Clinical findings in obligate carriers of type I Usher syndrome

Seventeen obligate carriers from nine families with autosomal recessive Usher syndrome type I underwent otological, audiological, vestibular, and ophthalmological examination in order to identify possible manifestations of heterozygosity. Linkage studies were performed and six families showed linkage to chromosome region 11q13.5 while 3 families have so far failed to show linkage to the candidate regions. Eight obligate carriers had an abnormal puretone audiogram. Two different audiometric patterns could be distinguished when hearing loss was corrected for age and sex. Four carriers (24%) had significant sensorineural hearing loss (SNHL) which increased at higher frequencies. The other 13 carriers had SNHL of about 10 dB at 0.25 and 0.5 kHz, but less at higher frequencies. Vestibular findings were generally normal. Electrooculography demonstrated a significant lower mean light peak/dark trough ratio in Usher type I carriers compared to normal control individuals. The methods used in this study were found not to be specific enough to clinically identify carriers of Usher type I syndrome. Nevertheless it is remarkable that a number of obligate carriers showed significant audiological and ophthalmological abnormalities. © 1995 Wiley-Liss, Inc.     

BRCA1 and sex ratio

Two recent papers suggest distorted sex and transmission ratios associated with BRCA1 mutations. If real, these would provide novel insights into the normal biological function of this gene and have implications for genetic epidemiologic methods used to estimate penetrance. We addressed these observations in two settings: offspring of 283 mutation carriers and 471 mutation negative subjects from BRCA1/2 mutation-positive families with multiple cases of breast and ovarian cancer (NCI families); and relatives of 115 BRCA1/2 mutation carriers from the Washington Ashkenazi Study (WAS). The male:female ratio was below one in both BRCA1 (0.85, 95% CI 0.7-1.1 in NCI families; 0.90, 95% CI 0.6-1.4 in WAS) and BRCA2 families (0.77, 95% CI 0.5-1.3 and 0.80, 95% CI 0.5-1.2, in the NCI and WAS study groups, respectively). None of the sex ratios deviated significantly from one, and there was no significant difference between BRCA1 and BRCA2 families. The reduced sex ratio was due largely to the offspring of males, a distortion that is probably an artifact of ascertainment biases. Among adult daughters without breast or ovarian cancer born to mutation carriers, as expected, fewer than 50% were mutation carriers (39% in BRCA1 families and 44% in BRCA2 families). It is difficult, due to ascertainment biases, to draw firm conclusions regarding sex ratios in studies of a sex-limited phenotype. Nonetheless, these observations do not support the idea that BRCA1 mutation carriers have a lower ratio of male offspring than BRCA2 mutation carriers.     

First report of management and outcome of pregnancies associated with hereditary orotic aciduria

Two pregnancies in a 25-year-old woman with hereditary orotic aciduria who was managed prenatally on uridine therapy are described. The first pregnancy resulted in an infant with multiple congenital anomalies and a 47, xx, inv(4)(p12q25), + der(22)t(11;22)(p23;q11) karyotype. The proposita was found to be a carrier of a de novo 11;22 translocation and a pericentric inversion of chromosome 4. Subsequently, several carriers of orotic aciduria in this family were identified with the inverted chromosome 4. The second pregnancy resulted in a normal male with an inverted chromosome 4.     

Segregation analysis of a translocation (16;21)(p11;q22) in a large pedigree

A large family with an inherited reciprocal translocation (16;21) is described. An unbalanced karyotype due to adjacent-1 segregation was documented in 6 cases, whereas 25 children dying within the first year of life and 4 individuals dying at later ages probably had the same abnormality. Therefore minimal and maximal risk estimates were calculated to be 6.0% and 26.5% for female, respectively, 4.8% and 33.3% for male translocation heterozygotes. Among the karyotyped phenotypically normal offspring of male as well as female carriers the ratio of normal children to balanced carriers was not different from 1:1.     

