Showing papers in "Journal of Medical Genetics in 1991"

Von Hippel-Lindau disease: a genetic study.

Abstract: Genetic aspects of von Hippel-Lindau (VHL) disease were studied in familial and isolated cases. Complex segregation analysis with pointers was performed in 38 kindreds with two or more affected members. Dominant inheritance with almost complete penetrance in the highest age classes (0.96 at 51 to 60 and 0.99 at 61 to 70 years) was confirmed and there was no evidence of heterogeneity between families ascertained through complete and incomplete selection. The point prevalence of heterozygotes in East Anglia was 1.89/100,000 (1/53,000) persons with an estimated birth incidence of 2.73/100,000 (1/36,000) live births. Reproductive fitness was 0.83. Direct and indirect estimates of the mutation rate were 4.4 (95% CI 0.9 to 7.9) x 10(-6)/gene/generation and 2.32 x 10(-6)/gene/generation respectively. There was no significant association between parental age or birth order and new mutations for VHL disease.

Hereditary motor and sensory neuropathies.

Abstract: The hereditary motor and sensory neuropathies (HMSN) represent a genetically heterogeneous collection of disorders in which patients develop a progressive muscular atrophy and sensory neuropathy of the distal extremities. Although Dyck' has noted seven types, the best described of these are HMSN types I and II (Charcot-Marie-Tooth disease) and Dejerine-Sottas (DS) disease, HMSN III. In contrast to other neurological disorders, such as Huntington's disease and myotonic dystrophy, there appears to be extensive genetic diversity in HMSN. The recent use of pedigree linkage analysis together with recombinant DNA techniques in these disorders has finally begun to clarify this confusing group of diseases. Charcot and Marie,s and independently Tooth,6 described a hereditary progressive muscular atrophy of the lower extremities in 1886. The former authors suspected the disorder represented a myelopathy, while Tooth considered it to be a 'true neuropathy'. Today Charcot-Marie-Tooth (CMT) disease represents the most common inherited neuropathy, with estimates of 36/100 0007 for the prevalence of its most frequent type, the autosomal dominant form. Presentation of symptoms is commonly in childhood or as a young adult. Initial weakness occurs in a peroneal nerve distribution with development of the characteristic foot drop, pes cavus, and hammer toes. Sensory examination is abnormal as well, but deficits are usually not symptomatic. The disease is progressive and atrophy of the distal upper extremities may occur in many subjects. Like many inherited neuro-logical disorders, CMT is marked by variable expres-sivity. Some patients may have only minimal symptoms, and their diagnosis may rest on nerve conduction studies or obligate carrier status, while others may require extensive orthopaedic intervention to maintain ambulation. A few patients may become wheelchair dependent. Ataxia and especially intention tremor are not uncommon.8 Prominence of these later symptoms led Roussy and Levy9 to describe what was initially believed to be a distinct syndrome. However, subsequent identification of families in which the CMT1 (HMSN I) and Roussy-Levy phenotypes segregate as one gene has led to the conclusion that patients with Roussy-Levy syndrome actually represent extreme expressions of CMT1.'0 With the known linkages to chromosomes 17 and 1 in CMT1, proof of this clinical impression may be obtained through future linkage analysis. In 1968, Dyck and Lambert\" 12 divided the autosomal dominant forms of CMT into two types, based on physiological and pathological criteria: (1) the demyelinating form, CMT1, with severely decreased nerve condition velocities (NCV) and hypertrophic changes on biopsy, and (2) CMT2, the …

Prevalence of fragile X syndrome.

Abstract: The much-quoted prevalence figure of 1:1,000 males for fragile X syndrome is an overestimate in a mixed ethnic population. A reexamination of the individuals from whom those data were derived using molecular diagnostic techniques demonstrates a more realistic figure of 1:4,000 males.

Osteogenesis imperfecta: translation of mutation to phenotype.

