clinical genetics society · acase of turner's syndrome, detected antenatally and complicated...

Journal of Medical Genetics, 1981, 18, 218-224

Clinical Genetics SocietyAbstracts of scientific papers presented on 18 and 19 September 1980in Aberdeen

A case of X;Y translocation which maps the Xg locusto Xp24- bpterE BOYD, M A FERGUSON-SMITH,M E FERGUSON-SMITH, AND R SANGERDepartment ofMedical Genetics, Royal HospitalforSick Children, Yorkhill, Glasgow

An X;Y translocation chromosome was detected in amale fetus during prenatal diagnosis for family history ofspina bifida. The breakpoints were interpreted as Xp24and 7qll. The fetus therefore had a duplication of themajor part of the long arm of the Y chromosome, and waslacking a small region from the short arm of the X. Thetranslocation chromosome was found to be inheritedfrom the mother and was also present in a clinicallynormal sister. The pregnancy was continued and a maleinfant was born. The clinical findings, family studies, andcytogenetics are described. Studies with BUdR incorpora-tion showed that in the mother X inactivation wasrandom. The results of Xg blood grouping studiesshowed that the mother had failed to inherit the Xg locusfrom her father, indicating that this locus is situated inthe region Xp24--Xpter.

Dicentric sex chromosomesM J W FAED, M A LAMONT, AND J ROBERTSONCytogenetics Laboratory, Department ofPathology,Dundee University, Dundee

Reports are given of two girls presenting with primaryamenorrhoea. The first, aged 17, was tall with big bonestructure. She had no breast development and scantypubic and axillary hair. The cervix and uterus weresmall, there was a streak ovary on the right side, and nogonadal tissue on the left. Examination of lymphocytesand fibroblasts showed one X to be replaced by anabnormal X, consisting of two apparently intact Xchromosomes joined by their long arms with just onefunctional centromere. Cultures with BUdR showed theabnormal chromosomes to be constantly late replicating.Both parents' karyotypes appeared normal, with noabnormality on BUdR studies. The second girl was aged19 when first seen. She had had one spontaneous periodaged 14 years but none since. She was short, with no truebreast development, no axillary hair, and scanty pubichair; there was some clitoral enlargement. Laparotomyshowed normal fallopian tubes, a very small uterus, andrudimentary ovarian tissue. Chromosome analysisshowed 20% cells to be XO; the remaining 80% containeda normal X and probably an isochromosome Y. Onreattendance 8 years later, banding techniques confirmedthe presence of a dicentric Y. In view of her chromosomal

status, the gonads were removed. The right gonad wasreplaced by a dysgerminoma with abundant mitoticactivity. The left streak gonad showed no malignantchange. A course in radiotherapy was given post-operatively. Three years later, she is well with no evidenceof recurrence of the tumour.

Do satellite associations result in non-random chromatiddistribution at mitosis?D P FOX, M Y YIP, AND A WHITEHEADDepartment of Genetics, University of Aberdeen,Aberdeen, and Regional Cytogenetics Laboratory,East Birmingham Hospital, Birmingham

Satellite associations are thought to result from nucleolarformation during interphase and often appear to involvephysical connections between chromosomes at metaphase.They may be involved in the production of aneuploidgametes by causing non-disjunction at meiosis though theevidence for their involvement is ambiguous. Anotherapproach to this question is to examine their influence onchromatid distribution at mitosis in cells substituted fortwo S phases with bromodeoxyuridine and stained by theFPG technique. Satellite associations are non-random inthe sense that at the second mitosis after substitutiondark chromatids associate with dark chromatids prefer-entially (and light with light). If this preferential associa-tion influences segregation this should be reflected in adistribution of dark chromatids between cells at the thirdand subsequent divisions which differs from that predictedby the binomial theorem. The evidence to date is consistentwith random chromatid distribution and thus does notsupport the notion that satellite associations can influencechromatid segregation at cell division.

Antecedents of Down's syndrome in ShetlandA WJOHNSTON,D F ROBERTS,AND M J ROBERTSDepartment ofMedicine, Aberdeen University,Aberdeen, and Department ofHuman Genetics,Newcastle University, Newcastle-upon-TyneIn 1978 a comprehensive survey of mental subnormalityin NE Scotland was published in an attempt to establishthe extent of mental handicap in the area. Among itsmany revealing findings, it emerged that Down's syndromeshowed a curious focus of prevalence in the ShetlandIsles with 1 * 39 per 1000 population, as compared with ageneral level of 0-5 per 1000. Enquiring into this, theantecedents of all the Shetland Down's syndrome patientswere traced. The paper reports the results of the extent ofinbreeding in the patients as compared with the generalpopulation.

