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PubMed2003

Down syndrome: a study of chromosomal mosaicism.

Recent data suggest that chromosome mosaicism is a possible mechanism for intrauterine and postnatal survival in cases of trisomy 18 and Turner syndrome (45X). The aim of this study was to evaluate if chromosomal mosaicism is a possible mechanism of survival in Down syndrome (DS) (trisomy 21) individuals. Mosaicism was studied by interphase fluorescence in-situ hybridization (FISH), using a specific probe for chromosome 21 (21q22.13-21q22.2) in 78 cases suspected of DS. To rule out tissue specific mosaicism, buccal cells or amniocytes were analysed in addition to blood in 20 DS cases. Thirty-three per cent of the cases studied by FISH in only peripheral blood were mosaics. In 20 cases of trisomy 21, two tissues were studied and mosaicism was not detected in either of the two tissues in 15 cases. The remaining five cases were mosaics in both the tissues analysed. Clinical comparisons in 17 DS mosaics showed a direct relationship between the percentage of trisomic cells and the degree of phenotypic manifestations. These results suggest that mechanism(s) other than mosaicism may exist for the intrauterine and postnatal survival of DS cases.

Amnion↗
PubMed1996

45,X/46,XY mosaicism: the role of ultrasound in prenatal diagnosis and counselling.

The purpose of this study was to assess the benefit of ultrasound evaluation for fetuses with prenatally diagnosed 45,X/46,XY mosaicism. The charts of all patients who underwent chorionic villus sampling and/or amniocentesis between 1 March 1990 and 31 October 1995 were screened for 45,X/46,XY mosaicism. Cases were divided on the basis of the results of the confirmatory amniocentesis into two groups: (1) confined placental mosaicism (n = 4); and (2) true fetal 45,X/46,XY mosaicism (n = 4). All patients underwent high-resolution detailed ultrasound study between 16 and 22 weeks. If the initial ultrasound study failed to visualize fetal genitalia, scanning was repeated in 2 weeks. Chromosome analysis was carried out on the newborn's skin to confirm the prenatal result. Six cases were found to have 45,X/46,XY mosaicism on chorionic villus sampling. Amniocentesis indicated a normal 46,XY male karyotype for three fetuses and true fetal 45,X/46,XY mosaicism for two cases. One patient declined follow-up amniocentesis. At birth, this newborn was documented to have normal male genitalia and a 46,XY karyotype. An additional two cases underwent amniocentesis only and were documented to have 45,X/46,XY mosaicism. High-resolution detailed ultrasound study between 16 and 22 weeks revealed seven fetuses with normal male genitalia and one fetus with ambiguous genitalia. Of the four neonates with true 45,X/46,XY mosaicism this was the only one found to have ambiguous genitalia. We conclude that the work-up of patients with 45,X/46,XY mosaicism should include ultrasound study to look for ambiguous genitalia. This allows appropriate counselling regarding the natural history of the condition and aids in the planning for management in the postnatal period.

Amniocentesis↗
PubMed1999

High rate of mosaicism in tuberous sclerosis complex.

Six families with mosaicism are identified in a series of 62 unrelated families with a mutation in one of the two tuberous sclerosis complex (TSC) genes, TSC1 or TSC2. In five families, somatic mosaicism was present in a mildly affected parent of an index patient. In one family with clinically unaffected parents, gonadal mosaicism was detected after TSC was found in three children. The detection of mosaicism has consequences for genetic counseling of the families involved, as changed risks apply to individuals with mosaicism, both siblings and parents. Clinical investigation of parents of patients with seemingly sporadic mutations is essential to determine their residual chance of gonadal and/or somatic mosaicism, unless a mosaic pattern is detected in the index patient, proving a de novo event. In our data set, the exclusion of signs of TSC in the parents of a patient with TSC reduced the chance of one of the parents to be a (mosaic) mutation carrier from 10% to 2%. In the five families with somatic mosaicism, the parent was given the diagnosis after the diagnosis was made in the child.

