Refining the map and defining flanking markers of the gene for autosomal recessive polycystic kidney disease on chromosome 6p21.1-p12.
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Base Sequence↗
Biomedical subjects
K Zerres
Publications and source records attributed to K Zerres.
Evidence of autosomal dominant mutations in childhood-onset proximal spinal muscular atrophy.
Autosomal recessive and dominant inheritance of proximal spinal muscular atrophy (SMA) are well documented. Several genetic studies found a significant deviation from the assumption of recessive inheritance in SMA, with affected children in one generation. The existence of new autosomal dominant mutations has been assumed as the most suitable explantation, which is supported by three observations of this study: (1) The segregation ratio calculated in 333 families showed a significant deviation from autosomal recessive inheritance in the milder forms of SMA (P = .09 +/- .06 for onset at 10-36 mo and .13 +/- .07 for onset at > 36 mo; and P = .09 +/- .07 for SMA IIIa and .12 +/- .07 for SMA IIIb). (2) Three families with affected subjects in two generations are reported, in whom the disease could have started as an autosomal dominant mutation. (3) Linkage studies with chromosome 5q markers showed that in 5 (5.4%) of 93 informative families the patient shared identical haplotypes with at least one healthy sib. Other mechanisms, such as the existence of phenocopies, pseudodominance, or a second autosomal recessive gene locus, cannot be excluded in single families. The postulation of spontaneous mutations, however, is a suitable explanation for all three observations. Estimated risk figures for genetic counseling are given.
Adolescent↗
Steinfeld syndrome: report of a second family and further delineation of a rare autosomal dominant disorder.
We report on a fetus with alobar holoprosencephaly, microphthalmia, midline cleft lip and palate, absent nose, dysplastic ears, radial defects, pentalogy of Fallot, unilateral renal aplasia, absent gallbladder, vertebral anomalies, and absence of ribs. The father had a cleft palate, bilateral colobomas of the iris and retina, a bifid uvula, vertebral anomalies, and unilateral congenital hearing loss. His sister had a cleft lip. On the basis of this family and the family reported by Steinfeld [1982], this malformation syndrome can be defined as a rare autosomal dominant syndrome whose main component manifestations are holoprosencephaly, predominantly radial limb deficiency, heart defects, kidney malformations, absence of gallbladder, and vertebral anomalies.
Abnormalities, Multiple↗
ADULT-syndrome: an autosomal-dominant disorder with pigment anomalies, ectrodactyly, nail dysplasia, and hypodontia.
We describe a family with at least seven living persons who are affected by an hitherto undescribed autosomal-dominant syndrome with variable expression, bearing close resemblance to the EEC syndrome and related disorders. The main manifestations are hypodontia and/or early loss of permanent teeth, ectrodactyly, obstruction of lacrimal ducts, onychodysplasia, and excessive freckling. We propose the acronym ADULT (acro-dermato-ungual-lacrimal-tooth)-syndrome for this condition.
Abnormalities, Multiple↗
Fine mapping and narrowing of the genetic interval of the spinal muscular atrophy region by linkage studies.
The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has recently been mapped to chromosome 5q12.2-q13, within a genetic distance of about 6 cM, and is proximally flanked by the locus D5S6 and distally by D5S112. Here, we report linkage analyses in 64 SMA families with nine polymorphic markers closely linked to the SMA gene, which allowed us to narrow the SMA region to about 4 cM and to define a new proximal genetic border by the locus D5S125 (EF(TG/AG)n. Based on haplotype analysis and specific recombination events, the following order of the loci was determined: 5cen-D5S76-D5S6-D5S125-SMA-(5'MAP-1B-3'MAP- 1B)/D5S112-JK53CA1/2-(D5S39-D5S127)-5qter. The location of the SMA gene between D5S125 and MAP-1B is further supported by multipoint linkage analysis.
Cell Line, Transformed↗
Recurrent mutations in the factor IX gene: founder effect or repeat de novo events. Investigation of the German haemophilia B population and review of de novo mutations.
