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Stephanie L Sherman

Publications and source records attributed to Stephanie L Sherman.

14 recordsLinked to original sources
PubMed2025

Complete chromosome 21 centromere sequencing of families with Down syndrome reveals centromere size asymmetry.

Down syndrome, the most common form of human intellectual disability, is caused by nondisjunction and chromosome 21 trisomy (T21). Small centromeres have been hypothesized to contribute to its aetiology and studies on mammals suggest that larger centromeres are more efficiently transmitted, yet complete sequencing of chromosome 21 (chr21) centromeres has been particularly challenging. Using long-read sequencing, we sequenced and assembled the centromeres from eight families that include a child with free T21 (1 trio, 6 child-mother duos, and 1 singleton) all resulting from maternal meiosis I errors. Two of these families carry the smallest chr21 centromeres (143 and 181 kbp) observed in female individuals to date, exhibiting a ~10.7- and ~19.4-fold centromeric α-satellite higher-order repeat array size difference between the maternally inherited homologs, respectively. In both cases, the longer centromere harbors a poorly defined centromere dip region, marked by DNA hypomethylation, in the proband but not in the mother. A comparison of all proband chr21 centromeres (n=24) to those of controls (n=261) shows that small centromeres are not enriched in families with T21 (p-value=0.73); contrarily, chr21 extreme centromere size asymmetry (>10-fold) is unique of T21 (p-value=0.003), suggesting that this feature may represent a genetic risk factor for a subset of families with free T21. Additionally, phylogenetic reconstruction reveals that human chr21 has been particularly prone to such variation with some of the biggest size differences occurring over the last ~17 thousand years of human evolution.

Down syndrome↗
PubMed2006

The FMR1 premutation and reproduction.

OBJECTIVE: To update clinicians on the reproductive implications of premutations in FMR1 (fragile X mental retardation 1). Fragile X syndrome, a cause of mental retardation and autism, is due to a full mutation (>200 CGG repeats). Initially, individuals who carried the premutation (defined as more than 55 but less than 200 CGG repeats) were not considered at risk for any clinical disorders. It is now recognized that this was incorrect, specifically with respect to female reproduction. DESIGN AND SETTING: Literature review and consensus building at two multidisciplinary scientific workshops. CONCLUSION(S): Convincing evidence now relates the FMR1 premutation to altered ovarian function and loss of fertility. An FMR1 mRNA gain-of-function toxicity may underlie this altered ovarian function. There are major gaps in knowledge regarding the natural history of the altered ovarian function in women who carry the FMR1 premutation, making counseling about reproductive plans a challenge. Women with premature ovarian failure are at increased risk of having an FMR1 premutation and should be informed of the availability of fragile X testing. Specialists in reproductive medicine can provide a supportive environment in which to explain the implications of FMR1 premutation testing, facilitate access to testing, and make appropriate referral to genetic counselors.

Adolescent↗
PubMed2005

CYP17 genotype predicts serum hormone levels among pre-menopausal women.

BACKGROUND: CYP17, which encodes cytochrome P450c17alpha, mediates both steroid 17alpha-hydroxylase and 17,20-lyase activities, and is essential for the production of glucocorticoids and sex steroids. There is evidence that a common polymorphism in CYP17 (T27C) is associated with estrogen levels, making it a potential marker of disease risk. METHODS: This is the first study to examine the relationship between CYP17 and estradiol (E2) using serum sampled exclusively from the early follicular phase of the menstrual cycle. We assessed the relationship between CYP17 and serum hormone levels, menstrual cycle length, bleed length, and age at menarche in 164 pre-menopausal women. RESULTS: Among women with body mass index (BMI) < or =25 kg/m2, those with the TC and CC genotypes had 19 and 42% higher E2 (P for trend 0.007) and 14 and 30% higher dehydroepiandrosterone sulphate respectively (P for trend 0.10) than women with the TT genotype. Androstenedione levels did not differ between genotypes. Among women with BMI >25 kg/m2, hormone levels did not differ by genotype. Women with the C allele were also more likely to have menstrual cycle lengths <27 days [odds ratio (OR) for TC=2.36, 95% confidence interval (CI)=1.24-4.52; OR for CC=5.59, 95% CI=1.53-20.43 compared to TT]. CYP17 genotype was not associated with menstrual bleed length or age at menarche. CONCLUSION: The CYP17 T27C polymorphism may be a marker of endocrine function.

