible karyotypic abnormality. However, DGS has also been described in cases where the cytogenetic abnormality does not involve 22q11; for instance, four cases of 10p- have been reported. In this study we have prospectively analyzed patients, by using DNA markers from 22q11, to assess the frequency of 22q11 rearrangements in DGS. Twenty-one of 22 cases had demonstrable hemizygosity for 22q11. Cytogenetic analysis had identified interstitial deletion in 6 of 16 cases tested; in 6 other cases no karyotype was available. When these results are combined with those from our previous studies, 33 of 35 DGS patients had chromosome 22q11 deletions detectable by DNA probes.
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A 2 year old girl presented with developmental delay and subtle dysmorphic features suggestive of Wolf-Hirschhorn syndrome (WHS). High resolution chromosome analysis was normal in the child and both parents. Molecular analysis indicated that the child had not inherited a maternal allele of probes from 4p16, confirming the clinical diagnosis. Prenatal diagnosis in the next pregnancy showed that again the fetus had no maternal allele for probes mapping to 4p16. Fluorescent in situ hybridisation in the mother showed a submicroscopic translocation, t(4;10). A normal karyotype in a child with clinical features of WHS is an indication for further investigation.
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder with no clinical or immunologic abnormalities in carrier females. The defective gene has been localized to proximal Xp. Carrier females have nonrandom use of the X chromosome in granulocytes, lymphocytes, and monocytes. We have used the probe M27 beta, which detects both a variable number tandem repeat polymorphism and methylation differences between the active and inactive X chromosome, in the investigation of families referred for genetic counseling. M27 beta detects the locus DXS255, which is tightly linked to WAS. As the probe that is used for investigation of X-inactivation patterns is also linked to the disease locus, it is possible to assign phase in families where this could not be done by conventional use of linked probes. The mothers of four isolated male cases had nonrandom use of the X chromosome. A new mutation was identified in one family with two affected males.
In order to gain information about the nature of the defect in X-linked severe combined immunodeficiency (XSCID), we investigated gene expression in different lymphoid and haematopoietic cells of female carriers by looking for non-random X chromosome usage. We have shown non-random X chromosome usage in T lymphocyte enriched (E+) fraction in all carriers. E- cells and monocytes showed non-random X chromosome usage in three carriers tested. In the B cell series one carrier showed non-random inactivation in all EBV lines tested (10) and the same X chromosome was shown to be active in all cells. In other carriers there was a preference for use of the normal X chromosome but some B cell lines used the mutant X as well as the normal X. Similar results were found with granulocytes. In two female carriers DNA made directly from whole blood showed a non-random pattern of X chromosome usage. In fibroblast cultures from two female carriers more cells had the normal gene on the active X chromosome than had the defective gene on the active X chromosome. Within families there was heterogeneous expression of the gene. The gene that is defective in XSCID is expressed in all the cell types studied and, therefore, is not a T lymphocyte differentiation gene. The results are consistent with the gene being in a metabolic pathway as in certain autosomal recessive forms of SCID i.e. adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency.
We describe a three generation family with three females showing minor features of orofaciodigital syndrome type I and a severely affected male in the third generation. In addition to the classical features of OFD I, the male had bilateral duplication of the halluces, a feature diagnostic of OFD II, and an atrioventricular septal defect. Heart defects have not previously been reported in OFD I but have been reported in OFD II. It is important to examine the mothers of all male neonates with orofaciodigital syndrome with care before making a diagnosis of OFD II.
We present a male infant with cranial hemi-hypertrophy, a lymphangioma, a lipoma, and epidermal naevi. A diagnosis of Proteus syndrome was made. His father had had a large lymphangioma resected from the right side of the face as a child. We propose that Proteus syndrome has been transmitted from father to son.
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Hypohidrotic ectodermal dysplasia has been mapped to Xq11-q13 by linkage studies and by a translocation in a manifesting female. We report a family with hypohidrotic ectodermal dysplasia in which the disease did not segregate with this region of the X chromosome as expected. Ten DNA probes which are localised between Xp11 and Xq22 were used in the investigation. The difficulties in diagnosing the carrier state in this condition and the possibility of non-allelic heterogeneity are discussed.
We present a linkage map of DNA probes around the X-linked severe combined immunodeficiency (IMD4) locus at Xq11-13. DXS159 and PGK1 show no cross-overs with the disease locus (Lod 3.01 at theta = 0.00). The order of loci is DXS1-DXS106-(DXS159-PGK1-IMD4)-DXS72 -DXYS1. Members of families whose carrier status has been established by X-inactivation patterns were included in the analysis. As the probe (pSPT/PGK), which is used for investigation of X-inactivation patterns, has been shown to be linked to the disease itself, it is possible to assign phase in mothers of sporadic cases who have been shown to be carriers, even when they have no surviving male offspring.