7号染色体臂间倒位伴Turner综合征家系分析

目的研究7号染色体臂间倒位的遗传机制。方法患儿及父母作染色体检查,并对患儿的家系进行调查。结果患儿的染色体核型为46,XX,inv(7)(p22q11)/45,X,inv(7)(p22q11),其中46,XX,inv(7)(p22q11),85%,45,X,inv(7)(p22q11),15%。父亲的核型为46,XY,inv(7)(p22q11),母亲的染色体正常,患儿的母亲第1胎为3月自然流产,家系中其它成员均无流产史,母系成员中身材均偏矮小。结论染色体臂间倒位能引起流产和畸胎,应作产前诊断。     

7号染色体臂间倒位伴Turner综合征家系分析

目的研究7号染色体臂间倒位的遗传机制.方法患儿及父母作染色体检查,并对患儿的家系进行调查.结果患儿的染色体核型为46,XX,inv(7)(p22q11)/45,X,inv(7)(p22q11),其中46,XX,inv(7)(p2q11),85%,45,X,inv(7)(p22q11),15%.父亲的核型为46,XY,inv(7)(p22q11),母亲的染色体正常,患儿的母亲第1胎为3月自然流产,家系中其他成员均无流产史,母系成员中身材均偏矮小.结论染色体臂间倒位能引起流产和畸胎,应作产前诊断.     

Genetic counseling in adult carriers of a balanced chromosomal rearrangement ascertained in childhood: experiences from a nationwide reexamination of translocation carriers.

PURPOSE: Prenatal diagnosis is offered to carriers of a balanced chromosomal rearrangement because it may predispose to offspring with an unbalanced karyotype. Therefore, carriers examined prenatally or in childhood should be informed before they reach reproductive age. We aimed to determine how many of the adult carriers ascertained in childhood currently know about their carrier status. METHODS: We used data obtained by a questionnaire study reexamining carriers of a balanced reciprocal translocation. When a carrier was older than 18 years of age and had been examined in childhood, relatives were asked whether she/he knew of the translocation. RESULTS: Among the 113 parents we interviewed, 10 carriers (9%) in 8 families had not been informed. In one of the eight families, an offspring with an unbalanced translocation was born 23 years after the father had been examined in childhood. CONCLUSION: Because of our findings, the practice of genetic counseling in Denmark has been changed: When a carrier of a balanced chromosomal rearrangement who was examined prenatally or in childhood turns 18 years of age, the parents will receive a letter reminding the family about the reproductive risk.     

Histopathological features of 'BRCAX' familial breast cancers in the kConFab resource

AIMS: In recent years histopathology has made an important contribution to the study of familial breast cancer, largely on the basis of the distinctive cancer phenotype commonly identified in BRCA1-mutation carriers. The aim of this study was to identify this phenotype amongst index cases from families in the kConFab familial breast cancer resource with no known pathogenic mutation ('BRCAX' families). METHODS: The histopathology of breast cancer from 180 individuals was reviewed: 132 members of individual BRCAX families, 26 BRCA1 and 15 BRCA2 mutation carriers and seven mutation negative individuals from families with a known pathogenic mutation. RESULTS: BRCAX breast cancers were a heterogeneous group with 25.8% grade 1, 37.9% grade 2 and 36.4% grade 3. Overall, 45/180 (25%) cases were designated 'BRCA1-phenotype' including 22/132 (16.7%) BRCAX cases, 18/26 (69.2%) BRCA1 and 5/15 (33.3%) BRCA2 mutation carriers. For BRCAX cases, a BRCA1 phenotype designation was negatively correlated with age. CONCLUSIONS: Characteristic breast cancer pathology is not diagnostic of a germline BRCA1 mutation, but it does indicate a pathogenic mechanism that occurs with increased frequency in BRCA1 mutation carriers. In BRCAX families, BRCA1 tumour phenotype may signal the presence of an unidentified BRCA1 mutation. However, this finding must be interpreted with regard to limits of the association between histopathology and genotype, and the importance of clinical context.     