Base Sequence↗
PubMed1999

Tissue-specific somatic mosaicism in spinal and bulbar muscular atrophy is dependent on CAG-repeat length and androgen receptor--gene expression level.

The factors influencing the tissue-specific pattern of somatic mosaicism in CAG-repeat diseases have not yet been fully resolved. We performed a detailed analysis of the degree of somatic mosaicism in various tissues from 20 patients with spinal and bulbar muscular atrophy (SBMA), including 4 who were deceased. The most outstanding feature was the prominent somatic mosaicism observed in the cardiac and skeletal muscles, composed predominantly of postmitotic cells, and in the skin, prostate, and testis. The CNS tissues, liver, and spleen showed the least mosaicism. The tissue distribution of somatic mosaicism in patients with SBMA was markedly different from that in patients with Huntington disease (HD) and from that in patients with dentatorubral-pallidoluysian atrophy (DRPLA). The degree of somatic mosaicism correlated with the CAG-repeat number but not with age at examination. Furthermore, tissues with a higher mosaicism level corresponded well to those with a higher expression level of androgen receptor protein. The tissue-specific pattern of somatic mosaicism related not only to cell composition with different cell turnover rates but to repeat size and gene expression levels, and postnatal cell division is unlikely to be a major cause of somatic mosaicism probably because of the relative stability of CAG repeat in SBMA.

Adult↗
PubMed2000

De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10.

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by deletion of most copies of the 3.3-kb subtelomeric D4Z4 repeat array on chromosome 4q. The molecular mechanisms behind the deletion and the high proportion of new mutations have remained elusive. We surveyed 35 de novo FSHD families and found somatic mosaicism in 40% of cases, in either the patient or an asymptomatic parent. Mosaic males were typically affected; mosaic females were more often the unaffected parent of a nonmosaic de novo patient. A genotypic-severity score, composed of the residual repeat size and the degree of somatic mosaicism, yields a consistent relationship with severity and age at onset of disease. Mosaic females had a higher proportion of somatic mosaicism than did mosaic males. The repeat deletion is significantly enhanced by supernumerary homologous repeat arrays. In 10% of normal chromosomes, 4-type repeat arrays are present on chromosome 10. In mosaic individuals, 4-type repeats on chromosome 10 are almost five times more frequent. The reverse configuration, also 10% in normal chromosomes, was not found, indicating that mutations may arise from transchromosomal interaction, to which the increase in 4-type repeat clusters is a predisposing factor. The somatic mosaicism suggests a mainly mitotic origin; mitotic interchromosomal gene conversion or translocation between fully homologous 4-type repeat arrays may be a major mechanism for FSHD mutations.

Age of Onset↗
PubMed2002

Chromosomal mosaicism throughout human preimplantation development in vitro: incidence, type, and relevance to embryo outcome.

BACKGROUND: A large percentage of in-vitro generated cleavage stage human embryos are chromosomally mosaic, consisting of both normal (diploid) and abnormal (non-diploid) cells. The present study characterized mosaicism at each stage of cleavage division and examined its effect on preimplantation development in vitro. METHODS: A total of 216 normally fertilized (two-pronucleate) embryos which were not selected for transfer to the patients were analysed for chromosomal abnormalities using multi-colour fluorescence in-situ hybridization DNA probes specific for three to five of nine different chromosomes (X, Y, 2, 7, 13, 16, 18, 21, 22). RESULTS: Overall, 48.1% of embryos were mosaic. The frequency of mosaic embryos increased from 15.2 to 49.4 to 58.1%, from the 2-4-cell to 5-8-cell to morula stages respectively, and the types of non-diploid cells detected were mostly aneuploid or chaotic. The incidence of mosaicism at the blastocyst stage was 90.9%; however, most of the mosaicism comprised diploid and polyploid cells. Arrested mosaic embryos had a higher incidence of chaotic abnormalities, and higher proportions of abnormal cells compared with the non-arrested group. CONCLUSIONS: Post-zygotic errors leading to mosaicism may occur, and persist throughout preimplantation development in vitro. Our results suggest that mosaicism involving multiple chromosomal imbalances and/or imbalances affecting a high proportion of cells in an embryo appear to impair development to the blastocyst stage.