The investigation of 114 unrelated patients, representing about half the sample of the German haemophilia B population, enabled us to delineate the causative mutation in 103 (90.4%) haemophilic factor IX genes. Of these 103 cases 84 (81.6%) turned out to be unique molecular events, the remainder being repeats. Haplotype analysis revealed that the great majority, if not all, of these recurrent observations occurred independently. This conclusion is supported by our finding that three de novo mutations could be demonstrated at two sites of frequent mutation. A further 20 de novo events could be established in an unselected sample of 37 families with sporadic haemophilia B and 37 families with a history of the disease. Altogether, the germ line of origin could be determined in 21 of these 23 cases, thereby indicating a ratio of male to female mutation rates close to 2. On the basis of the data available, it is becoming clear that rearrangements in the factor IX gene (35.4% of de novo cases) are responsible for haemophilia B at a higher frequency than has been observed today (12.3%). More than two-thirds of the de novo cases cause the severe form of the disease, thereby reflecting the deficit of these haemophilic genes in the actual gene pool because of excess mortality in the past. In addition 40% (12/30) of the de novo single-base mutations were transitions at CpG dinucleotides. Compared with the expected at-random frequency, this observation indicates an 83-fold enhancement of mutation at CpG.
DNA Mutational Analysis↗
Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk. German Working Group on Paediatric Nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie.
In a systematic study on the clinical picture and genetics of cystic kidneys in children, in association with the German working group on paediatric nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie), we have investigated 79 children with early manifestation of autosomal dominant polycystic kidney disease (ADPKD). They belonged to 64 families (64 index patients and 15 affected sibs). Early manifestation was defined in this study as clinical symptoms (hypertension, proteinuria, impaired renal function, palpably enlarged kidneys) occurring before the age of 15 years. In order to estimate the recurrence risk to sibs of a previously diagnosed patient with early manifesting ADPKD, we found that 15 out of a total of 65 sibs of the 64 index patients (45% of the theoretically expected 32.5 gene carriers) showed comparable early manifestation. Another 10 symptom free children were diagnosed sonographically as having ADPKD before the age of 18 years, so that the total number of affected sibs was 25/65 in the study group, representing 76% of the gene carriers. Although the gene in childhood manifesting ADPKD can be transmitted through both sexes, a statistically significant (p < 0.05) maternal predominance was observed (M:F = 23:41). In affected sibs ages of onset, initial presentation, and the development of complications appeared to be similar in the majority of families. Our data indicate a high recurrence risk to sibs for early manifestation of ADPKD which has important implications for genetic counselling and clinical care of affected families and gives clues to the underlying genetic mechanism of childhood onset ADPKD.
Adolescent↗
Pregnancy and delivery in Charcot-Marie-Tooth disease type 1.
We report the obstetric complications and the influence of pregnancy and delivery in 21 Charcot-Marie-Tooth disease type 1 (CMT 1) patients with 45 gestations. Sixteen patients had subjective disabilities from childhood or youth, and five with late onset had subclinical CMT when they became pregnant. The rate of obstetric complications in the study group was in accordance with that of the normal population, and there was no deleterious effect on fetal outcome. Of the 21 participants, 38% (8 of 21) reported an exacerbation of CMT in at least one pregnancy. These patients noted increasing weakness in 81% (17 of 21) of their gestations. A temporary worsening occurred in 35% (6 of 17) of these pregnancies, and neurologic disabilities persisted after 65% of the deliveries (11 of 17). Patients who had pregnancy-associated progression in the first gestation (7 of 21) experienced similar deterioration in subsequent pregnancies (10 of 11), ie, there is a high risk for recurrence of exacerbations. Four women (19%) stated that their last deliveries were responsible for either an exacerbation or the onset of the neuropathy. The remaining nine patients (43%) denied any effect of their gestations on the progression of the neuropathy. Among the patients who had subjective disabilities from childhood or youth, the risk of a noticeable exacerbation in at least one pregnancy was 50% (8 of 16) and affected 81% of their gestations (17 of 21), whereas there was no influence of pregnancy in the five patients with adult onset of CMT, although the first symptoms were noticed postpartum in two of them.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Direct and indirect estimation of the sex ratio of mutation frequencies in hemophilia A.