Adolescent↗
PubMed2005

Women's attitudes toward testing for fragile X carrier status: a qualitative analysis.

Fragile X syndrome (FXS) is primarily due to a repeat expansion mutation found in the FMR1 X-linked gene. We have conducted a qualitative analysis of responses from women concerning their attitudes toward testing for carrier status of the fragile X mutation among reproductive-age women. We obtained responses from focus groups including women with and without FXS in their families. We found the following themes: (1) mothers of children with FXS have difficulty formulating their opinions on population screening because of their unique experiences surrounding their own carrier diagnosis and their relationship with their children with FXS, (2) the motivation for carrier testing and need for information differ by family history of FXS and parental status, and (3) the timing of carrier testing with respect to a woman's life stage dictates whether carrier information will be viewed as beneficial or detrimental. There was evidence that non-carrier women from the general population would be wholly unprepared for positive carrier results. These findings have significant implications for genetic counseling as well as for population screening.

Attitude↗
PubMed2004

Association between maternal age and meiotic recombination for trisomy 21.

Altered genetic recombination has been identified as the first molecular correlate of chromosome nondisjunction in both humans and model organisms. Little evidence has emerged to link maternal age--long recognized as the primary risk factor for nondisjunction--with altered recombination, although some studies have provided hints of such a relationship. To determine whether an association does exist, chromosome 21 recombination patterns were examined in 400 trisomy 21 cases of maternal meiosis I origin, grouped by maternal age. These recombination patterns were used to predict the chromosome 21 exchange patterns established during meiosis I. There was no statistically significant association between age and overall rate of exchange. The placement of meiotic exchange, however, differed significantly among the age groups. Susceptible patterns (pericentromeric and telomeric exchanges) accounted for 34% of all exchanges among the youngest class of women but only 10% of those among the oldest class. The pattern of exchanges among the oldest age group mimicked the pattern observed among normally disjoining chromosomes 21. These results suggest that the greatest risk factor for nondisjunction among younger women is the presence of a susceptible exchange pattern. We hypothesize that environmental and age-related insults accumulate in the ovary as a woman ages, leading to malsegregation of oocytes with stable exchange patterns. It is this risk, due to recombination-independent factors, that would be most influenced by increasing age, leading to the observed maternal age effect.

Adult↗
PubMed2004

A study of the distributional characteristics of FMR1 transcript levels in 238 individuals.

Fragile X syndrome, the most common form of inherited mental retardation, is caused by hyperexpansion and hypermethylation of a CGG repeat tract in the 5' untranslated region of the FMR1 gene. This methylation causes the gene to be transcriptionally silenced. In addition to the common allele form with less than 41 repeats, there are two other allelic forms of the FMR1 gene that are unmethylated: premutation (61-200 CGG repeats) and intermediate (41-60 CGG repeats). Recently, premutation-specific phenotypes not related to fragile X syndrome have been reported: a 20-fold increased risk for premature ovarian failure (POF) among female carriers and an increased risk for a tremor ataxia syndrome (TAS) primarily among older male carriers. At the molecular level, increased levels of FMR1 transcript have been observed among premutation carriers. Increased levels of transcript may be causally related to the POF or TAS phenotypes or may be a surrogate of some other allelic property. In this report, we have examined the distributional properties of transcript levels by repeat size and gender among 238 individuals. We have confirmed a significant linear relationship between transcript level and repeat size in males and females. The evidence for the linear effect is primarily within the premutation size alleles.

Alleles↗
PubMed2004

A trisomic transmission disequilibrium test.