Adult↗
PubMed1976

Dermatoglyphics in mosaic Down's syndrome.

To determine whether quanitative dermal indices are useful in ascertaining the liability for or severity of mosaic Down's syndrome (DS), dermatoglyphics of 107 subjects with proven 46/47,+21 DS were scored by four quantitative dermal indices. The distribution of mosaics by weighted mean percentage of +21 cells ranged from 1 to 95 and was bimodal. Mean maternal age at birth of mosaics (32.9 +/- 7.5 years) was elevated when compared with control maternal ages in the literature. The distribution of quantitative dermal indices for the total mosaic population fell roughly midway between those in the literature for normal and full DS individuals: 73% of mosaics were classified as definitively DS, 21% were in the intermediate range, and 6% were normal. For mosaics who were minimally affected, 24% were DS, 53% intermediate, and 23% normal. One can conclude: (1) For any suspect mosaic, a dermal score in the DS range is highly suggestive of karyotypic pathology. (2) The high prevalence of intermediate scores in normal subjects severely restricts their diagnostic value in screening for mosaics in the general population. For a selected population, such as parents of +21 children, the screening value of quantitative dermal indices remains an open question. Weighted regression analyses demonstrate a highly significant correlation (P less than 0.001) of dermal index score with the weighted mean proportion of +21 cells transformed to the logit scale. One may exploit this correlation to predict the ratio of +21/normal cells in infants, in whom early karyotype evolution can preclude an estimate of the ultimate syndrome based on initial degree of mosaicism. Furthermore, this correlation provides additional indirect evidence that dermal microsymptoms in DS are a reflection of the presence of +21 cells.

Dermatoglyphics↗
PubMed1999

Trisomy 15 CPM: probable origins, pregnancy outcome and risk of fetal UPD: European Collaborative Research on Mosaicism in CVS (EUCROMIC).

Different origins for trisomy 15 mosaicism confined to the placenta have been suggested. We have analysed the data on trisomy 15 mosaicism in EUCROMIC. Trisomy 15 mosaicism or non-mosaic feto-placental discrepancy on CVS was registered in 0.027 per cent of samples karyotyped (34/126 465): 28/34 had confined placental mosaicism (CPM), 1/34 was probably true fetal mosaicism and 5/34 could not be classified. In 17 of the 28 pregnancies with CPM, cytogenetic information existed on both cytotrophoblast lineage (direct CVS preparation or short-term incubation) and extra-embryonic mesoderm, EEM (villus culture): CPM was of type I (restricted to the cytotrophoblast) in 5/17 (29 per cent); type II (restricted to the EEM) in 4/17 (24 per cent) and type III (both cytotrophoblast and EEM) in 8/17 (47 per cent). Testing for uniparental disomy (UPD) for chromosome 15 in the fetus or child was done in nine cases, showing upd(15)mat in 1/9, and biparental inheritance in 8/9. Upd(15)mat, clinically diagnosed due to Prader Willi syndrome, but without DNA analysis, was registered in one additional liveborn child. Analysis of these 17 cases, in conjunction with 10 similar reports in the literature also having cytogenetic data from both cell lineages, indicates two categories of trisomy 15 CPM. One has a high proportion of trisomic cells, often with a type III distribution, and an observed high risk of UPD and adverse pregnancy outcome. The second has lower proportions of trisomic cells, primarily of type I or II distribution, and a lower empirical risk of UPD or pregnancy loss. Based on this cytogenetic analysis, supported by the available DNA data, we suggest that, in contrast to trisomy 16 CPM, the trisomic cell line originates from a meiotic error in only about 50 per cent of cases of trisomy 15 CPM, the rest being the result of post-zygotic, mitotic non-disjunction. Despite this, we recommend amniocentesis following the finding of a mosaic or non-mosaic trisomy 15 by CVS, in order to exclude both UPD and potential true fetal mosaicism.

