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Objectives: To define pregnancy episodes and estimate gestational age within electronic health record (EHR) data from the National COVID Cohort Collaborative (N3C)., Materials and Methods: We developed a comprehensive approach, named Hierarchy and rule-based pregnancy episode Inference integrated with Pregnancy Progression Signatures (HIPPS), and applied it to EHR data in the N3C (January 1, 2018-April 7, 2022). HIPPS combines: (1) an extension of a previously published pregnancy episode algorithm, (2) a novel algorithm to detect gestational age-specific signatures of a progressing pregnancy for further episode support, and (3) pregnancy start date inference. Clinicians performed validation of HIPPS on a subset of episodes. We then generated pregnancy cohorts based on gestational age precision and pregnancy outcomes for assessment of accuracy and comparison of COVID-19 and other characteristics., Results: We identified 628 165 pregnant persons with 816 471 pregnancy episodes, of which 52.3% were live births, 24.4% were other outcomes (stillbirth, ectopic pregnancy, abortions), and 23.3% had unknown outcomes. Clinician validation agreed 98.8% with HIPPS-identified episodes. We were able to estimate start dates within 1 week of precision for 475 433 (58.2%) episodes. 62 540 (7.7%) episodes had incident COVID-19 during pregnancy., Discussion: HIPPS provides measures of support for pregnancy-related variables such as gestational age and pregnancy outcomes based on N3C data. Gestational age precision allows researchers to find time to events with reasonable confidence., Conclusion: We have developed a novel and robust approach for inferring pregnancy episodes and gestational age that addresses data inconsistency and missingness in EHR data., Competing Interests: K.R.B. and S.L. are employees of Palantir Technologies. Y.K. and L.L. are employees of Sema4. M.N.L. is Managing Director of IPQ Analytics, LLC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

The coronavirus disease 2019 (COVID-19) pandemic has posed a burden to healthcare systems around the world and has changed the way people access health services, including contraception. This document sets forth guidance from the Society of Family Planning for providing contraceptive care in the context of the COVID-19 pandemic, including when access to healthcare is restricted due to pandemic response. It also outlines the role of telehealth for providing contraceptive care beyond the pandemic. Clinicians can use synchronous telemedicine visits and other forms of telehealth to provide many aspects of contraceptive care. Both audio-video and audio-only visits are acceptable forms of telemedicine. Access to permanent contraception should be maintained, especially in the postpartum period. Combined hormonal contraceptive (CHC) users who have asymptomatic or mild COVID-19 infection may continue their contraceptive method, while those admitted to the hospital with severe infection should suspend CHC use until they are clinically recovered. CHC users who take Paxlovid for mild-moderate COVID-19 infection can consider a back-up contraceptive method for the duration of therapy, but clinically relevant drug interactions are unlikely. Future research should examine contraceptive outcomes in people who receive care via telemedicine; and access to telemedicine among historically excluded populations such as adolescents, people of color, people of low socioeconomic status, disabled people, or people who do not speak English as a primary language., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To define pregnancy episodes and estimate gestational aging within electronic health record (EHR) data from the National COVID Cohort Collaborative (N3C)., Materials and Methods: We developed a comprehensive approach, named H ierarchy and rule-based pregnancy episode I nference integrated with P regnancy P rogression S ignatures (HIPPS) and applied it to EHR data in the N3C from 1 January 2018 to 7 April 2022. HIPPS combines: 1) an extension of a previously published pregnancy episode algorithm, 2) a novel algorithm to detect gestational aging-specific signatures of a progressing pregnancy for further episode support, and 3) pregnancy start date inference. Clinicians performed validation of HIPPS on a subset of episodes. We then generated three types of pregnancy cohorts based on the level of precision for gestational aging and pregnancy outcomes for comparison of COVID-19 and other characteristics., Results: We identified 628,165 pregnant persons with 816,471 pregnancy episodes, of which 52.3% were live births, 24.4% were other outcomes (stillbirth, ectopic pregnancy, spontaneous abortions), and 23.3% had unknown outcomes. We were able to estimate start dates within one week of precision for 431,173 (52.8%) episodes. 66,019 (8.1%) episodes had incident COVID-19 during pregnancy. Across varying COVID-19 cohorts, patient characteristics were generally similar though pregnancy outcomes differed., Discussion: HIPPS provides support for pregnancy-related variables based on EHR data for researchers to define pregnancy cohorts. Our approach performed well based on clinician validation., Conclusion: We have developed a novel and robust approach for inferring pregnancy episodes and gestational aging that addresses data inconsistency and missingness in EHR data.