Certain congenital disorders that are rare in the general population are quite common in individuals with trisomic conditions. For example, complete atrioventricular septal defect occurs in about 20% of individuals with Down syndrome, an approximately 500-fold increase in risk as compared to individuals without Down syndrome. Genetic variation on the chromosome involved in the trisomy may affect susceptibility to these trisomy-specific disorders. That is, increased dosage of a variant may be directly involved in increasing the risk of a disorder, or it may be indirectly involved by causing up- or downregulation of other genes. As in standard disomic gene-mapping, one can search for genes using linkage or association methods. Within association methods, one can consider case-control methods or family-based control methods such as the transmission disequilibrium test (TDT). Most gene-mapping methods need to be substantially redesigned for use with trisomic data. In this paper, we present a "trisomic TDT", a statistical method of testing for nonrandom transmission of alleles from parents to trisomic children. We demonstrate the method on a dataset of parent-child trios in which the child has Down syndrome.

Adult↗
PubMed2004

Linkage disequilibrium mapping in trisomic populations: analytical approaches and an application to congenital heart defects in Down syndrome.

Many of the birth defects associated with trisomy exhibit both variable expressivity and incomplete penetrance. This variability suggests that it is allelic variation and not simply the presence of an additional chromosome that leads to the development of certain trisomy-associated birth defects. With the proper tools, one may use trisomic populations to identify genes involved in the development of specific birth defects. A trisomic population may be advantageous over a normal population if the defect is over-represented in the trisomic population. Alternatively, one can view the trisomic populations as a "model system" to offer insight into aspects of both normal and abnormal embryonic development. Standard disomic linkage disequilibrium mapping approaches need to be adjusted to account for the presence of the additional genetic material in the trisomic individuals. We present an approach for linkage disequilibrium mapping of variable phenotypes in a trisomic population that adequately accounts for the additional alleles and the pattern of non-independent inheritance. We establish the laboratory methods and statistical tools necessary to conduct an association study in a trisomic population. As an example, we have applied these tools to a pilot study of Down syndrome-associated congenital heart defects.

Alleles↗
PubMed2003

Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles.

The CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 gene (FMR1) exhibits remarkable instability upon transmission from mothers with premutation alleles. A collaboration of 13 laboratories in eight countries was established to examine four issues concerning FMR1 CGG-repeat instability among females with premutation (approximately 55-200 repeats) and intermediate (approximately 46-60 repeats) alleles. Our central findings were as follows: (1) The smallest premutation alleles that expanded to a full mutation (>200 repeats) in one generation contained 59 repeats; sequence analysis of the 59-repeat alleles from these two females revealed no AGG interruptions within the FMR1 CGG repeat. (2) When we corrected for ascertainment and recalculated the risks of expansion to a full mutation, we found that the risks for premutation alleles with <100 repeats were lower than those previously published. (3) When we examined the possible influence of sex of offspring on transmission of a full mutation-by analysis of 567 prenatal fragile X studies of 448 mothers with premutation and full-mutation alleles-we found no significant differences in the proportion of full-mutation alleles in male or female fetuses. (4) When we examined 136 transmissions of intermediate alleles from 92 mothers with no family history of fragile X, we found that, in contrast to the instability observed in families with fragile X, most (99/136 [72.8%]) transmissions of intermediate alleles were stable. The unstable transmissions (37/136 [27.2%]) in these families included both expansions and contractions in repeat size. The instability increased with the larger intermediate alleles (19% for 49-54 repeats, 30.9% for 55-59, and 80% for 60-65 repeats). These studies should allow improved risk assessments for genetic counseling of women with premutation or intermediate-size alleles.

5' Untranslated Regions↗
PubMed2002

Obligate short-arm exchange in de novo Robertsonian translocation formation influences placement of crossovers in chromosome 21 nondisjunction.