Amniotic Fluid↗
PubMed1977

A search on karyotypic mosaicism in mongoloid patients and their parents.

The frequency of chromosomal mosaicism among patients with clinical diagnosis of mongolism was determined. Among 50 patients with at least 32 cells studied, 2 (or 4%) were found to be mosaics of the 46/47, +G type. Among 350 patients with at least 5 cells studied, 2 (or 0.57%) 46/47, +G mosaic cases were detected. Taking in account the probability of detecting mosaicism when 5 cells are analysed, a frequency of 0.58% of mosaic cases was estimated for this sample. The mosaic patients were submitted to repeated cytogenetic examination. One of these cases showed significant differences between the frequencies of normal cells, but a linear regression analysis showed that there was no correlation between the frequency of these cells and the patient's age. Clinically, the mosaic patients showed no consistent differences in the severity of the syndrome when compared to mongoloids without mosaicism. A frequency of 16 translocation cases (4%) was found in the total number of mongoloid patients studied. In a sample of 190 parents of regular trisomy-21 children no mosaicism was found in the blood. Also no significant differences were observed between the frequencies of aneuploid, hyperdiploid or hypodiploid cells and those obtained by other authors in the general population.

Adolescent↗
PubMed2006

Pre- and postnatal findings in trisomy 17 mosaicism.

Trisomy 17 mosaicism is one of the rarest autosomal trisomies in humans. Thus far, only 23 cases have been described, most of them detected prenatally. In only five instances has mosaicism been demonstrated in lymphocytes and/or fibroblasts postnatally, and only in these have multiple congenital anomalies (MCA), facial dysmorphisms, and mental retardation been reported. Patients with trisomy 17 mosaicism at amniocentesis and a normal karyotype in blood and fibroblasts (n = 17) were always healthy. Here, we report on pre- and postnatal clinical, cytogenetic, molecular-cytogenetic, and molecular findings in four patients with trisomy 17 mosaicism. The first case was detected in cultured but not in short-term chorionic villi and amniocytes. Due to MCA on prenatal ultrasound examination the pregnancy was terminated. The second patient is a 13-month-old healthy boy, in whom low level trisomy 17 mosaicism was detected in cultured chorionic villi only. The third patient is a 2-year-old girl with growth retardation, developmental delay, MCA, and trisomy 17 mosaicism in amniocytes, fibroblasts, and placenta, but not in blood and buccal smear. The fourth patient is a 9-year-old boy with growth and mental retardation, sensoneurinal hearing loss, and MCA. Cytogenetic analyses showed trisomy 17 mosaicism in amniocytes, skin fibroblasts, and urinary sediment cells, whereas in blood and buccal smear a 46,XY karyotype was found. Molecular investigations in all four cases indicated biparental inheritance of chromosome 17. Formation of trisomy was most likely due to a maternal meiosis I error in Patient 1 and a postzygotic non-disjunction of the paternal chromosome 17 in Patient 4. Cerebellar malformations, reported in two cases from the literature and in two reported here may be a specific feature of trisomy 17 mosaicism. Since the aberration has rarely been reported in lymphocytes, chordocentesis is not indicated in prenatal diagnosis. Prenatal genetic counseling for trisomy 17 mosaicism in chorionic villi or amniocytes should consider that the clinical significance remains uncertain.

Adult↗
PubMed1995

Large retinal ganglion cells in the channel catfish (Ictalurus punctatus): three types with distinct dendritic stratification patterns form similar but independent mosaics.