Abstract: By the end of the recently completed Fourth International Conference on Osteogenesis Imperfecta (Pavia, Italy, 9-12 September 1990) more than 70 mutations in the two genes that encode the chains of type I collagen, the major protein of bone, had been identified as the molecular cause of different forms of osteogenesis imperfecta (OI). Although by no means complete, the set of mutations in hand provides a rough guide to how to predict the phenotypic effects of mutations in type I collagen genes, predicts that certain classes of mutations will give rise to very mild phenotypes that will blend with common disorders, such as osteoporosis, and clarifies the genetic aspects of the widely used clinical classification of O.1

Hereditary multiple exostoses.

Abstract: Hereditary multiple exostoses (HME) is a skeletal disorder which primarily affects enchondral bone during growth. It is characterised by multiple exostoses, usually arising in the juxtaepiphyseal region of the long bones. Exostoses that affect \"almost every bone in the body\" were first mentioned by John Hunter in his Lectures on the principles of surgery in 1786.1 The first family affected by HME was described by Boyer2 in 1814. Virchow3 named the disorder multiple exostoses in 1876, and Keith4 suggested the name diaphyseal aclasis; this term is still popular in the UK. Several other names have been used in the past and are still used today, including 'osteogenic disease', 'chondral osteogenic dysplasia', 'chondral osteoma', 'dyschondroplasia', 'deforming chondrodysplasia', 'multiple hereditary osteochondromata', 'multiple cartilaginous exostoses', or simply 'exostosis' or 'exostotic dysplasia'. Papers that were especially important in further delineatinj the disorder were those of Jaffe,5 Solomon, and Shapiro et al.9 HME may be found not only in man, but also in horse, cattle, dog, cat, lion, and lizard.'0 11 A large exostosis was even found on the scapula of a dinosaur.'0

Maternal uniparental disomy for chromosome 14.

Abstract: We report the first case of maternal uniparental disomy of chromosome 14 in humans. The male proband inherited a balanced 13;14 Robertsonian translocation from his mother. Molecular studies showed that neither chromosome 14 was of paternal origin. The proband is of above average intelligence, but he has hydrocephalus, a bifid uvula, premature puberty, short stature, and small testes. It is not known if the clinical findings are related or coincidental to the uniparental disomy.

Velocardiofacial (Shprintzen) syndrome: an important syndrome for the dysmorphologist to recognise

Abstract: We report the dysmorphological, genetic, and speech therapy aspects of 38 cases of velocardiofacial syndrome presenting to a craniofacial clinic and a specialised children's hospital, to indicate a relatively low incidence of clefting, good response to pharyngoplasty, considerable variability of the syndrome, and two further familial cases. We emphasise the low index of suspicion by paediatricians and paediatric subspecialists which resulted in delayed diagnosis and delayed treatment for the hypernasal speech and velopharyngeal insufficiency for periods of four months to seven years.

Genetic aspects of antibiotic induced deafness: mitochondrial inheritance.

Abstract: Analysis of 36 pedigrees with a positive family history of aminoglycoside antibiotic induced deafness, ascertained in a population of 483,611 in Zhabei District in Shanghai, showed that the susceptibility to antibiotic ototoxicity was transmitted by females exclusively, indicating mitochondrial inheritance. Reanalysis of 18 other published pedigrees confirmed this conclusion.

Fragile X syndrome: genetic localisation by linkage mapping of two microsatellite repeats FRAXAC1 and FRAXAC2 which immediately flank the fragile site.

Abstract: We report the genetic localisation of the fragile site at Xq27.3 associated with fragile X syndrome. The position of the fragile site within the multipoint linkage map was determined using two polymorphic microsatellite AC repeat markers FRAXAC1 and FRAXAC2. These markers were physically located within 10 kilobases and on either side of the p(CCG)n repeat responsible for the fragile site. FRAXAC1 has five alleles with heterozygosity of 44% and is in strong linkage disequilibrium with FRAXAC2 which has eight alleles and a heterozygosity of 71%. No recombination was observed either between these markers in 40 normal CEPH pedigrees or with the fragile X in affected pedigrees. These markers provide the means for accurate diagnosis of the fragile X genotype in families by rapid polymerase chain reaction analysis and were used to position the fragile X within the multipoint map of the X chromosome to a position 3.7 cM distal to DXS297 and 1.2 cM proximal to DXS296.

