Novel rhodopsin mutations and genotype-phenotype correlation in patients with autosomal dominant retinitis pigmentosa.

AIM: To identify novel or rare rhodopsin gene mutations in patients with autosomal dominant retinitis pigmentosa and description of their clinical phenotype. METHODS: The complete rhodopsin gene was screened for mutations by DNA sequencing in index patients. Mutation specific assays were used for segregation analysis and screening for controls. Eight patients from five families and their relatives were diagnosed with autosomal dominant retinitis pigmentosa (adRP) by means of clinical evaluation. RESULTS: Mutation screening identified five different rhodopsin mutations including three novel mutations: Ser176Phe, Arg314fs16, and Val20Gly and two missense mutations, Pro215Leu and Thr289Pro, that were only reported once in a mutation report. Electrophysiological and psychophysical testings provide evidence of an impaired rod system with additionally affected cone system in subjects from each genotype group. Visual function tended to be less affected in subjects with the Arg314fs16 and Val20Gly mutations than in the Ser176Phe phenotype. In contrast, Pro215Leu and Thr289Pro mutations caused a remarkably severe phenotype. CONCLUSION: The ophthalmic findings support a correlation between disease expression and structural alteration: (1) extracellular/intradiscal Val20Gly and cytoplasmic Arg314fs16 mutation-mild adRP phenotype; (2) Ser176Phe mutation-"mostly type 1" disease; (3) predicted alteration of transmembrane domains TM V and TM VII induced by Pro215Leu and Thr289Pro-severe phenotype. However, variation of phenotype expression in identical genotypes may still be a typical feature of RHO mutations.

Clinical and molecular cytogenetic characterization of two patients with partial trisomy 1q41-qter: further delineation of partial trisomy 1q syndrome.

We report the clinical and molecular cytogenetic characterization of two patients with partial trisomy 1q. The first patient is a currently 11-year-old female proposita with a de novo unbalanced translocation 46,XX,der(8)(8qter-8p23.3::1q41-1qter), leading to a partial trisomy 1q41-qter and a partial monosomy for 8p23.3-pter. The most prominent clinical features of the girl are a triangular face, almond-shaped eyes, low-set ears, short stature with relatively long legs, and mild psychomotor retardation. To our knowledge, the cytogenetic aberration in this girl is the most proximal partial trisomy 1q leading to a mild phenotype. Recently, we identified a second patient with a similar partial trisomy 1q combined with a cri du chat syndrome caused by a de novo unbalanced translocation 46,XX,der(5)(5qter-5p13.1::1q41-1qter). Comparison of the phenotype of the two girls as well as with already published trisomy 1q cases was performed, and fluorescence in situ hybridization probes from selected YACs were used to delineate the extent of the partial trisomy in more detail.

Familial mental retardation syndrome ATR-16 due to an inherited cryptic subtelomeric translocation, t(3;16)(q29;p13.3).

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.

Mosaicism in a fragile X male including a de novo deletion in the FMR1 gene.

In most cases the fragile X syndrome is caused by an amplification of the CGG trinucleotide repeat in the 5' untranslated region of the FMR1 gene, in combination with the hypermethylation of the proximal CpG island. Recently, also a few cases with deletions or a mosaic of a deletion and a full mutation in the FMR1 gene, leading to the same phenotype, have been described. Here we report the molecular analysis of a patient with typical fragile X phenotype and mosaicism of the FMR1 genomic region consisting of a premutation, a full mutation of the CGG repeats, and a 215 bp deletion, diagnosed by Southern blot hybridisation and polymerase chain reaction (PCR). Sequence analysis of the deletion demonstrated that the 5' breakpoint of the deletion is located within a putative hotspot region 75-53 bp proximal to the CGG repeat.

Clinical, cytogenetic and molecular analysis of three 46,XX males.