Retinal ganglion cells in the channel catfish (Ictalurus punctatus) were retrogradely labelled, and those with the largest somata and thickest primary dendrites were categorized by their levels of dendritic stratification. Three types were found, each forming a mosaic making up approximately 1% of the ganglion cell population. Using a system based on established sublaminar terminology, we call these the alpha-a (alpha a), alpha-b (alpha b), and alpha-c (alpha c) ganglion cell mosaics. Cells of the alpha a mosaic had large, sparsely branched trees in sublamina a at 10-30% of the depth of the inner plexiform layer (IPL), sclerad to those of all other large ganglion cells. Some alpha a somata were displaced into the IPL or inner nuclear layer (INL) but belonged to the same mosaic as their orthotopic counterparts. Cells of the alpha b mosaic had dendrites that branched a little more and arborized in sublamina b at 50-60% of the IPL depth. Many also sent fine branches into sublamina a, and some were fully bistratified in a and b. The alpha c cells arborized in the most vitread sublamina, sublamina c, at 80-95% of the IPL depth. The soma areas of the three types in the largest retina studied ranged between 139 microns 2 and 670 microns 2 with significant differences in the order alpha a > alpha c > or = alpha b. Analyses based on nearest-neighbour distance (NND) and on spatial auto- and cross-correlograms showed that each mosaic was statistically regular and independent of the others. Mosaic spacings were similar for each type, giving mean NNDs of 242-279 microns in the largest retina and 153-159 microns in a smaller one. Correspondences between these mosaics, previously defined large ganglion cell types in catfish, and other mosaic-forming large ganglion cells in fish and frogs are discussed along with their implications for neuronal classification, function, development, and evolution.

Animals↗
PubMedDate not supplied

Large retinal ganglion cells in the pipid frog Xenopus laevis form independent, regular mosaics resembling those of teleost fishes.

Population-based studies of retinal neurons have helped to reveal their natural types in mammals and teleost fishes. In this, the first such study in a frog, labeled ganglion cells of the mesobatrachian Xenopus laevis were examined in flatmounts. Cells with large somata and thick dendrites could be divided into three mosaic-forming types, each with its own characteristic stratification pattern. These are named alpha a, alpha ab, and alpha c, following a scheme recently used for teleosts. Cells of the alpha a mosaic (approximately 0.4% of all ganglion cells) had very large somata and trees, arborizing diffusely within sublamina a (the most sclerad). Their distal dendrites were sparsely branched but achieved consistent coverage by intersecting those of their neighbors. Displaced and orthotopic cells belonged to the same mosaic, as did cells with symmetric and asymmetric trees. Cells of the alpha ab mosaic (approximately 1.2%) had large somata, somewhat smaller trees that appeared bistratified at low magnification, and dendrites that branched extensively. Their distal dendrites arborized throughout sublamina b and the vitread part of a, tessellating with their neighbors. All were orthotopic; most were symmetric. Cells of the alpha c mosaic (approximately 0.5%) had large somata and very large, sparse, flat, overlapping trees, predominantly in sublamina c. All were orthotopic; some were asymmetric. Nearest-neighbor analyses and spatial correlograms confirmed that each mosaic was regular and independent, and that spacings were reduced in juvenile frogs. Densities, proportions, sizes, and mosaic statistics are tabulated for all three types, which are compared with types defined previously by size and symmetry in Xenopus and potentially homologous mosaic-forming types in teleosts. Our results reveal strong organizational similarities between the large ganglion cells of teleosts and frogs. They also demonstrate the value of introducing mosaic analysis at an early stage to help identify characters that are useful markers for natural types and that distinguish between within-type and between-type variation in neuronal populations.

Animals↗
PubMed1998

Properties of a virus causing mosaic and leaf curl disease of Celosia argentea L. in Nigeria.