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Clinical Genetics Society

A family study of Charcot-Marie-Tooth disease in theEdinburgh areaA P BROOKS AND A E H EMERYDepartment of Human Genetics, University of Ediniburgh,Edinburgh

Charcot-Marie-Tooth disease is defined as those inherited,chronic, progressive, mixed but predominantly motor,peripheral neuropathies presenting with distal leg andperoneal muscle weakness and wasting and often withfoot deformity. In a family study in the Edinburgh area

the prevalence was 1 in 16 400. Cases were divided intothree genotypes on the basis of family history verified byexamination of available first degree relatives and theresults of forearm nerve maximum motor conductionvelocity: nine families had autosomal dominantdemyelinating (ADD); three families had autosomaldominant neuronal (ADN); five families had autosomalrecessive neuronal (ARN). A family with a probableX linked recessive demyelinating genotype was also seen.Analysis of clinical features showed peroneal muscleweakness to be progressive with age in the ADD genotype(r =-0 54), but to be more severe than expected for agein the ARN. Women were less severely affected than menin the ADD (and were often asymptomatic carriers), butas severely affected in ARN. Forearm nerve maximummotor conduction velocity was not found to be reliable indistinguishing clinically affected from normal in ADD, but25 of 26 otherwise normal subjects had velocities less than30 metres per second, and all affected subjects in ADN andARN had velocities greater than 40 metres per second.

Epidemiology of motor neurone disease in ScotlandS M HOLLOWAY AND A E H EMERYDepartment of Human Genetics, University of Edinburgh,Edinburgh

A study has been made of the frequency of motorneurone disease (MND) in Scotland. It would appear thatthe disease has an approximately equal frequency in allcountries of the world in which this has been measured,apart from a few areas of very high frequency, forexample, the island of Guam. In Scotland, in commonwith some other countries, the disease would appear to beincreasing in frequency. This may be because of an

increase in the accuracy of diagnosis but could possiblyreflect the frequency of some infectious agent. In thepresent investigation people resident in the north andeast of Scotland and those engaged in agriculturalwork have been found to have an increased risk ofdeveloping the disease. It is possible that MND mightresult from a persistent viral infection secondary toimpaired immune response.

A clinical and genetic survey of 200 families withcerebellar and spinocerebellar degenerationsA E HARDINGMRC Clinical Genetics Unit, Institute of Child Health,30 Guilford Street, London WCI

Clinical and family studies have been undertaken on 228index cases from 200 families with progressive cerebellar

and spinocerebellar degenerations. A further 197 subjects(living or dead) were affected with a similar disorder tothat of the index cases. Of these, 52 were seen personally,in addition to a considerable number of unaffectedrelatives. Thecases were broadly divided into the followinggroups. (1) Classical Friedreich's ataxia (90 families:autosomal recessive). (2) Cerebellar ataxia of early onset(20 families: probably autosomal recessive). (3) Hereditaryspastic paraplegia (29 families: 20 autosomal dominant,9 autosomal recessive). (4) Late onset cerebellar ataxia(11 families with autosomal dominant inheritance plus36 single cases). (5) Other syndromes (14 families).Further subdivision of these patients was possible onclinical, genetic, and statistical grounds.

Huntington's chorea in the west of ScotlandJ M W BOLTHartwood Hospital, Shotts, Scotland

Study over the last 50 years has revealed a large numberof cases throughout the country, chiefly in the west ofScotland. By late 1978, 1384 subjects with some connec-tion with the west of Scotland had been identified: over900 had always lived there, about 100 had moved in, andanother 100 moved out, while 200 relatives had alwayslived elsewhere. There were 1126 definitely affected, 204possibly affected, and at least 54 heterozygotes. Therewere 357 kindreds initially identified but further informa-tion from the families and the Registrar-General reducedthis to 284 with the possibility of further reduction to 262.Approximately 3/5 were indigenous to the west, 1/5 eachcoming from elsewhere in Scotland and the rest of theBritish Isles, with a handful from abroad. Prevalence in1965 was at least 8 6 per 100000, and if possible caseswere included 9 8 per 100 000. The mean age of onset wasabout 42 years and that at death 56-6 years. Children ofaffected fathers tended to have an earlier onset and death,but childless married women also had an earlier onset sothat this may be an artefact. Possible reasons for the lackof family history were identified in 122 'sporadic' cases.There were 151 elderly patients, with onset over 50 and/ordeath over 65, and 32 juvenile cases, with onset under20 years. The series also produced 61 patients whoappeared to be only mildly affected and 36 who weresubnormal. The relationship of psychiatric syndromes tothe appearance of chorea was noted in 207 patients.