Unusual segregation of t(11;22) resulting from crossing-over followed by 3:1 disjunction at meiosis I

Reciprocal translocation t(11;22)(q23;q11) is of particular interest because the unbalanced offspring of the translocation carriers usually present with a supernumerary derivative chromosome 22. This common unbalanced karyotype is the result of 3:1 chromosome segregation during meiosis. We report the third case of a rare segregation pattern of a paternal 11; 22 translocation. The proband's karyotype revealed the presence of a der(11) and two copies of a der(22), i.e. 47, XX, t(11; 22)(q23;q11), +der(22) t(11;22)pat. The karyotype is the result of paternal 3:1 segregation after crossing-over involving the derived and the normal chromosome 22, as revealed by chromosome polymorphism analysis. Contrary to the preferential maternal transmission of this common unbalanced translocation, the data from the literature, including our case, may suggest preferential paternal transmission of this rare type of unbalanced translocation.     

A complex chromosome rearrangement forms the BCR-ABL fusion gene in leukemic cells with a normal karyotype

Chromosome in situ hybridization studies showed that the normal karyotype of leukemic cells from a patient with Ph1-negative, BCR-positive chronic myeloid leukemia (CML) concealed a complex t(9;22;20)(q34;q11;p13). The close association of 5'-BCR and 3'-ABL was demonstrated by field inversion gel electrophoresis, and in situ hybridization showed that BCR-ABL was located on the short arm of chromosome 20. Our findings further indicate that chromosome rearrangement is the cause of BCR-ABL gene fusion in leukemic cells that show a normal karyotype. Results from in situ hybridization studies were consistent with formation of the t(9;22;20) by a two step chromosomal rearrangement, but field inversion gel electrophoresis results indicated a more complex rearrangement.     

Statistical inference on segregation ratios for D/G-translocations, when the families are ascertained in different ways

The present paper discusses the estimation of the risk rates for D/G-transloeation carriers of having offspring which are either (1) mongols or (2) phenotypically normal D/G-translocation carriers. The analysis is based upon 38 families, most of them taken from the literature; the others are personal communications. For all the sibships in the material only one of the parents is a carrier. The families are ascertained through mongols in different ways which may be classified according to the number of mongols through which the family is ascertained, whether they are in the same or different sibships, and whether the carrier parents are of the same or different sex. There are two levels of observations: (1) the phenotypical level and (2) the cytological level, depending on whether an individual has been investigated cytologically or not. At the phenotypical level it is possible to decide if a person is a mongol or phenotypically normal. At the cytological level it is possible to decide if a person is a D/G-translocation mongol, phenotypically normal D/G-translocation carrier or karyotypically normal. Several persons in the families have died or are unavailable for cytological investigations, and the medical diagnosis concerning mongolism has been improved during the last decades. In separate papers (Stene, 1970a, b) methods of handling materials of this kind have been developed. These methods are applied in the present paper. No inhomogeneities of segregation ratio are found in the offspring of female carriers, but segregation ratios in mongols and non-mongols vary in the offspring of male carriers. The segregation ratio in the offspring of carrier males is less than in the offspring of carrier females. The segregation ratio or risk rate for female carriers is estimated. Owing to the detected inhomogeneity a corresponding estimate cannot be given for male carriers. For the conditional segregation of phenotypically normal individuals in translocation carriers and karyotypically normal individuals no such inhomogeneity is detected. This conditional segregation ratio is found to be equal in the offspring of carriers of both sexes, but is not found to be different from the ratio 1/2. A method suggested by Hamerton (1966, 1968) is shown to be approximate and biased.     