A sap transmissible virus, causing mosaic and leaf curl disease of Celosia argentea, was isolated at vegetable farms in Amuwo Odofin, Tejuoso, and Abule Ado, Lagos, Nigeria. The virus had a restricted host range confined to a few species of the Amaranthaceae, Chenopodiaceae and Solanaceae families. It failed to infect several other species of the Aizoaceae, Brassicaceae, Cucurbitaceae, Fabaceae, Lamiaceae, Malvaceae, Poaceae and Tiliaceae families. The virus was transmitted in a non-persistent manner by Aphis spiraecola and Toxoptera citricidus but not by eight other aphid species tested. There was no evidence of transmission by seeds of C. argentae varieties. The viral coat protein had a relative molecular mass (M(r)) of about 30.2 K. Electron microscopy of purified virus preparations revealed flexuous rod shaped particles of about 750 nm in length. Serological studies were performed using the enzyme-linked immunosorbent assay (ELISA), immunosorbent electron microscopy (ISEM) and Western blot analysis. The virus reacted positively with an universal potyvirus group monoclonal antibody (MoAb) and MoAb P-3-3H8 raised against peanut stripe potyvirus. It also reacted with polyclonal antibodies raised against several potyviruses including asparagus virus-1 (AV-1), turnip mosaic virus (TuMV), maize dwarf mosaic virus (MDMV), watermelon mosaic virus (WMV-2), plum pox virus (PPV), soybean mosaic virus (SoyMV), lettuce mosaic virus (LMV), bean common mosaic virus (BCMV) and beet mosaic virus (BMV) in at least one of the serological assays used. On the basis of host range, mode of transmission, and available literature data, the celosia virus seems to be different from potyviruses previously reported to infect vegetables in Nigeria. The name celosia mosaic virus (CIMV) has been proposed for this virus.

Animals↗
PubMed1996

The number of CGG repeats of the FMR1 locus in premutated and fully mutated heterozygotes and their offspring: implications for the origin of mosaicism.

The size of the CGG repeat of the FMR1 gene was investigated with probe StB12.3 in 154 transmissions to the offspring of heterozygotes for the premutation and the full mutation. Among the 135 offspring of premutated heterozygotes there were three decreases in size of the repeats: in two of these cases a full mutation was present along with the decreased premutation, and in a third mosaic (46,fra(X)(q27.3),Y), a normal allele was observed. In the 19 offspring of fully mutated females with no detected mosaicism, there were three mosaics and three individuals who had full mutations that included a number of repeats smaller than those present in their mothers. Among the 32 offspring who received a premutation from their premutated mothers, 27 alleles were increased in size and 5 remained unaltered. Among 11 mosaic offspring of premutated mothers, the premutation increased in 4, decreased in 3, and was unchanged in 4. In contrast to the trend of an increasing premutation size in the non-mosaic offspring, the premutation present in mosaics can be smaller, larger, or of unaltered size with approximately equal frequencies. These data suggest that the premutations present in mosaics result from mitotic instability of the inherited full mutations. This is further supported by the finding of a mosaic male with a normal sized allele.

DNA↗
PubMed2002

Pigmentary mosaicism of the hyperpigmented type in two half-brothers.

Pigmentary mosaicism is a heterogeneous cutaneous phenotype that is often associated with extracutaneous anomalies. It is widely accepted that these phenotypes arise de novo as a result of a postzygotic mutation, leading to a mosaic status of the embryo. In the vast majority of cases, the occurrence of pigmentary mosaicism is sporadic. We report two paternal half-brothers affected with pigmentary mosaicism of the hyperpigmented type. The hyperpigmentation in both patients is distributed along the lines of Blaschko. In addition, mental retardation, facial asymmetry, short stature, scoliosis, and short fingers with clinodactyly of the 5th digit were noted in one of them. Chromosome analysis in this 15-year-old patient demonstrated a mosaic 46,XY,dup(3)(p21.3;pter)/46,XY with 12% aberrant cells in lymphocytes and 2% in skin fibroblasts derived from a hyperpigmented area. His nine-year-old half-brother had similar systematized hyperpigmented skin lesions, macrocephaly, facial asymmetry, and clinodactyly of the 5th digit. Chromosome analysis of peripheral lymphocytes showed a normal karyotype 46,XY. A skin biopsy could not be obtained. So far, some familial cases of hypopigmentation along the lines of Blaschko have been reported, but familial occurrence of the hyperpigmented type of pigmentary mosaicism appears to be extremely unusual. It is difficult to establish a causal relationship with the chromosomal mosaicism as observed in patient 1. Paradominant transmission seems unlikely because this would likewise imply that the chromosomal mosaicism is an incidental finding.