Prenatal detection of Turner's syndrome in conjunctionwith trisomy 20 mosaicism (45,X/46,X, +-20)J L WATT, D A COUZIN, A W JOHNSTON,V JANDIAL, AND E S GRAYDepartment of Genetics, University of Aberdeen,Aberdeen

A case of Turner's syndrome, detected antenatally andcomplicated by the finding of trisomy 20 mosaicism in50% of cells from each of two amniotic fluid cultures, isdescribed. Cultures from seven fetal tissues in thesubsequent abortion revealed a predominance of 45,Xcells with a very low level of trisomy 20 mosaicism in three

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fetal tissues. The interpretation of trisomy 21 mosaicismpresents a diagnostic dilemma.

Detection of familial translocationsT ANDREWS AND E V DAVISONDepartment ofHuman Genetics, University of Newcastle,Newcastle-upon-Tyne

Familial translocations are usually ascertained throughthe birth of an abnormal child and by cytogeneticinvestigation of repeated fetal loss. Five familialtranslocations were presented, each ascertained by a

different method. Case 1. A 9;22 translocationt(9;22)(ql 1 ;q22) identified through the birth of anabnormal child. Case 2. A 3 ;7 translocationt(3;7)(pl4;q26) identified through a couple with three1st trimester spontaneous abortions. Case 3. A 13;14Robertsonian translocation t(13;14)(pll;qll) identifiedthrough the cytogenetic analysis of spontaneous abortionmaterial of a couple's first pregnancy. The secondpregnancy was antenatally diagnosed as a balanced 13 ;14translocation. Case 4. A 1 ;5 translocation t(1 ;5)(q23 ;q35)identified in the mother of a trisomy 21 Down's syndromechild. Case 5. A 13;14 Robertsonian translocationt(I3 ;14)(ql 1 ;ql 1) identified in a patient having antenataldiagnosis for increased maternal age.

De novo translocations in a selected populationP M ELLIS AND D KELLYCytogenetics Laboratory, Royal Hospitalfor SickChildren, Edinburgh

A recent apparent 'clustering' of de novo translocationsin cases referred to the Lothian Region CytogeneticsLaboratory has prompted a review of the incidence ofsuch rearrangements in the selected population whichthese referrals represent. A total of 10 spontaneouslyoccurring non-Robertsonian rearrangements and five suchRobertsonian translocations have been detected over6 years. These 15 rearrangements represent an incidencein our material of approximately 0-24% as comparedwith 0-5% in the newborn population in this region(Jacobs etal, 1974; Buckton etal, 1980). The abnormalitiescan be divided into those of apparently balanced asagainst clearly unbalanced karyotype. Comparisonsbetween the two groups were undertaken with regard toindications for referral, parental age at birth, and birth-weight in relation to (1) determining the reality orotherwise of the recent apparent increase in abnormalityin our population; (2) assessing the significance of eachtranslocation to the carrier; and (3) searching for anyunderlying common factor which might be related to theorigin of the structural abnormality in each case. Thesmall number of cases involved makes proper interpreta-tion of the observations difficult, but there seems noreason to doubt the reality of the difference in incidencebetween the unselected newborn population and ourselected population.


Clinicopathological and cytogenetic study of a truehermaphrodite presumed to be an XX/XO mosaicS A AL-AWADI, T I FARAG, AND K NAGUIBMedical Genetics Centre, Ministry ofPublic Health,Kuwait

We report a 7-year-old true hermaphrodite with 46,XX/45,XO sex chromosome mosaicism. The patientshowed female phenotype and female gender identity withambiguity of her external genitalia, left ovary, rightinguinal ovotestis, apparently normal Miillerianderivatives, and absent Wolffian derivatives. Histo-pathological study confirmed the diagnosis of type III(a) unilateral true hermaphroditism (Jones and Scottclassification, 1971). The ovotestis of the proband wasremoved with corrective surgery to restore normal femaleexternal genitalia. We discuss the major theories whichhave been proposed to explain the paradoxical develop-ment of testicular tissue in the absence of a Ychromosome: 'occult' sex chromosome mosaicism, Y;Xor Y;autosome translocation, male autosomal sexdetermining genes, and maleHY antigen hypotheses.