Carrier detection tests were carried out in 119 families with hemophilia A by using the data obtained with current DNA techniques (e.g., RFLP analysis and direct identification of mutations), conventional carrier detection tests (e.g., factor VIII:C and von Willebrand factor antigen), and pedigree information. On the basis of this data, we estimated the sex ratio of mutation frequencies with three completely different methods and compared the results. Since the classical indirect method derived from Haldane is substantially influenced by reproductive fitness (f), the sex ratio of mutation frequencies was estimated for both f = .3 and f = .5, resulting in a male:female mutation ratio of 5.37 (95% confidence interval 2.16-13.02) and 3.26 (95% confidence interval 0.97-8.73), respectively. According to the equilibrium-independent indirect method formulated by Rosendaal et al., the male:female ratio was estimated to be 3.4 (95% confidence interval 1.18-8.81). Since current DNA techniques provide information on the grandparental origin of the patient's X chromosome, we were twice able to estimate directly the male:female mutation ratio as 15:1, by using the quotients of mutation origin (maternal grandfather/maternal grandmother and maternal grandfather/patient's mother, respectively). Application of the Fisher test shows that the male mutation rate is higher than the female rate (P = 8.55 x 10(-7). Since all three completely different approaches unequivocally showed a higher male than female mutation frequency, this should be considered to be an established fact in calculating the risk in hemophilia A families.
Adolescent↗
Chromosomal findings in fetuses with ultrasonographically diagnosed ventriculomegaly.
Out of 1101 fetuses with prenatally diagnosed malformations and/or growth retardation 166 (15.1%) revealed a ventriculomegaly. Out of these 18 fetuses (10.8%) demonstrated a chromosomal disorder. Within the group of 97 fetuses with isolated hydrocephalus 6 (6.2%) revealed a chromosomal abnormality. Two fetuses among 29 (6.9%) with hydrocephalus and spina bifida as the only additional sign showed pathologic karyotypes. Among fetuses with additional malformations, 10 out of 40 (25.0%) had a chromosomal disorder. Our data demonstrate that a prenatally diagnosed hydrocephalus should be regarded as an indication for a chromosomal analysis, with the highest amount of chromosomal disorders in fetuses with different additional malformations.
Cardiomegaly↗
Campomelic dysplasia without overt campomelia.
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Bone Diseases, Developmental↗
[Spinal muscular atrophy in childhood. Possibilities and limits of clinical and molecular genetic diagnosis].
The proximal spinal muscular atrophies (SMA) are a clinically and genetically heterogeneous group of neuromuscular disorders which are characterized by selective degeneration of motor neurons in the spine and brainstem. The clinical features resemble other muscle diseases, the diagnostic criteria of proximal SMA have recently been defined by the International SMA Consortium. The classification of the clinical picture in different subgroups is still a focus of discussion. At present it seems likely that childhood onset SMA represents a broad spectrum of various ages of onset and different degrees of disability. Apart from different modes of inheritance, there is further evidence of heterogeneity in proximal SMA. The autosomal recessive forms represent the second frequent recessive disorder after cystic fibrosis, whereas autosomal dominant inheritance is an exception in childhood onset SMA. There are no convincing reports of X-linked SMA hitherto. With mapping of acute and chronic forms of childhood SMA to chromosome 5q11.2-13.3 diagnosis by use of DNA markers in affected families has become available. The current possibilities but also problems and limitations of genotype analysis are discussed, with special regard to the application of prenatal diagnosis. We report on the first experiences with prenatal diagnosis in 37 SMA families.
Adolescent↗
No genetic differences between affected and unaffected members of a German family with Leber's hereditary optic neuropathy (LHON) with respect to ten mtDNA point mutations associated with LHON.