A convenient multiplex PCR system for the detection of dystrophin gene deletions: a comparative analysis with cDNA hybridisation shows mistypings by both methods.

Abstract: Existing reactions for the multiplex PCR amplification of exons in the dystrophin gene have been modified to produce two multiplex reactions which separately cover the 5' and 3' major deletion 'hotspots' in the gene, and together detect approximately 98% of all deletions detectable by Southern cDNA hybridisation. A comparative study of 148 patients showed mistypings in both the cDNA hybridisation data (4%) and the PCR analysis (1.2%). We suggest means of circumventing the underlying problems in order to avoid mistyping and subsequent misdiagnosis, and conclude that, with appropriate precautions, multiplex PCR amplification can be the method of choice for detecting deletions in the dystrophin gene.

Genetic counselling in facioscapulohumeral muscular dystrophy.

Abstract: Clinical data are presented from a survey of 41 families with dominantly inherited facioscapulohumeral muscular dystrophy (FSHD) in which over 500 family members were examined, including 168 affected subjects. New mutation could account for six isolated cases. Results suggest that 33% of heterozygotes over 40 years are mildly affected and a majority develop significant lower limb weakness; 19% over 40 years require wheelchairs. Presymptomatic testing of serum creatine kinase level (CK) is limited as a raised level occurs in only 80% of affected males under 40 years and 48% of affected women. Distribution of weakness, severity, age at onset, and CK varied between subjects, but provided no clinical evidence for genetic heterogeneity in a comparison between the 11 largest families. The conclusion of genetic homogeneity in FSHD, including subjects previously diagnosed as FSH type spinal muscular atrophy, is strongly supported by recent genetic linkage data.

Deletion of chromosome 13 in Moebius syndrome.

Abstract: A girl aged 2 1/2 years with Moebius syndrome was found to have a deletion of band q12.2 in chromosome 13 (46,XX,del(13)(q12.2]. This is the second report concerning involvement of chromosome 13q and Moebius syndrome. The observation raises the possibility that a gene responsible for Moebius syndrome is located in this region of chromosome 13.

Coffin-Siris syndrome.

Abstract: In 1970 Coffin and Siris described three unrelated female children with severe mental and developmental retardation, sparse scalp hair, and coarse appearing facies with bushy eyebrows, a wide mouth, and thick lips. There were, in addition, lax joints and brachydactyly of the fifth digits of both hands and feet with absence of the nails and terminal phalanges.' To our knowledge, there have been 31 cases of this condition reported and these are reviewed in the present paper with the addition of two new cases.

On the incidence of fits and mental retardation in tuberous sclerosis.

Abstract: OBJECTIVES--To establish the frequency of fits and mental retardation in an unbiased group of tuberous sclerosis patients. METHODS--Known tuberous sclerosis families with more than one affected person were ascertained for a genetic linkage study. A number of members were born after genetic counselling had been given after identification of the proband. These subjects were then carefully examined clinically and in many cases with cranial computerised tomography, renal ultrasound, and skeletal survey but not echocardiography. They provide an unbiased group of tuberous sclerosis patients and allow affected patients with normal intellect to be diagnosed. PATIENTS--Thirty-seven tuberous sclerosis families were ascertained and 26 patients born after the family proband were identified. RESULTS--Sixteen of these 26 patients suffered fits (62%) and 10 patients were mentally retarded (38%). CONCLUSIONS--A lower incidence of fits and mental retardation has been found in an unbiased sample of tuberous sclerosis patients. The lifetime risk for fits might be higher had we been able to follow the patients for longer. However, we believe these are more appropriate figures to use in genetic counselling for this disease.

On the parental origin of de novo mutation in man.