Inhibitors of amniotic fluid cholinesterasesM J SELLERPaediatric Research Unit, Guy's Hospital Medical School,London SE]

Polyacrylamide gel electrophoresis of amniotic fluid andan examination of the cholinesterases is proving anextremely useful technique in the prenatal diagnosis ofneural tube defects. Because the method uses severalnoxious chemicals, it is advised that protective glovesshould be worn during the process. It was discovered thatif a commonly used disposable medical glove (Triflex,Travenol Laboratories) was used, all cholinesteraseactivity was inhibited. However, if the gloves are firstthoroughly washed, there is no interference with theenzyme activity. Enzyme inhibition is caused by agents inthe corn starch powder lubricant on the outer surface ofthe gloves.

Screening for major fetal abnormalities by ultrasoundM d'A CRAWFURD, H B MEIRE, ANDP FARRANTNorthwick Park Hospital, Harrow, Middlesex

There is now a rapidly increasing literature on theprenatal diagnosis of a wide range of fetal morphologicalabnormalities by ultrasound. Most of the publishedreports are case reports of individual sporadicallyoccurring cases of neural tube defect, microcephaly,exomphalos, gastrointestinal anomalies, renal anomalies,etc. Recent technical developments in ultrasoundscanning equipment have both improved the imageand made the apparatus easier to use and thereforegreatly increased our ability to examine large numbers ofpregnant patients for the exclusion of fetal abnormality.In our institution several thousand patients have nowbeen screened by ultrasound and a wide range ofabnormalities have been detected. In particular, all cases



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of neural tube defect have been correctly identified with abetter false positive and false negative rate than a-fetoprotein assay. Ultrasound has been shown to be bothcheaper and more cost effective than AFP screeningprogrammes and, in addition to excluding neural tubedefect, will also diagnose a wide range of other abnor-malities and supply valuable obstetric information at thesame examination. A more extensive trial of the value andlimitations of ultrasound as an abnormality screeningtechnique would seem to be justified.

The effect of the introduction of prenatal diagnosis onthe reproductive history of women at increased riskfrom neural tube defectsK M LAURENCE AND J MORRISDepartment ofChild Health, Welsh National School ofMedicine, Cardiff

The reproductive histories of 45 couples at increased riskfor neural tube defect (NTD) who came for geneticcounselling in 1970 and 1971 were compared with asimilar number counselled in 1975 and 1976, whenprenatal diagnostic tests were freely offered. They weresubsequently interviewed in their homes and had theirreproductive history recorded to the end of 1973 and1978, respectively. Nearly all had a previous child with anNTD and none of the women was pregnant at the time ofcounselling. The effect of prenatal diagnosis was to speeddecision about further pregnancies but the number ofcouples deciding on no further children was almostidentical in the two groups, with an average number ofpregnancies of three per family and only 1 2 survivingchildren. The reasons for not attempting furtherpregnancies in both groups included very high risk ofrecurrence, a surviving spina bifida child, and inability toaccept the test or its implications. Of the second group,90% had prenatal tests. Their reactions to the tests werefavourable, but all complained of the waiting timebetween amniocentesis and obtaining the results; allwould have tests again in any future pregnancy. Thereason for women not having prenatal diagnostic testsincluded inability to accept termination. It is concludedthat couples in south Wales decide either to have no morechildren or to have further pregnancies regardless of tests,but tests speed a decision. They enable the women toenjoy the pregnancy after obtaining the results. Atermination for an NTD seems much more acceptable tomost than an NTD at term.

An autosomal recessive arachnodactyly syndromeN R DENNIS, R J PURVIS, AND P CAMMUniversity of Southampton, Southampton, and DorsetCounty Hospital, Dorchester, Dorset

All three children born to first cousin parents whosecommon ancestors lived in Shropshire had strikinglylong and slender fingers and toes, the big toes beingdisproportionately long. All had mild camptodactyly andhyperextensibility of the elbows and knees. The two girlshad complained of intermittent pain and swelling in theinterphalangeal joints, which in one was treated as

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rheumatoid arthritis. There were no ocular or cardiacabnormalities. Their heights were around the 97thcentile, with parental heights on the 90th centile. X-rayshowed an epiphysis at both ends of the first metacarpalsand metatarsals and most of the phalanges, apart from thedistal phalanges.