Cytogenetic analysis, fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) were applied to characterize the Y-chromosomal breakpoints of three XX male patients. Two of these patients show a breakpoint within a protein kinase gene, PRKY, previously described as a hotspot of ectopic recombination between homologous regions on X and Y chromosomes during male meiosis. The slightly different clinical phenotypes of the three patients cannot be correlated with the localization of the breakpoints.

[Pregnancy termination after prenatal diagnosis--data of the Styrian malformation register (1985-1992)]. / Schwangerschaftsabbruch nach Pränataler Diagnostik--Daten des Steirischen Fehlbildungsregisters (1985-1992).

3098 embryos, fetuses or newborns with congenital anomalies were registered in the period from 1985 to 1992 by the Styrian Malformation Register (prevalence 2.88%) the common screening tool for prenatal diagnosis is sonography. About 1/2 of all pregnant women aged 35 or more took advantage of karyotyping offered to this group of patients. Altogether 4004 fetal karyotypes were performed, leading to 89 terminations of pregnancy. A total of 181 terminations of pregnancy following prenatal diagnosis of congenital anomalies were recorded by the Styrian Malformation Register. The annual rate of terminations of pregnancy did not change over the years (5.3-6.7%). About 2/3 of severe congenital anomalies were missed or diagnosed too late in pregnancy. A comparison of our data with those of EUROCAT, the central malformation register of Europe, showed that hydrocephalus was terminated significantly more frequently in the EUROCAT data, but the difference in other congenital anomalies was less marked. It follows that prenatal diagnosis in Austria and all over Europe is subject to equal social demands and medical standards. The study highlights, furthermore, the need for specialist doctors to receive standardized high-quality training in prenatal diagnosis in Austria.

[The triple test scenario for Styria. With data of the Styria Abnormalities Register]. / Triple-Test-Szenario für die Steiermark. Mit Daten des Steirischen Fehlbildungsregisters.

OBJECTIVE: The aim of the study was to clarify by a cost-effectiveness analysis, if a triple-marker screening for trisomy 21 (triple test) should be established in Austria. METHODS: The published triple-test results of the last years were combined with the data of the Styrian Malformation Register covering the years 1985-1992. The cost-effectiveness analysis was based on total costs of prenatal diagnosis, costs per fetus diagnosed as affected, the number of affected fetuses detected, and the number of procedure-related losses. RESULTS: If low costs are given priority, the triple test should be offered to women 35 years of age or older. If a high detection rate is given top priority, the test should be offered to all pregnant women. CONCLUSION: The results suggest that the present policy of maternal age screening in Austria should be replaced by maternal serum screening.

[Doppler ultrasound of the umbilical artery in fetuses with sonographically abnormal findings and/or chromosome abnormalities (corrected)]. / Doppler-Sonographie der Arteria umbilicalis bei Feten mit sonographisch auffälligem Befund und/oder Chromosomenanomalien [corrected].

We performed 77 Doppler blood flow studies of the umbilical artery in 45 foetuses with malformations and/or chromosomal abnormalities. 20 foetuses had chromosomal abnormalities and 34 records of the second and third trimester were analysed. In 25 foetuses with malformations, but without chromosomal abnormalities, 43 investigations were performed between 21st and 40th weeks of gestation. In the second trimester, 3 of 11 foetuses with chromosomal abnormalities had an absence of enddiastolic flow velocities, whereas the other foetuses had pulsatility indices within the range for foetuses with a normal karyotype. In the third trimester, 7 of 10 foetuses with chromosomal abnormalities had pathological Doppler findings. Four cases had absent or reversed enddiastolic (ARED) flow velocities. Altogether 10 of 13 foetuses beyond the 19th weeks of gestation had pathological Doppler findings (sensitivity = 77%). The structure and the function of the placenta is influenced by the abnormal karyotype, which is demonstrated by pathological Doppler findings. Only 3 of 43 investigations in foetuses with malformations but normal karyotype, showed abnormal PI values and there was no case of ARED flow. In a group of 24 foetuses with ARED flow, 6 foetuses had chromosomal abnormalities. All foetuses with malformations and ARED flow had an abnormal karyotype. Prenatal chromosome analyses of foetuses with suspicious sonographic findings, revealed a rate of 29% chromosomal abnormalities, nearly all of them with a maternal age under 35 years. Whereas Doppler sonography cannot exclude chromosomal abnormalities before the 20th weeks of gestation, there is a good correlation between chromosomal abnormalities and abnormal Doppler findings later on.(ABSTRACT TRUNCATED AT 250 WORDS)