Abstract: Studies tracing parental origins of human mutations by means of cytogenetic polymorphisms and RFLPs show that most trisomics arise out of maternal errors of segregation at the first meiotic division in oocytes. Temporal disturbance of meiotic progression seems likely to underly aneuploidy production in the female mouse, and this could equally be true in women, most especially as they approach the menopause when irregular cyclicity sets in. For human monosomy X, a high proportion of cases show loss of the paternal sex chromosome, and from experimental data giving similar findings in the mouse, it seems likely that the error could arise at the pronuclear stage after sperm entry into the egg, rather than at meiosis in the male. For human point mutations and structural rearrangements, a bias exists towards paternal origins. Errors arising during spermatogonial proliferation in men could contribute point mutations, these accumulating over a lifetime to give paternal age effects. For structural rearrangements, the hypersensitive stage is likely to be the post-meiotic differentiating spermatid, a stage not subject to germinal selection, and one which in Drosophila has been shown to combine high breakability with enhanced repair. Lack of a comparable cell type to the condensing spermatid of the male might be a reason why balanced structural rearrangements are produced rather rarely in females, at least in the mouse.

Selection in blood cells from female carriers of the fragile X syndrome: inverse correlation between age and proportion of active X chromosomes carrying the full mutation.

Abstract: We have studied the patterns of mutation and X inactivation in female carriers of a fragile X mutation, to try to correlate them with various phenotypic features. We used a simple assay, which shows simultaneously the size of the mutation, its methylation status, and DNA fragments that represent the normal active and inactive X chromosomes. We have observed an age dependent process, whereby the 'full' fragile X mutation is found preferentially on the inactive X in leucocytes in adult females, but not in younger ones. This phenomenon was not observed in female carriers of a 'premutation', who have little phenotypic expression. Preliminary data suggest that young females who show preferential presence of a full mutation on the active X in leucocytes may be at increased risk for mental retardation. We have also obtained preliminary evidence for an age dependent decrease in the somatic heterogeneity of full mutations, possibly owing to selection for smaller mutated fragments. If confirmed, the latter phenomenon might account for the known decrease with age of the expression of the fragile site. Our observations suggest that a gene whose expression is affected by the presence of a full mutation (possibly the FMR-1 gene) has a cell autonomous function in leucocytes, leading to a slowly progressive selection for cells where the mutation is on the inactive X chromosome.

The UK Northern region genetic register for familial adenomatous polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk calculations.

Abstract: A polyposis register has been established in the Northern Region of England. A total of 48 families with 71 living affected subjects has been identified during the first three years of operation, a prevalence of 2.29 x 10(-5). Indirect ophthalmoscopy identifies the majority of gene carriers by showing multiple areas of congenital hypertrophy of the retinal pigment epithelium (CHRPE). The absence of this sign in families limits its value where a relative with CHRPE has not been identified. Combining eye examination with data on age of onset and linked DNA markers is highly effective in carrier exclusion; 38% of 528 first, second, and third degree relatives had their carrier risk reduced to less than 1 in 1000. Even with such assurance many subjects will request continued bowel screening at a reduced frequency. Little interest has been shown in prenatal diagnosis. The principal value of a genetic register with domiciliary nurse visiting is the reduction in early mortality among unrecognised gene carriers.

Age at onset in Huntington's disease: effect of line of inheritance and patient's sex.

Abstract: The Leiden Roster for Huntington's disease (HD) contained data on 2617 cases up to July 1988. The age at onset (AO) was known in 1084 cases and in 1020 of these both their AO and the sex of the affected parent was known. The mean AO was higher for females than for males and higher for maternal than for paternal cases. However, in the group born before 1925 only females with maternal inheritance had a higher mean AO. Data on influence of sex and line of inheritance were present for the grandparents as well as for the great grandparents. Influence of the line of inheritance from the grandparents was particularly present for the grandmother-father (MP) lineage; regarding the great grandparents a significant difference was found between the MPM and PMP lineage. The results obtained for juvenile HD cases were comparable to those previously published. In late onset cases (over 50 years) no maternal preponderance in inheritance was found.