Analysis of X chromosome inactivation in T-lymphocyte DNA from two obligate carriers of X-linked severe combined immunodeficiency showed a non-random pattern. This method was then used to establish carrier status in at-risk females in X-linked pedigrees. It was further used to differentiate between X-linked and autosomal recessive inheritance of the disease when the mode of inheritance was not clear from the pedigree. In addition, a mother of a boy affected by the sporadic form of the disease was found to have non-random X inactivation in her T lymphocytes and she is therefore a carrier of the X-linked disease.
S21 (DXS17) and pXG12 (DXS94), two probes linked to the locus of X-linked agammaglobulinaemia (XLA), were used for genetic prediction in 13 such families. A method of allowing for nonallelic genetic heterogeneity was demonstrated in the calculation of the genetic risks, specifying a certain proportion of unlinked families. We further estimated the impact due to the uncertainty of the proportion of unlinked families on the final genetic risks in each family and this can be taken into account during genetic counselling.
In August 1985 we instituted a carrier and prenatal testing service for Duchenne muscular dystrophy (DMD) using direct DNA analysis. The experience over the first nine months is described. We have analysed samples for RFLPs from 154 people including 53 women at risk of being DMD carriers from 37 families. We used the probes pERT87.8 (BstXI and TaqI polymorphisms), 87-15 (TaqI polymorphism), and pXJ1.1 (TaqI polymorphism). Forty-one of the women have had their risks altered. We found one deletion (pERT87-8) out of 23 DNA samples analysed from affected boys. We used a recombination fraction of 0.05 in risk calculations but did not detect any known crossovers. In nine of the families there is only an isolated case of DMD. In families where we have not been able to alter the risk of the women being a carrier (for example, because all brothers are dead), we have offered prenatal exclusion and have carried out one first trimester prenatal diagnosis on this basis. Lowering the risk of an affected fetus to less than 2.5% appears to be a satisfactory situation for many (most) of the women involved and seems to justify the introduction of genetic prediction based on single intragenic probes despite the 5% recombination frequency.
Twenty-nine patients with Apert's syndrome were ascertained through hospital records. The mean age was 19.3 years (range eight to 35 years). Further information was obtained on their intelligence, education, and employment records. Fourteen patients (48%) had a normal or borderline IQ (greater than 70), nine patients (31%) were mildly mentally retarded (IQ 50 to 70), four patients (14%) were moderately retarded (IQ 35 to 49), and two patients (7%) were severely retarded (IQ less than 35). Early craniectomy did not appear to improve intellectual outcome. Six of the seven school leavers with normal or borderline intelligence were in full time employment or vocational training.
We describe a family in which an X-chromosome deletion is segregating with choroideremia, and X-linked recessive condition. The DNA sequences DXYS1 and DXS3, defined by the probes pDP34 and 19.2 respectively, are absent in the affected male (who is also mentally retarded), and hemizygous in his mother and in his carrier sister, who presented early in pregnancy. Analysis of chorionic villus DNA formed the basis of prenatal exclusion of choroideremia in her male fetus. In three female relatives, studied with late-labelling techniques, the deleted X was preferentially inactivated in 86-100% of cells studied. This family confirms the localisation of the choroideremia locus to within Xq13----21, and places the loci for anhidrotic ectodermal dysplasia and the X-linked immunodeficiencies outside this region.
Type IX collagen represents 5-20% of the total collagen in hyaline cartilage. The molecules of this collagen are composed of three genetically distinct polypeptide subunits. One of these subunits, alpha 2(IX), contains covalently bound glycosaminoglycan (chondroitin sulfate or dermatan sulfate). We report here on the structure of the glycosaminoglycan attachment site of type IX collagen-proteoglycan. We show, by a combination of cDNA and peptide sequencing, that the attachment region contains the sequence Gly-Ser-Ala-Asp, located within the noncollagenous domain NC3 of the alpha 2(IX) chain. By comparing the exons encoding the NC3 domain in the alpha 2(IX) and alpha 1(IX) genes, we find that the exon coding for the glycosaminoglycan attachment site in the alpha 2(IX) gene is 48 base pairs long, whereas the homologous alpha 1(IX) exon is 33 base pairs. The NC3 domain is, therefore, five amino acid residues longer in alpha 2(IX) than in alpha 1(IX). The extra sequence in alpha 2(IX), Val-Glu-Gly-Ser-Ala, provides a simple explanation for the kink observed at the NC3 domain of type IX molecules when examined by electron microscopy. The inserted block of amino acid residues also provides the NC3 domain of alpha 2(IX) chains with a serine residue, not present in alpha 1(IX) that serves as attachment site for a glycosaminoglycan side chain. Our data show that the amino acid sequence that surrounds the glycosylated serine residue in type IX collagen-proteoglycan differs from glycosylated sequences in noncollagenous core proteins. The data also provide strong evidence that glycosylation of type IX collagen is not a chance glycosylation of a serine residue in a noncollagenous domain, but is a specific post-translational modification of this unusual collagen molecule.