The genetics of fibrodysplasia ossificans progressivaJ M CONNORDepartment of Medicine, University ofLiverpool,Liverpool

Fibrodysplasia ossificans progressiva (FOP, also knownas myositis ossificans progressiva) is a rare disorder inwhich there is progressive ossification of the muscles andligaments in association with characteristic skeletalanomalies. It is believed to be an autosomal dominantcondition. Forty-four cases ofFOP have been identified inBritain in a national survey which aimed for total as-certainment. This indicates a minimum prevalence of1/1 .64 x 106 of the general population. The age range ofthese patients is 3 to 70 years and the sex incidence is1 1 males to 1 female. Their biological fitness is zero andno patient has an affected relative; thus they all representnew mutations. The mutation rate is estimated at1 8 ± 1.04 x 10-6 mutations/gene/generation. A birthorder effect is evident using the method of Haldane andSmith (1947) and the mean parental ages are significantlyraised in comparison with the general population. Analysiswith the method of Smith (1972) reveals that advancedpaternal age is the most important factor in the occurrenceof these new FOP mutations (df = 4.74, 2 SE 4 579).

A genetic study in hereditary angio-oedemaB M DALY, D I FRANCE, A W JOHNSTON,AND R A MAINDepartment of Dermatology, Aberdeen Royal Infirmary,Aberdeen

Hereditary angio-oedema (HAE) is a rare disorderassociated in 850% of cases with a quantitative defect ofCT inhibitor protein. In the remaining 150% there is aqualitative defect in this protein. Although the disease isbest recognised by episodes of visible oedema, the earlysymptoms of this condition are frequently related to thegastrointestinal tract. Laryngeal oedema is common andmay be fatal. The biochemical abnormality is constantwithin families suggesting that there are two types ofgenetic defect. A family manifesting this condition hasbeen studied where there is a quantitative defect inheritedas an autosomal dominant trait. The clinical course,treatment, and the genetic mechanism have beenstudied.

The association between high IQ and various genetic diseasesJ A SOFAER, AND A E H EMERYDepartment ofHuman Genetics, Edinburgh University,Edinburgh

In an attempt to understand more of the possible role ofgenetic and biochemical factors in cerebral development,an investigation has been undertaken to study the



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incidence of certain genetic disorders among subjects withsuperior intelligence. Each British member of Mensa(n = 2100) was sent a postal questionnaire asking forinformation about specific conditions in themselves as

well as in their first degree relatives. Positive responses forrarer conditions were confirmed by contacting thehospitals where affected subjects had been seen. Theconditions studied were retinoblastoma, torsion dystonia,phenylketonuria, infantile autism, myopia, and gout.There was a suggestion that infantile autism, myopia,and gout may be more frequent among those with highIQ than in the general population.

Clinical and genetic patterns in osteogenesis imperfectaR WYNNE-DAVIES AND J GORMLEYDepartment of Orthopaedic Surgery (Clinical Genetics),University of Edinburgh, Edinburgh

Clinical and genetic patterns, and hence genetic advice, inosteogenesis imperfecta are unsatisfactory and anattempt has been made to resolve the problem in a surveyof 101 index patients and their relatives. It was found thatthe terms 'congenita' and 'tarda' were not valid indistinguishing between types. It is suggested that there aretwo common non-lethal forms of the disease, both ofautosomal dominant inheritance, but genetically unrelatedsince they do not occur in each other's family. Theycannot be differentiated with certainty in the first year ortwo of life, but after this are sharply divided by differencesin stature and (less certainly) the colour of the sclerae.The blue sclerae/dominant type is well known; thesecond group is similar at birth, but is later characterisedby severe progressive shortness of stature (under -6 SD)together with pale blue or normal white sclerae.Autosomal recessive forms of osteogenesis imperfectaare noted, both lethal and non-lethal, but they appear tobe extremely rare and not necessarily clinically dis-tinguishable from autosomal dominant types.