[Holoprosencephaly: criteria and consequences for prenatal diagnosis]. / Holoprosenzephalie: Kriterien und Konsequenzen der pränatalen Diagnostik.

Two cases of prenatal diagnosis of holoprosencephaly are described. The characteristic sonographic findings in the second trimester were: microcephaly, absence of the midline echo, hypotelorism and typically flattened profile without sufficient configuration of the nose. Both foetuses had midline facial clefts, one of which was diagnosed prenatally. One case demonstrated a dorsal intracranial cyst. Analysis of the karyotype after foetal blood sampling and amniocentesis revealed translocation trisomy 13 in one case. The mother of this foetus had a balanced translocation 13/14. This foetus also had many extracranial abnormalities in contrast to the other foetus, which had a normal karyotype. Additionally we report of the prenatal diagnosis of a third case with cyclopia and trisomy 13. The findings of the autopsy of the foetuses are described and the criteria for prenatal diagnosis are compared to those found in the literature.

[Chromosome analysis in abortion]. / Chromosomenanalysen bei Abortus.

Many spontaneous abortions are caused by chromosome abnormalities of zygotes or embryos. We found chromosome aberrations in 15 of 59 successful cultivated tissues of miscarriages. The detecting of one trisomy 2 in these investigations is remarkable. At the same time we examined the chromosomes of couples suffering from repeated abortions. 21 of 512 tested females and 12 of 474 tested males showed abnormal chromosome sets. The results and their consequences are discussed.

[Type and incidence of abnormalities in 23,939 newborn infants in a 5-year period]. / Art und Häufigkeit von Missbildungen unter 23,939 Neugeborenen eines Zeitraumes von 5 Jahren.

23,939 children born consecutively at the Department of Obstetrics and Gynaecology, University of Graz, over a 5-year period ending 31. 12. 1984 were surveyed for the presence of major malformations. 394 (1.6%) had a major congenital defect. Within the same time 392 infants died during the perinatal period, 86 of them being malformed (22%). The malformations were listed according the most likely mode of inheritance, revealing a total of 80 different congenital defects. About 70% of these malformations are associated with an increased recurrence risk (greater than 1%) and 15% carry a high risk of recurrence (greater than 10%). These facts point to the importance of prenatal diagnosis and proper genetic counselling.

Prenatal diagnosis of campomelic dysplasia by ultrasonography.

Consanguineous partners had a boy with campomelic dysplasia who died of increasing respiratory distress soon after birth. The next pregnancy was monitored frequently by ultrasonography and a healthy male infant was born at term. During a further pregnancy, ultrasonography suggested campomelic dysplasia in the 16th week of gestation. This was confirmed in the 18th week. The pregnancy was terminated and the fetus showed the typical radiological, anatomical and histological findings.

[Prenatal diagnosis: results and observations (author's transl)]. / Ergebnisse und Erfahrungen bei der pränatalen Diagnose.

In a period of over 7 years, 57 pathological results were obtained on analysis of 1470 amniotic fluid samples. The findings are tabulated in this paper and attention is drawn to the importance of the demonstration of rapidly adherent neural cells and specific neurogenic acetyl cholinesterase in the amniotic fluid in the diagnosis of open neural defects. Experience gained in this field is the basis for suggested guide lines applicable to prenatal diagnostic centres.

