Journal of Medical Genetics

Cox, D W; Wills, D E; Quan, F; Ray, P N

doi: 10.1136/jmg.25.10.649pmid: 3225819

Apolipoprotein CII Toronto is a mutant non-functional apo CII resulting in apo CII deficiency. A portion of the mutant apo CII gene was cloned into lambda gt10 and subclones were sequenced. A deletion of one base was found in the codon for amino acid Thr68, resulting in alteration of six amino acids and premature termination of the protein at amino acid 74.

Taylor, R; Jeenah, M; Seed, M; Humphries, S

doi: 10.1136/jmg.25.10.653pmid: 2906372

We have studied four different restriction fragment length polymorphisms (RFLPs) for the LDL receptor gene, detected using the restriction enzymes StuI, PvuII, ApaLI, and NcoI, in normal subjects and in patients with familial hypercholesterolaemia (FH) from London. Significant linkage disequilibrium was detected between all four RFLPs. Used together they give a polymorphism information content (PIC) of greater than 0.7 which makes them useful for studying the inheritance of the LDL receptor gene in more than 70% of families with FH. The NcoI and ApaLI RFLPs were found to be the most useful, giving a combined PIC value of 0.6. The allele frequencies of all four polymorphisms were compared in the normal and FH groups and the frequency of the rarer N2 allele of the NcoI RFLP was found to be significantly higher in the FH group. This suggests that a mutation has occurred on the rare NcoI N2 allele and that it may be making a significant contribution to the defects causing FH in this patient group. We have also used these RFLPs to look for evidence that variation at the LDL receptor gene locus contributes to the determination of cholesterol levels in the normal population. People with different RFLP genotypes do not have significantly different levels of serum total or LDL cholesterol. At present we have no evidence that variation at this locus may be determining cholesterol levels in the non-FH population.

Wells, R A; Wonke, B; Thein, S L

doi: 10.1136/jmg.25.10.660pmid: 3225820

DNA fingerprinting was performed to verify the pedigree structure of a family under investigation for an unusual case of beta thalassaemia. A higher than expected proportion of hypervariable bands was shared by the proband and his mother, leading to suspicion that the child had been the product of a consanguineous mating. Further analysis of the mother's brother showed that he was almost certainly the proband's father.

Jeanpierre, M

doi: 10.1136/jmg.25.10.663pmid: 3225821

Calculation of carrier risk of an X linked disease may be performed on a small computer after DNA analysis, but a method for rapid hand estimation of the risk is still useful for a quick check of the results and weighing the relative importance of each element of information, such as the determination of a haplotype. Each risk estimation is a function of a prior risk and the product of likelihood ratios and these terms are derived themselves from parameters such as fitness or the relative mutation rate in male and female gametes. Even if it is often difficult to have strong experimental estimation of these variables, the existence of a normal father or grandfather must be considered whenever male fitness is not null. The likelihood ratio for a woman for not being a carrier, when her father is not affected and her mother has herself a likelihood R for not having the mutated gene, may be expressed as the ratio 2R/(CmR + 1), with Cm being a function of male fitness and relative mutation rate. Cm represents the odds ratio for the mother of a carrier not to be a carrier, given that the father of the known carrier is not affected. This formula can be used recurrently and reduces to 2R/(R + 1) in lethal X linked disease. When likelihood ratios are expressed as an algebraic function, maximum values are easily determined, hence fixing the limits of DNA analysis.

Roberts, A G; Elder, G H; Newcombe, R G; Enriquez de Salamanca, R; Munoz, J J

doi: 10.1136/jmg.25.10.669pmid: 3225822

The concentration of immunoreactive uroporphyrinogen decarboxylase has been measured in erythrocytes from 17 patients with porphyria cutanea tarda (PCT) from 10 families, from 74 of their relatives, and from 47 control subjects. The 10 families were divided into two groups according to their erythrocyte enzyme concentrations. Group A contained four families in which at least two subjects had overt PCT. All members of these families, including seven patients with overt PCT, had normal erythrocyte uroporphyrinogen decarboxylase concentrations and activities. Apart from their family history, patients in group A were clinically and biochemically indistinguishable from cases of type I (sporadic) PCT. Group B contained six families with the only previously described form of familial PCT (type II PCT) in which decreased erythrocyte uroporphyrinogen decarboxylase segregates as an autosomal dominant trait. These findings show that familial PCT is heterogeneous and suggest that inheritance contributes to the pathogenesis of at least some cases of type I PCT.

Krause, A; Lane, A B; Jenkins, T

doi: 10.1136/jmg.25.10.677pmid: 3225823

A South African Afrikaans speaking family is reported in which a new high activity plasma cholinesterase variant was found to occur in the mother and son. The variant has the same electrophoretic mobility as the "usual' enzyme, but greater heat stability. Its higher specific activity is associated with a normal number of enzyme molecules. The variant may be inherited as a dominant trait, though its locus is uncertain.

Looij, B J; te Slaa, R L; Hogewind, B L; van de Kamp, J J

doi: 10.1136/jmg.25.10.682pmid: 3225824

Hereditary osteo-onychodysplasia (HOOD, nail-patella syndrome) is an autosomal dominant condition characterised by nail dysplasia, patellar hypoplasia or aplasia, and nephropathy. The risk for HOOD patients to have a child with HOOD who will develop renal failure cannot easily be deduced from published pedigrees. We have studied a large family with 30 patients with HOOD and have analysed 34 kindreds with HOOD nephropathy from published reports, comprising 213 patients. For a patient with HOOD from a family in which HOOD nephropathy occurs, the risk of having a child with HOOD nephropathy is about 1:4; the risk of having a child in whom renal failure will develop is about 1:10.

Raas-Rothschild, A; Goodman, R M; Meyer, S; Katznelson, M B; Winter, S T; Gross, E; Tamarkin, M; Ben-Ami, T; Nebel, L; Mashiach, S

doi: 10.1136/jmg.25.10.687pmid: 3066902

A second family with the autosomal recessive disorder now referred to as the limb/pelvis-hypoplasia/aplasia syndrome is reported. It is speculated that the gene for this rare skeletal dysplasia may be confined to the Middle East gene pool. The disorder has been shown to be diagnosable prenatally in a pregnancy at risk by using ultrasonography.

Hodge, S E; Van Dyke, D C; Goldman, A S; Heide, F; Hill, R; Zmijewski, C M

doi: 10.1136/jmg.25.10.698pmid: 3225825

During investigation of HLA types among children exposed to diphenylhydantoin (DPH) in utero, we found no evidence of a distortion in haplotype sharing among affected sib pairs. Unexpectedly, however, we found a marked increase in the proportion of all sib pairs (not just affected ones) sharing maternal haplotypes. Among 14 two child families, 12 shared the maternal haplotype (expected would be seven); among families with more than two children the distortion was also pronounced. This finding, if verified in future studies, could indicate that something in the mothers, whether DPH use during pregnancy, or some genetic factor associated with seizures, or some effect of the seizures themselves, may be leading to non-random segregation of HLA haplotypes in their offspring.

Fryns, J P; Chrzanowska, K

doi: 10.1136/jmg.25.10.703pmid: 2906373