Symposium on genetic factors ininternal medicineBleeding disordersB BURNETTDepartment of Medicine, Aberdeen University, AberdeenThe haemorrhagic disorders, now individually definedwith considerable precision, clearly show differentpatterns of inheritance. The commonest, classicalhaemophilia (haemophilia A; factor VIII deficiency), isthe prototype X chromosomal linked recessive disorder.Bleeding symptoms are thus expressed almost exclusivelyin males, though occasionally female carriers of theabnormal gene may suffer minor bleeding. Severity ofsymptoms in males is constant within individual familiesbut varies considerably between different kindreds.Spontaneous mutation is said to account for a significantproportion of new cases, but molecular studies suggestthat this event may be less common than was formerlysupposed. Biochemical and immunological studies have


recently established clear differences at the molecularlevel between classical haemophilia and the autosomaldominant bleeding disorder von Willebrand's disease,which is also characterised by factor VIII deficiency.Immunological methods now allow detection of thecarrier state with greater accuracy than had formerly beenpossible and prenatal diagnosis of the haemophilic stateis a possibility. Haemophilia is a major consumer ofresources, grossly disproportionate to its numericalincidence in the community. Advances in carrier detectionand prenatal diagnosis should contribute in a major wayto management of the problem.

The genetics of ischaemic heart diseaseW ROBERTSONDepartment of Genetics, University ofAberdeen,AberdeenEvidence for a genetic contribution to coronary disease isof several kinds. There is extensive statistical evidence ofincreased incidence in first degree relatives of heartattack patients. Assuming polygenic variation severalestimates of high heritability of liability to coronarydisease have been reported. Pedigrees often suggest singlegene determination of hyperlipidaemia, of which the bestexample is familial hypercholesterolaemia for which abiochemical test is available. But where such independentevidence is lacking, doubt exists as to the nature of theinheritance. Circumstantial information is provided bydifferences in degree of genetic control of the serumconcentration of the major lipoprotein fractions. Theconsequences of an increase in their serum concentrationsdiffer: smaller risk of CHD with raised HDL, increasedrisk with the others, especially LDL. The recent discoveryof apoprotein E polymorphism by Utermann andco-workers presents a new approach. Since the alternativealleles are common, the genotypes differ in their effects onserum concentration ofLDL and VLDL, and there is alsoevidence for interaction with other genes andlor conditionswhich influence serum lipid concentration. We arecurrently investigating the natural history of this poly-morphism in NE Scotland with particular reference tocoronary risk and lipoprotein profiles.

Geneticists' mistakesC A CLARKEMedical Services Study Group ofthe Royal CollegeofPhysicians, London NWJSix examples, in various Orders, of mistakes or conun-drums associated with genetics were given. (1) ABO bloodgroups and duodenal ulcer; necessity of using unaffectedsibs as controls. (2) Association of duodenal ulcer withR1R2 and MN blood groups; shown to be an effect oftransfusion. (3) Fertility of female mules; a back cross toa stallion produces a horse foal and to a donkey a mule.A reason for this was suggested. (4) Evolution of mimicryin butterflies; in particular in a species cross the mimeticpattern was not broken down as predicted. (5) Bistonbetularia, the peppered moth; predation by birds, longthought to be the major factor in maintaining the poly-morphism, is now challenged. (6) Increased incidence ofischaemic heart disease in Scotland; both genetic and



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environmental factors have been suggested, but most ofthe data are based on death certificates and more accurateinformation is desirable.

Gastrointestinal diseaseP BRUNTDepartment of Medicine, Aber-deenz UniversitY', Aberdeen

HLA and diseaseA M MACLEOD, R J MASON, AND G R D CATTODepar-tmenit ofMedicinie, University ofAber-deen, AberdeenThe discovery of red blood cell polymorphism in maninspired much research which demonstrated only weakassociations. White blood cell groups were found morethan two decades ago with much greater polymorphism.The gene complex which codes for these antigens in manis known as the HLA system and is located on the shortarm of chromosome 6. HLA genes are co-dominant andthus two cell surface antigens are expressed from eachlocus. A, B, and C antigens are on most body cellswhereas D and DR antigens are expressed principally onB lymphocytes, monocytes, and macrophages. During thelast decade many diseases have been noted to be associatedwith specific HLA antigens (for example, multiplesclerosis with DR2). Although the precise mechanismsunderlying these associations remain obscure, severaltheories have been proposed: (1) HLA molecules may actas receptors for viruses; (2) viral molecular structuresmay mimic HLA antigens and thus limit the immuneresponse; (3) viruses may modify HLA antigens whichthen become susceptible to the immune response; (4)HLA antigens may be markers for closely linked productsof the Ir genes. Whatever the final explanation, it seemslikely that it is not the HLA genes themselves but closelylinked genes which account for the associations.