[Treatment of subacute pelvic inflammatory diseases with the antibiotic compound sulfametrol-trimethroprim (author's transl)]. / Die Behandlung subakuter Entzündungen der Adnexe mit der Antibiotikakombination Sulfametrol-Trimethoprim.

40 patients with subacute pelvic inflammations were treated with the antibiotic compound sulfametrol-trimethoprim. The patients received twice a day 2 tablets with some liquid in the morning and evening. The average duration of treatment was 16.1 days. In 37 patients (92.5%) the disease could be cured completely or a distinct improvement could be achieved. In 3 cases (7.5%) the results were unsatisfactory. Side-effects were seen merely in 2 cases (sickness with allergic exanthem and diarrhea respectively).

[A 5-year review of prenatal diagnosis in Graz (author's transl)]. / 5 Jahre pränatale Diagnose in Graz.

Between 1/7/1974 and 30/6/1979 we analysed 532 amniotic fluid cell cultures. In 402 cases a genetic indication for amniocentesis was given; 57 prenatal diagnoses were carried out for gynaecological and other medical indications. We also analysed 73 amniotic fluid test samples. Altogether 19 pathological results (3.6%) were found. We observed 16 abnormal findings in 459 diagnostic amniocenteses and 3 pathological results in the test cultures. The transmission of parental chromosomal polymorphisms to the fetus is discussed here. The importance of prenatal diagnosis in genetic counselling, along with cost-benefit reflections, are stressed in this paper.

[Asymmetric mixed gonadal dysgenesis (author's transl)]. / Asymmetrische gemischte Gonadendysgenesie mit besonderem gonosomalem Mosaik.

We would like to report a girl, 11 7/12 years old, with the typical signs of an asymmetric mixed gonadal dysgenesis (amgd). The external genitalia were ambiguous, the inner genital organs contained a dysgenetic testis on the right side an ovarian "streak" on the left. At laparatomy follopian tubes were found bilaterally. On the right side the microscopic specimen showed an epididymis. There was an unicornuate malformation of the uterus. The karyotype, first examined 1969 in the age of a few month, showed chromosomal mosaicism, 45 XO/46 XX. In 1980 this problem was reevaluated, because now the HY-antigen-determination was available, this was uniformally found to be positive in our patient. Now the new karyotype with special methods was 45 XO, 46 X dic (y)/47 XY + dic (y). This karyotype was, to ower knowledge, never seen before in amgd. Particular emphasis was payed to the discussion of the pathogenesis of this karyotype and the amgd in general. We would like to consider this intersexual malformation as a prototype of a chromosomal induced disturbance of somatic sexual differentiation.

[Clinical importance of chromosomal translocations (author's transl)]. / Klinische Bedeutung chromosomaler Translokationen.

5835 chromosomal analyses were performed between May 1, 1962 and December 31, 1978. We found 68 translocations (1.1%). 36 translocation carriers were identified as being chromosomally balanced, of whom 24 were healthy and 12 clinically abnormal (5 showed centric fusions - 3 x D/D, 2 x D/G - and 7 other chromosomal rearrangements). 32 translocation carriers were chromosomally non-balanced, among them 28 patients with centric fusions (12 x G/G, 2 x D/D, 14 x D/G) and 4 with other rearrangements combined with characteristic clinical features. A review of the chromosomal translocations found in our laboratory is presented. The relation between clinical appearance and chromosomal rearrangement is discussed.

[Prenatal diagnosis of trisomy-18-fetus of two women with chromosomal aberrations (author's transl)]. / Pränatale Diagnose von Trisomie-18-Feten bei zwei Frauen mit Chromosomenaberrationen.

In two pregnant women a prenatal diagnosis was performed because of their advanced age. In both cases trisomy 18 was found. The mothers had chromosomal variations, not known until then. In one woman a structural aberrant chromosome No. 9 was found, the other woman had a gonosomal mosaic. In connection with the advanced maternal age these chromosomal findings possibly induced the trisomies in the children.