London Dysmorphology Database

Abstract: should increase charges for services; bill for all services provided to family members; charge for all genetics professionals' time, including that of counselors and social workers; and even request payment at the time of service\" (p 359). Unfortunately, much of the burden of genetic disease even in the First World is borne by the poor, so-called minority groups (blacks in the Americas, Asians, Caribbeans, and Greek Cypriots in the UK), those least able to afford private health care. Medical geneticists in the UK, notably Bernadette Modell, have pleaded that such people must be spared the cost of screening tests and genetic counselling, if they are to be helped to cope successfully with their genetic problems, the most important of which are the haemoglobinopathies. The book is a mine of information and an excellent index will facilitate its use as a valuable reference for physicians and other health care professionals working in Africa or in countries with significant numbers of people of African descent; the more than 800 references will help direct their further reading. There are useful appendices in which are listed genetic variants and disorders commoner or rarer in blacks than in other peoples, charts of developmental indices in African-American children, and a list of polymorphic traits of exceptionally high or low frequency in peoples of African origin, although this table lacks references.

A cytogenetic and molecular study of a series of 45,X fetuses and their parents.

Abstract: The parental origin of the single X chromosome in 10 45,X fetuses was studied using DNA restriction fragment length polymorphisms. In six the single X was maternal in origin, in one it was paternal, and in one the results were consistent with a paternal origin. Therefore the parental origin of the X in 45,X fetuses that survive to the second or third trimester of pregnancy is similar to that of spontaneous abortions and live births with a 45,X constitution. The mothers of two of the fetuses were themselves found to have an abnormal sex chromosome complement, but in neither case did it appear to be related to the chromosome abnormality in the fetus.

Clinical and radiographic dental findings in X linked hypohidrotic ectodermal dysplasia

Abstract: X linked hypohidrotic ectodermal dysplasia was studied in the dentition of both affected males and carrier females. Hypodontia was more severe in males than females and there were differences in the pattern of tooth absence between the sexes. Abnormal crown form, with the maximum diameter of the teeth being apically displaced, was noted particularly in the anterior teeth. Taurodontism was commonly seen radiographically.

Watson syndrome: is it a subtype of type 1 neurofibromatosis?

Abstract: Over 20 years ago, Watson described three families with a condition characterised by pulmonary valvular stenosis, cafe au lait patches, and dull intelligence. Short stature is an additional feature of this autosomal dominant condition. A fourth family with Watson syndrome has since been reported. We have had the opportunity to review members of three of these four families. The clinical phenotype of Watson syndrome has been expanded to include relative macrocephaly and Lisch nodules in the majority of affected subjects, and neurofibromas in one-third of family members. Because the additional clinical findings enhance the similarity between Watson syndrome and neurofibromatosis 1, molecular linkage studies have been performed using probes flanking the NF1 gene on chromosome 17. Probe HHH202 showed the tightest linkage to Watson syndrome with a maximum lod score of 3.59 at phi = 0.0 (95% confidence limits of phi = 0.0-0.15). This suggests either that Watson syndrome and neurofibromatosis 1 are allelic, or that there is a series of contiguous genes for pulmonary stenosis, neurocutaneous anomalies, short stature, and mental retardation on 17q.

Epidemiological and genetic study in 207 cases of oral clefts in Alsace, north-eastern France.

Abstract: The epidemiology of oral clefts was studied in the geographical area covered by our registry of congenital malformations. For each of the 207 new cases studied during the period 1979 to 1987, more than 50 factors were compared in probands and controls. The incidence of oral clefts was 1.75 per 1000, with cleft lip/palate (CL(P] 0.98 and cleft palate only (CP) 0.77 per 1000. A total of 8.2% of cleft cases were stillbirths and 5.3% were induced abortions. The more common types of associated malformations in the 76 affected cases (36.7%) with at least one anomaly other than oral cleft were neural tube defects and skeletal malformations. At birth, infants with oral clefts and other malformations were smaller, weighed less, and their head circumference was lower than in controls. Placental weight was also lower than in controls. Pregnancies with oral clefts were more often complicated by threatened abortion, polyhydramnios, and arterial hypertension. There was a significant association between clefting and consanguinity; heritability of CL(P) was 81% and first degree relatives of probands had more than three times the prevalence of noncleft malformations as controls. These results are of relevance to genetic counselling.

Non-specific X linked mental retardation.

Abstract: Non-specific X linked mental retardation (MRX) is mental retardation in persons of normal physical appearance who have no recognisable features apart from a characteristic pedigree. Review of published reports shows that there is clinical variability in the degree of mental retardation within families and genetic heterogeneity, based on gene localisation, between families. We propose a classification based on genetic localisation and a set of minimal clinical features that should be recorded in the hope of identifying possible specific phenotypes.