Adolescent↗
PubMed1989

Chromosome mosaicism in 6,000 amniocenteses.

Multiple cell-multiple flask mosaicism was found in 0.20% of 6,000 amniocenteses, and multiple cell-single flask mosaicism was found in 0.92%. Multiple cell-multiple flask mosaicism usually was found in fetal or infant tissues at delivery or elective abortion. Most multiple cell-multiple flask mosaicism involved sex chromosomes and was either 45, X/46, XY or 45, X/46, XX. Except for one fetus with 45, X/46, XX and an aortic coarctation, phenotypic abnormalities associated with sex chromosome mosaicism were not found in these patients. One normal boy has continued to show 45,X mosaicism during the first 4 years of life. Autosome abnormalities found in multiple cell-multiple flask mosaicism included del(18q) associated with fetal anomalies. Apparently normal phenotypes were associated with prenatal trisomy 17, two de novo supernumerary marker chromosomes, and monosomy 21. Since an aberrant cell line present in only one primary amniotic fluid cell culture was occasionally identified from another amniocentesis or at birth, multiple cell-single flask mosaicism involving a sex chromosome or a viable autosome abnormality cannot be assumed to be an in vitro event. Maternal cell contamination, which was found in 0.49% of amniocenteses, could have resulted in an erroneous diagnosis of fetal sex in two cases if cells from independent culture vessels were not examined.

Amniocentesis↗
PubMed1994

Modeling methylation and IQ scores in fragile X females and mosaic males.

Both fragile X females and mosaic males carry a methylated FMR1 allele in some cells and an unmethylated allele in other cells. Due to FMR1 protein produced in cells with an unmethylated allele, these individuals are expected to display a less severe cognitive phenotype than non-mosaic affected males. A larger range in cognitive abilities is expected for these individuals due to individual variation in X-inactivation or mosaicism ratios. These cognitive effects are well documented for females and have been suggested for mosaic males. Data on fragile X females suggest an approximately linear decrease in mean IQ score as a function of the fraction of cells with the mutation carried on the active X chromosome. Analysis of these data suggests that threshold effects in the relationship between IQ score and X-inactivation ratios are negligible, and that X-inactivation occurs randomly (with no preferential inactivation of either X chromosome) at a stage when the embryo consists of approximately 5 cells. A similar analysis of future data on mosaic males could yield estimates of the probability that a given cell will carry a methylated FMR1 allele and of the number of embryonic cells at the time that mosaicism is established. Distributions of IQ scores among a population of heterozygotes or mosaic male are predicted for several values of these parameters. These distributions include random contributions to IQ scores due to non-fragile-X-related effects, as well as X-inactivation or mosaicism ratios that vary from one individual to another.

Alleles↗
PubMed1994

Mosaicism in fragile X affected males.

Fragile X affected males have an expansion of a CGG repeat and a hypermethylated CpG island 5' to the FMR-1 gene. Mosaic males with both a premutation and full mutation have been noted among the affected individuals. Such mosaic males are most easily identified by the presence of a methylated restriction fragment characteristic of the full mutation and an additional unmethylated fragment in the premutation range in Southern analyses with EcoR I and the methylation-sensitive enzyme Eag I and a probe such as StB12.3. We analyzed a group of affected fragile X males by Southern blotting and found 41% (61/148) to be mosaic. The 148 individuals were divided between 36 pairs of brothers and 76 unrelated males. Little difference in the number of mosaics was seen between the brothers and the unrelated males nor was the expected distribution of mosaicism in brother pairs different from observed. Thus, these data do not suggest a familial basis for mosaicism. Our observation that 41% affected fragile X males were mosaic is significantly higher than previous reports. The difference is likely due to technical modifications which permitted the identification of faint premutation bands in some patients. The high percentage of affected males with mosaicism seen here suggests that the occurrence of such individuals may be a much more frequent event than presently recognized.

Blotting, Southern↗