Pericentric inversion of chromosome 2 in a patient with the empty follicle syndrome: case report

The empty follicle syndrome (EFS) is defined as a lack of retrieved oocytes from follicles, at the time of repeated aspiration and flushing, following ovulation induction. The actual mechanism responsible for the EFS is still unknown. The aim of this study was to offer more information regarding the possible connection of this syndrome with pericentric inversion of chromosome 2. We give a case report of a patient who had multiple failed IVF attempts, due to the absence of oocyte and granulosa cells in the follicular fluid, following oocyte retrieval in both stimulated and natural cycles. Chromosomal analysis showed the presence of a pericentric inversion of chromosome 2: 46,XX,inv(2)(p11q21) in the female partner karyotype, while the male partner had a normal karyotype. Our case showed possible genetic factor influence in the aetiology of EFS.     

Der(22)t(11;22) resulting from a paternal de novo translocation, adjacent 1 segregation, and maternal heterodisomy of chromosome 22.

The t(11;22) (q23;q11) translocation is the most frequently identified familial reciprocal translocation in humans. In translocation carriers, 3:1 meiotic segregation with tertiary trisomy can occur resulting in abnormal progeny with the der(22) as the supernumary chromosome. Affected children have a distinct phenotype with multiple anomalies and severe mental retardation. We have identified a child with developmental delay and multiple anomalies consistent with the der(22) phenotype. Cytogenetic analysis showed an abnormal chromosome complement of 47,XX,+der(22)t(11;22)(q23; q11) in all 50 cells analysed. FISH analysis using chromosome 11 and 22 painting probes showed a pattern consistent with a reciprocal translocation of the distal bands 11q23 and 22q11 respectively. Parental karyotypes were normal. RFLP analysis of locus D22S43, which maps above the t(11;22) breakpoint, showed that the der(22) was paternal in origin and indicated that the normal chromosomes 22 were the probable result of maternal heterodisomy. RFLP analysis of locus D22S94, which maps below the t(11;22) breakpoint, also suggested that both normal chromosomes 22 of the child represented the two maternal homologues. Non-paternity was excluded through the analysis of 10 microsatellite markers distributed on 10 different chromosomes and three VNTRs on three different chromosomes. To the best of our knowledge, this is the first reported case of a patient with an abnormal karyotype resulting from a de novo translocation in the paternal germline with probable unbalanced adjacent 1 segregation and maternal non-disjunction of chromosome 22 in meiosis I.     

Risks of unbalanced progeny at amniocentesis to carriers of chromosome rearrangements: data from United States and Canadian laboratories

Data on 1,237 prenatal (amniocyte) diagnoses in cases of familial chromosome rearrangements were collated from 79 American and Canadian laboratories. These were added to European data (Daniel et al: Prenatal Diagn 6:315-350, 1986) on 596 reciprocal translocations (rcp) from 71 collaborative laboratories. The total data set was examined for relationships between balanced or unbalanced result and mode of ascertainment, sex of carrier parent, chromosomes involved, and (in cases of reciprocal translocations and pericentric inversions) for potential or actual chromosome imbalance size (% haploid autosome length). Risk rates for unbalanced segregants were markedly dissimilar. These ranged from approximately 50% down to essentially a negligible risk. The risk was approximately 50% for carriers of the following: complex chromosome rearrangements (ccr); insertions (ins); and for 2:2 segregating rcp ascertained by mode 1 (term unbalanced proband) with small imbalance segments. Pooled carriers (either sex) of 2:2 segregating rcp of mode 1 had a risk of 20-25% whereas female Robertsonian (rob) translocation (D;21) carriers and pericentric inversion (pii) carriers of pii with small distal segments had a risk of 10-15%. Pooled 2:2 segregating rcp carriers ascertained by mode 2 (a couple with recurrent miscarriages) and male carriers of rob (D;21) had a risk of 1.5-5%. The risk of unbalanced segregants was 1-2% (in this data) for male and female rob (13;14) carriers and for pooled pericentric inversion carriers. However, for carriers of most "type" (recurrent breakpoints) pii, for all paracentric inversions, and (as expected) for rob not involving 13 or 21, there were no term unbalanced progeny. For 2:2 segregating reciprocal translocations plots were prepared that could be used to determine broad risk groups for carriers of such rcp. In 3:1 segregating rcp there were 3.3 times fewer male than female carriers, whereas there were 1.3 times fewer male carriers in 2:2 segregating rcp. In 2:2 segregating rcp there is little effect on the fertility of male carriers and risks of unbalanced progeny were found to be equal to those for female carriers, whereas in the 3:1 segregating rcp, risks were much less for male as compared to female carriers. This indicates that 3:1 segregating rep are more similar to Robertsonian translocations in their greater effect on the fertility of male carriers.(ABSTRACT TRUNCATED AT 400 WORDS)     