X linked mental retardation.

Abstract: Classification of mental retardation Mental retardation (MR) can be classified within approximate IQ ranges assuming a population mean of 100 and a standard deviation of 15. Mild MR is defined as being within the IQ range 50 to 70 (-2-0 to -3-3 SD), moderate MR within the IQ range 35 to 50 (-3 3 to -4 3 SD), severe MR within the IQ range 20 to 35 (-4-3 to -5-3 SD) and profound MR within the IQ range 0 to 20 (less than -5*3 SD).' A simplification of this classification into two large groups is often used; severe mental retardation (SMR), which includes the profound, severe, and moderate categories, and mild mental retardation (MMR).2 SMR has an estimated incidence of just less than 4 per 1000 live births.3-5 The MMR group comprises some 2 to 3% of the population but many of these persons, especially at the top end of this IQ range, will make satisfactory adjustments and not be regarded as abnormal.6 The estimates of the fraction of genetically determined handicap contributing to SMR range from 0-257 to 0-52.3 In addition, a large idiopathic fraction (between 0-127 and 0-514) exists and this component almost certainly contains unrecognised genetic disease. Even for MMR, traditionally considered to represent the lower end of the multifactorial distribution of intelligence, pathological causes have been delineated which include genetic conditions.6 8

Deletion 14q (q22q23) associated with anophthalmia, absent pituitary, and other abnormalities.

Abstract: A fetus is described with anophthalmia, absent pituitary, hypoplastic adrenal glands and kidneys, absent left horn of the uterus, underdeveloped genitalia, and clinodactyly, with a deletion of 14(q22q23). A review of published reports found no similar deletion cases.

A newly defined X linked mental retardation syndrome associated with alpha thalassaemia.

Abstract: In 1981 three northern European families were described in which a severely mentally retarded son also had haemoglobin H (Hb H) disease.' These findings were of interest because Hb H disease, a relatively severe manifestation of a thalassaemia, is rare in northern Europeans although it is frequently seen in Mediterranean and Oriental racial groups in which it is not known to be associated with an increased frequency of mental retardation. Furthermore, whereas the common forms of Hb H disease are always inherited in a mendelian fashion, in these northern European families this appeared not to be so. Hb H disease occurs when a greater than 50% reduction in synthesis of the a globin chains of adult haemoglobin (Hb A, a212) results in the accumulation of excess 1 globin chains which form 14 tetramers (Hb H). The common mendelian forms of HbH disease result from mutations of both allelic a globin complexes, most commonly owing to deletions or less frequently to small rearrangements or point mutations. The a globin complex is located close to the telomere of the short arm of chromosome 16, within band 16pl3.3. By 1990, a total of 13 subjects with a thalassaemia and mental retardation (ATR) had been identified and two distinct syndromes were delineated.34 Eight patients had large (1 to 2 megabases) deletions of the tip of chromosome 16p; the clinical features of this so called ATR-16 syndrome were rather variable, in

A de novo translocation t(3;17)(q26.3;q23.1) in a child with Cornelia de Lange syndrome

Abstract: A female infant with Cornelia de Lange syndrome and severe limb reduction defects is described. Chromosome analysis showed a de novo translocation with breakpoints at 3q26.3 and 17q23.1. This is the first reported case of a de novo translocation associated with this syndrome.

The Holt-Oram syndrome.

Abstract: The classical description of this syndrome of upper limb abnormalities and congenital heart lesions was by Holt and Oram in 1960.1 They were from King's College Hospital in London and reported a four generation family with nine affected subjects. Many other families were then recognised to have the same condition, which led to a series of reports in the early 1960s. The names atriodigital dysplasia, the hearthand syndrome, the upper limb-cardiovascular syndrome, the cardiac-limb syndrome, and the cardiomelic syndrome were suggested, but it is the HoltOram syndrome that has remained in common use. There have been over 200 cases published and it is found throughout the world. A genetics department in the UK near a cardiology referral centre may expect to see a new family about once every two years.