The following poster demonstrationswere among those shown. (A full listof titles will appear in a future issue.)Amniotic fluid acetylcholinesterase: retrospective andprospective results with the qualitative testS J FENNELL, A P READ, AND R HARRISDepartment ofMedical Genetics, St Mary's Hospital,ManchesterThe isozyme pattern of acetylcholinesterase (AChE) inamniotic fluid was determined by the method of Smithet al (Lancet 1979; i: 685). In the first phase of the study 90stored fluids from pregnancies with known outcome werescored blind by two observers. All 29 open neural tubedefects gave two bands, including two with false negativeamniotic AFP, and all 50 normal fetuses gave one band,including three with false positive AFP. Two of threeencephaloceles gave two bands and three of four exom-phalos gave a barely discernible second band. The testwas then introduced into routine prospective use and655 fluids have been tested to date. There were 634 fluidswith normal AFP and one band and 14 with raised AFPand two bands (seven anencephalics, six spina bifida, one

probable exomphalos). Two fluids with normal AFP gavetwo bands; both pregnancies continued and one hasalready delivered a normal infant. We hope that inhibitorstudies will throw light on these apparent false positives.Fluids with raised AFP but one band present difficultiesin counselling. Of the five in this series two fetuses provedseriously abnormal after termination (one with con-strictions and amputations resulting from amniotic bands,the other with exomphalos), two were not seriouslyabnormal (one with herniation of a loop of intestinethrough the umbilicus, one normal fetus with hae-mangioma of the cord), and one is still under investigation.

Characterisation by scanning electron microscopy ofcell types in amniotic fluid culturesC J HARRISON AND R HARRISDepartment of Medical Genetics, Manchester Univer-sity,Manchester

The cell types present in cultures of amniotic fluids fromnormal pregnancies were studied by light and scanningelectron microscopy (SEM). The majority of cellsadhering to the substratum within the first 24 hours werespherical, epithelioid, or bipolar, and some of them wereof similar morphology to the 'neurological' cells observedin amniotic fluids associated with NTD fetuses. SEMexamination of these cell types revealed common surfacemorphological features. Therefore, they appeared tobelong to the same fibroblastic population in variablestages of attachment or at different stages of the cell cycle.All viable cells were spherical upon initial attachment andexhibited progressive flattening onto the substratum asadhesion increased. Studies of highly synchronised cellsdemonstrated a defined series of morphological changesassociated with the individual phases of the cell cycle.Therefore, variation in rate of attachment within anasynchronous population showed a range of cell shapesat any given time. With continued incubation theseisolated cells formed colonies. Contact with neighbouringcells induced flattening with an associated decrease insurface projections. Sheets of slowly dividing epithelialcells were also observed within the cultures. The highlyproliferative and migratory fibroblast populationsurrounded these epithelial colonies and eventuallydominated the cultures. An additional population of giantmultinucleate cells was also demonstrated. These threecell populations were consistently observed in all normalamniotic fluid cultures over a range of gestational ages.

Mapping the structural gene for galactose-1-phosphateuridyl transferase (GALT E C 2.7.7.12.) by linkage topericentric inversions and heteromorphisms ofchromosome 9J S PATERSON, D A AITKEN, H J JACKSON,AND M A FERGUSON-SMITHUniversity Department ofMedical Genetics,Yorkhill Hospital, GlasgowSomatic cell hybridisation and gene dosage studies haveassigned the structural gene for GALT to the short arni ofchromosome 9, possibly in, or close to, 9p13. In this

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project, members of families in which pericentricinversions or prominent heteromorphisms ofchromosome9 are segregating were typed by gel electrophoresis forDuarte or Los Angeles variants of GALT. Familiesfound to have GALT variants were examined forrecombinants between the variant and the chromosomemarker. Preliminary results suggest close linkage.