Application of an intragenic genomic probe to genetic counselling for haemophilia B in the west of Scotland.

Total ascertainment revealed 28 families with haemophilia B in the west of Scotland (prevalence 1/26 870 males). In 12 of these families more than one person was affected and 26 living obligate carriers were identified and tested. Of these, 42% were heterozygous for a DNA polymorphism recognised by a factor IX genomic probe. No recombination was observed in 11 phase known and four phase unknown informative meioses. Definitive genetic counselling was possible for 14 of 42 females at risk, 11 could not be traced, in 10 the probe was not informative, and in seven paternal absence prevented interpretation. Linkage disequilibrium was apparent for this restriction fragment length polymorphism and haemophilia B in the west of Scotland.     

血友病甲基因分析技术的改进及其在产前诊断中的应用

目的对血友病甲基因分析技术进行改进并应用于携带者检查和产前诊断。方法长距离聚合酶链反应方法直接检测凝血因子Ⅷ第22内含子倒位,对非倒位家系用FⅧ基因内限制酶切位点XbaⅠ、HindⅢ、二核苷酸重复序列多态性位点STR13和STR22,以及基因外可变数目串联重复序列DXS52(St14)位点进行基因连锁分析。结果52个家系共检出71位携带者。21个家系为第22内含子倒位,28个家系经连锁分析得到明确诊断,3个家系无法诊断,可诊断家系占94.2%。为18个家系做胎儿产前诊断,其中10例诊断为血友病甲胎儿;诊断7例正常男胎和1例携带者女胎,随访1年发育正常。结论应用长距离聚合酶链反应和多位点基因连锁分析技术可以快速有效地进行血友病甲携带者检查和产前诊断。     

Histopathological features of breast cancer in carriers of ATM gene variants

AIMS: Germline variants in the ataxia telangiectasia mutated (ATM) gene have been implicated in increased breast cancer risk. The aim of this study was to determine whether the histopathology of breast cancers occurring in ATM variant carriers is distinctive or resembles the described BRCA1 mutation-associated phenotype. METHODS: The histopathological features of breast cancers occurring in ATM variant carriers from multiple-case breast cancer families were compared with matched controls. The test group included 21 cases of in situ and/or invasive cancer from carriers of either the IVS10-6T-->G, 2424V-->G or 1420L-->F ATM variants in the absence of BRCA1 or BRCA2 mutations. An additional four invasive cancers from carriers of a pathogenic BRCA1 mutation in the context of a familial ATM variant were also examined. RESULTS: The histopathology of breast cancers in ATM variant-only carriers was not significantly different from controls and known features of BRCA1 mutation-associated cancer were rarely seen. In contrast, these features were prominent in the small group of cases with a pathogenic BRCA1 mutation. CONCLUSIONS: Breast cancer occurring in carriers of ATM variants is not associated with distinctive histopathological features and does not resemble the tumour phenotype commonly observed in BRCA1 mutation carriers.     