Robertsonian translocations (ROBs) involving chromosome 21 are found in approximately 5% of patients with Down syndrome (DS). The most common nonhomologous ROB in DS is rob(14q21q). Aberrant recombination is associated with nondisjunction (NDJ) leading to trisomy 21. Haplotype analysis of 23 patients with DS and de novo rob(14q21q) showed that all translocations and all nondisjoined chromosomes 21 were maternally derived. Meiosis II NDJ occurred in 21 of 23 families. For these, a ROB DS chromosome 21 genetic map was constructed and compared to a normal female map and a published trisomy 21 map derived from meiosis II NDJ. The location of exchanges differed significantly from both maps, with a significant shift to a more distal interval in the ROB DS map. The shift may perturb segregation, leading to the meiosis II NDJ in this study, and is further evidence for crossover interference. More importantly, because the event in the short arms that forms the de novo ROB influences the placement of chiasmata in the long arm, it is most likely that the translocation formation occurs through a recombination pathway in meiosis. Additionally, we have demonstrated that events that occur in meiosis I can influence events, such as chromatid segregation in meiosis II, many decades later.

Chromosome Aberrations↗
PubMed2002

Prevalence of the fragile X syndrome in African-Americans.

Since the development of a molecular diagnosis for the fragile X syndrome in the early 1990s, several population-based studies in Caucasians of mostly northern European descent have established that the prevalence is probably between one in 6,000 to one in 4,000 males in the general population. Reports of increased or decreased prevalence of the fragile X syndrome exist for a few other world populations; however, many of these are small and not population-based. We present here the final results of a 4-year study in the metropolitan area of Atlanta, Georgia, establishing the prevalence of the fragile X syndrome and the frequency of CGG repeat variants in a large Caucasian and African-American population. Results demonstrate that one-quarter to one-third of the children identified with the fragile X syndrome attending Atlanta public schools are not diagnosed before the age of 10 years. Also, a revised prevalence for the syndrome revealed a higher point estimate for African-American males (1/2,545; 95% CI: 1/5,208-1/1,289) than reported previously, although confidence intervals include the prevalence estimated for Caucasians from this (1/3,717; 95% CI: 1/7,692-1/1,869) and other studies. Further population-based studies in diverse populations are necessary to explore the possibility that the prevalence of the fragile X syndrome differs among world populations.

Alleles↗
PubMed2002

Paternally transmitted FMR1 alleles are less stable than maternally transmitted alleles in the common and intermediate size range.

Fragile X syndrome, a form of X-linked mental retardation, results from the hyperexpansion of a CGG trinucleotide repeat located in the 5' untranslated region of the fragile X mental retardation (FMR1) gene. Relatively little is known about the initial mutation that causes a stable allele to become unstable and, eventually, to expand to the full mutation. In the present study, we have examined 1,452 parent-child transmissions of alleles of common (< or =39 repeats) or intermediate (40-59 repeats) sizes to study the initial mutation events. Of these, 201 have been sequenced and haplotyped. Using logistic regression analysis, we found that parental origin of transmission, repeat size (for unsequenced alleles), and number of the 3' CGGs (for sequenced alleles) were significant risk factors for repeat instability. Interestingly, transmission of the repeat through males was less stable than that through females, at the common- and intermediate-size level. This pattern differs from that seen for premutation-size alleles: paternally transmitted alleles are far more stable than maternally transmitted alleles. This difference that depends on repeat size suggests either a different mutational mechanism of instability or an increase in selection against sperm as their repeat size increases.

Alleles↗
PubMedDate not supplied

Maternal meiosis II nondisjunction in trisomy 21 is associated with maternal low socioeconomic status.

PURPOSE: We evaluated whether the association of socioeconomic risk factors for trisomy 21 differed by type of maternal meiotic error. METHODS: We determined meiotic errors by DNA analysis for 150 trisomy 21 cases, and maternal lifetime exposures to low socioeconomic factors by questionnaire. RESULTS: Mothers of meiosis II cases were significantly more likely to be exposed to four low socioeconomic factors than mothers of meiosis I cases (odds ratio = 9.50; 95% confidence interval = 1.8-49.8). CONCLUSION: Maternal lifetime exposure to poor socioeconomic environment is a risk factor for a trisomy 21, particularly if nondisjunction leads to a maternal meiosis II.

California↗