A case of X;Y translocation which maps the Xg locusto Xp24 -pterE BOYD, M A FERGUSON-SMITH,M E FERGUSON-SMITH, M E JAMIESON,J E RUSSELL, D A AITKEN, R SANGER,AND P TIPPETTDepartment ofMedical Genetics, University ofGlasgow,Glasgow, andMRC Blood Group Unit, London

An abnormal X chromosome detected during prenataldiagnosis was found to be an X;Y translocation inheritedfrom the mother. Breakpoints were interpreted as

Xp24 and Yql 1. The mother's karyotype was thus46,X,t(X;Y)(Xqter - Xp24:Yqll - Yqter). Studies withBUdR incorporation in the mother showed that Xinactivation was random. Two cases with karyotypeidentical to this fetus were known at that time (Van denBerghe et al, Hum Genet 1977; 36: 129, Tiepolo et al,

Hum Genet 1977; 39: 277). These were discussed with themother who decided to continue the pregnancy. A malechild was born and when examined at age 6 months hisgeneral development was satisfactory, but he hadgeneralised ichthyosis. The results of family studies andXg blood grouping showed that grandparental karyotypeswere normal and that the mother had failed to inherit theXg locus along with her father's X chromosome. Thisprovides the first conclusive evidence that the Xg locus isin the region Xp24 -pter. Preliminary studies on steroidsulphatase (STS) levels showed that the mother had STSactivity in the range of a normal male, while the fetus hadzero activity. Thus the locus for X linked ichthyosis(known to be linked to Xg) has also been lost along withthis region of Xp, confirming the localisation for STSmade by Muller et al(Hum Genet 1980; 54: 201). Evidenceis thus accumulating that this locus and the Xg locus donot become inactivated, confirming earlier predictions(JMed Genet 1965; 2: 93).

Scanning electron microscopy of human metaphasechromosomesC J HARRISON AND R HARRISDepartment ofMedical Genetics,University ofManchester, Manchester

A variety of light microscope methods have beendeveloped to reveal the presence ofG bands in metaphasechromosomes. A series ofchromatin sub-units in the armsof Chinese hamster metaphase chromosomes were shownby transmission electron microscopy to correspond to theG banding pattern. No scanning electron microscope


(SEM) study to date has demonstrated the presence ofG bands. We have developed a high resolution techniqueto examine uncoated human metaphase chromosomes inthe SEM after preparation for light microscopy andsubsequent G banding. Chromosomes were of roundedthree-dimensional morphology, with well-defined chrom-atids and centromeres. A filamentous morphologywas observed over the surface of the chromatids,corresponding in diameter to the chromatin folded fibremodel. Transverse grooves were also demonstrated in thechromosome arms which subdivided the sister chromatidsinto parallel segments. The segments appeared to representcoiling in a manner corresponding to chromosomequaternary structure. A characteristic coiling pattern wasconsistently observed for each chromosome pair. There-fore, individual chromosomes possess an inherentspecificity of quaternary structure. This property has beenutilised to demonstrate a correlation between the Gbanding pattern in the light microscope and the coiling ofthe chromosome arms by the presentation of an SEMkaryotype.

Mosaicism in amniotic fluid cell culturesC BRANDRETH, J TRACEY, AND D DONNAIDepartment ofMedical Genetics,University ofManchester, Manchester

Chromosomal mosaicism in amniotic cultures may begenuine or artefactual. In our culture method at least oneculture is harvested in situ, allowing study of individualcolonies and identification of artefacts. Mosaicism wasdetected in amniotic cultures from three patients andsubsequently confirmed. Case 1. Amniocentesis wasperformed on a 36-year-old woman whose karyotype was47,XX,+ marker (bisatellited with a single centromere).The pregnancy continued and a phenotypically normalfemale was delivered. The baby's lymphocyte cultureconfirmed the presence of two cell lines. Case 2. Amnio-centesis was performed on a woman with a family historyof Down's syndrome. The in situ harvests revealedseparate colonies of each cell line. Because of theassociation ofG group monosomy mosaicism with mentaland physical retardation the couple elected for termina-tion. The fetus was phenotypically normal but mosaicismwas confirmed in skin and muscle. Case 3. Amniocentesiswas performed on a 37-year-old woman. Both cell lineswere found within individual colonies from the in situharvest. The patient elected for termination, the fetus wasphenotypically normal, but mosaicism was confirmed inall tissues examined. It proved impossible even withbanding to identify the extra chromosome. Althoughsimilar to a D group, silver staining was negative andsatellite association was never observed. In cases 2 and 3our culture method allowed us to be confident that fetalmosaicism was genuine. In case 1, in which only sub-cultures were analysed, mosaicism involved an Xchromosome which would be unlikely to carry a seriousrisk of mental handicap.



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