Recombinant Down syndrome: a case report and literature review

We report a case of a child with features of Down syndrome (DS) but with an atypical karyotype. Initial chromosome analysis was 46,XX,dup(21q).ish 21(wcp21+). The father's chromosomes were normal. However, the mother was found to have mosaicism for a pericentric inversion of chromosome 21 (19/30 cells). The revised chromosome result of the child was 46,XX,rec(21)dup(21q)inv(21)(p12q21.1)mat. A literature review of similar cases (hereafter referred to as rec dup(21q)) was conducted to aid counselling about recurrence risks and the prognosis for this child. All previous reports of rec dup(21q) were secondary to a maternal pericentric inversion. Male carriers did not seem to be at risk of having offspring with the rec dup(21q), although the number of male carriers was limited. In those with rec dup(21q), the risk of congenital heart disease was similar to that of trisomy 21. In reported cases, the facial appearance was suggestive of Down syndrome but perhaps less striking. Although the data are limited, there is an indication the developmental disabilities and short stature are milder in those with rec dup(21q) compared to trisomy 21. These observations promote the concept that the region of chromosome 21 proximal to the duplication contains genetic information contributing to the expression of some features of Down syndrome.     

Is chromosome analysis mandatory in the initial investigation of normovulatory women seeking infertility treatment?

BACKGROUND: There is no agreement about the frequency of chromosomal abnormalities (CAs) in the female partner of an infertile couple and therefore there is no evidence base for determining whether karyotype analysis is mandatory before the initiation of infertility treatment. The aim of this prospective study was to estimate the prevalence of karyotype abnormalities in normovulatory women attending an infertility clinic and compare it to that known to be present in the newborn female population. METHODS: Cytogenetic testing was performed in 1206 women with normal ovulatory cycle seeking infertility treatment. At least 15 GTG-banded metaphases were analysed in each case. In the case of a structural abnormality, fluorescent in situ hybridization (FISH) analysis and high resolution banding (HRB) were performed on a new blood sample to elucidate the aberration. When mosaicism was suspected, the number of analysed metaphases was increased to a total of 115 and an additional analysis of 200 metaphases was done on a second blood sample. RESULTS: A chromosomal abnormality was demonstrated in 0.58% (95% CI: 0.28-1.19) of cases which did not differ significantly from that reported in female newborns (0.79%; 95% CI: 0.68-0.94). Balanced reciprocal translocation was observed in 0.4% of patients (n = 5), paracentric inversion of chromosome X in 0.08% (n = 1) and gonosomal mosaicism in 0.08% (n = 1). However, chromosomal aberrations were less common among females with primary infertility compared to those with secondary infertility (0.25 versus 1.25%, P = 0.04). CONCLUSIONS: The present study suggests that routine cytogenetic analysis cannot be advocated in normovulatory infertile women. Nevertheless, the relatively higher frequency of abnormal karyotypes in women with secondary infertility indicates that this subgroup of patients might benefit from a routine karyotype analysis.     

全染色体涂抹探针在女性罗伯逊易位携带者植入前遗传学诊断中的临床应用

目的应用全染色体涂抹探针（whole chromosome painting probe，WCP）对女性罗伯逊易位携带者进行卵母细胞第一极体的植入前遗传学诊断（preimplantation genetic diagnosis，PGD）。方法应用全染色体涂抹探针进行第一极体荧光原位杂交，对4例女方罗伯逊易位携带者进行了4个周期的PGD。患者染色体核型均为45，XX，der（13；14），（q10；q10）。所有周期取卵后6h内通过活检取出第一极体，采用WCP探针进行荧光原位杂交，受精后第3天选择染色体组成正常或平衡的胚胎进行宫腔内移植。结果4个周期共获卵61个，其中54个成熟可进行活检，活检成功率92．6％（50／54），固定成功率90．O％（45／50）。40个获得明确诊断，总体诊断率为74．1％（40／54）。卵胞浆内单精子注射后受精率64．8％（35／54），优质胚胎率为65．7％（23／35）。获得2例临床妊娠。其中1例于孕9周胚胎停止发育，绒毛染色体分析核型为45，X；另1例产前诊断证实核型为46，XX。2006年6月足月分娩一正常活女婴。结论全染色体涂抹探针可准确区分正常、平衡以及异常卵子，从而可有效应用于女性染色体易位携带者的PGD。