In order to investigate possible synergistic influences of different mtDNA mutations on penetrance and severity of Leber's hereditary optic neuropathy (LHON), a large German LHON pedigree is characterized with respect to 10 different mutations associated with LHON. All members of the family carry three different mtDNA mutations (at nucleotide 4,216, 11,778 and 13,708) in a homoplasmic form, regardless of whether or not they are clinically affected. Testing for another 7 mutations reveals negative results in all family members. Hence, the variable disease expression of the family members cannot be explained by varying combinations of LHON-associated mtDNA mutations.
Base Sequence↗
Routine examination of children at risk of autosomal dominant polycystic kidney disease.
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Child↗
Autosomal recessive polycystic kidney disease.
Autosomal recessive polycystic kidney disease is a rare inherited disorder which usually becomes clinically manifest in early childhood, whereas autosomal dominant polycystic kidney disease usually is a disorder of adult onset. With increasing knowledge and improving diagnostic techniques, it becomes evident that the spectrum of both entities is much more variable than generally known. The presentation of autosomal recessive polycystic kidney disease at later ages and survival into adulthood have been reported. The diagnostic criteria, clinical course, genetics and differential diagnosis of autosomal recessive polycystic kidney disease will be presented.
Caroli Disease↗
Chromosomal findings in fetuses with prenatally diagnosed cysts of the choroid plexus.
Choroid plexus cysts were diagnosed in 25 out of 823 fetuses with prenatally diagnosed abnormalities (growth retardation/malformations). Among these, 5 revealed a chromosomal disorder (4 cases with trisomy 18 and one case with a translocation trisomy 21). Additional abnormalities, such as growth retardation, holoprosencephaly, hydrocephalus and club foot, were found in 6 out of the 20 fetuses with no chromosomal abnormality. All fetuses with a chromosomal disorder revealed further typical prenatally recognizable abnormalities. Our observation indicates that prenatally diagnosed choroid plexus cysts should be considered as an indication for prenatal chromosomal diagnosis, although the risk of there being an underlying chromosomal disorder is low in cases with no additional abnormalities.
Abnormalities, Multiple↗
Pregnancy and spinal muscular atrophy.
We investigated the course and outcome of pregnancy and its influence on muscle weakness in 12 females with proximal spinal muscular atrophy (SMA) who delivered a total of 17 infants when aged 18-32 years. In 4 females the SMA clearly followed an autosomal recessive mode of inheritance. The disease was autosomal dominantly inherited in 2 patients; the other 6 were sporadic cases. Ages of onset of SMA ranged from 8 months to 29 years; all the females learned to walk, and 10 out of 12 are still ambulatory aged 30-60 years. Pregnancy and delivery were complicated in 10 out of 12 patients by premature labour (4), prolonged labour (3) and delayed postpartum recovery (6). Caesarean section was performed in 3 cases. No deleterious effects on fetal outcome could be detected. Exacerbation of muscle weakness after the second trimester of pregnancy was experienced by 8 females: 5 noticed a persistent deterioration of SMA; in 3 muscle weakness worsened temporarily during pregnancy and was followed by marked improvement in the puerperium. The psychological perceptions, in retrospect, of 10 females concerning their decision to have children were evaluated.
Adult↗
Clinical variability of autosomal dominant spinal muscular atrophy.
Autosomal dominant spinal muscular atrophy (SMA) is generally classified into a juvenile and an adult onset form. Clinical data of 20 affected members out of 6 families with autosomal dominant proximal SMA are reported. Three families could largely be classified as the adult onset form (onset after 20 years of life). They showed a benign course, most of them remaining ambulatory 10-40 years after clinical onset. Intrafamilial variability of onset was small, the progression of weakness within one family appeared to be very similar. Three patients of the other 3 families suffered from the juvenile onset form (first symptoms before the age of 12 years) with walking difficulties throughout life, whereas other family members would have been classified as adult onset SMA. The latter had an onset between age 17 and 28 years, and were only moderately handicapped when last examined (aged 38-60 years). The great intrafamilial variability in at least some of the families with autosomal dominant SMA is not compatible with the distinction of two clinically defined genetic entities. This observation is important with respect to a reliable prediction in clinical practice and genetic counselling.
Adolescent↗