Background: Depot medroxyprogesterone acetate (DMPA) is a commonly used contraceptive in areas where use of tenofovir disoproxil fumarate and emtricitabine for HIV pre-exposure prophylaxis (PrEP) is increasing., Objectives: We aimed to investigate the impact of DMPA on PrEP drug pharmacokinetics and pharmacodynamics in women using PrEP before and after DMPA administration., Methods: In this pilot study, 12 HIV-negative women ages 18-45 underwent biological sample collection at 3 time points: before study drug, after 2 weeks of daily PrEP use alone, and after 2 weeks of daily PrEP and concomitant DMPA use. We measured drug and drug metabolites in plasma, peripheral blood mononuclear cells, cervicovaginal fluid, cervical tissue, and rectal fluid after each 2-week course of PrEP. We measured HIV replication ex vivo in genital tissue biopsies and innate anti-HIV activity in cervicovaginal fluid before PrEP and after both courses. We compared drug concentrations after PrEP alone to after PrEP and DMPA in the same participant using Wilcoxon signed-rank tests. We used mixed effects linear regression models to compare pharmacodynamic measures for each participant at predrug baseline, after PrEP alone, and after PrEP and DMPA., Results: We found no significant differences in PrEP drug and drug metabolite concentrations in any compartment during concomitant DMPA use compared with use of PrEP alone, except for a reduction in emtricitabine concentration in cervical tissue. We found no difference in HIV replication in cervical tissue or anti-HIV activity in cervicovaginal fluid during concomitant DMPA and PrEP use compared with during PrEP use alone., Conclusions: Concomitant use of DMPA does not clinically alter pharmacokinetics or pharmacodynamics of PrEP in women. These data support the safety of DMPA use in women using PrEP.

Background: Trichomonas vaginalis is a common treatable sexually transmitted infection among older women. Persistent T. vaginalis infection after treatment is common among women with human immunodeficiency virus (HIV). We sought to determine if HIV-negative women were as likely as women with HIV to have persistent T. vaginalis infection., Methods: We performed a retrospective cohort study of women 45 years or older with T. vaginalis infection. We evaluated differences in persistent T. vaginalis infection according to HIV status using χ analysis. We performed regression analyses to describe factors associated with persistent and recurrent infection in older women., Results: Over a 10-year study period, we identified 282 women with T. vaginalis, 46 with HIV. Most women (240, 86%) were treated in accordance with 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases treatment guidelines. Half of the women (144, 53%) had a repeat T. vaginalis test 90 to 365 days after treatment, and one third had persistent infection (39/125, 31%). Persistent infection was similar between women with HIV and HIV-negative women treated according to Centers for Disease Control recommendations (17% vs 33%, P = 0.3). When adjusting for age and incidental diagnosis, tobacco use was associated with an increased risk of more than 1 or recurrent T. vaginalis infection during the study period (adjusted odds ratio, 2.8; 95% confidence interval, 1.5-4.9)., Conclusions: The HIV status did not affect persistent T. vaginalis infection in women 45 years or older. Given over one third of women have a positive test within a year after the recommended treatment, our data support repeat testing in women 45 years and older treated for T. vaginalis.

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG triplet repeat in the 3' untranslated region of the DMPK gene that encodes a serine-threonine kinase. Patients with larger repeats tend to have a more severe phenotype. Clinical laboratories require reference and quality control materials for DM1 diagnostic and carrier genetic testing. Well-characterized reference materials are not available. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community, the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members, and the Coriell Cell Repositories, has established and characterized cell lines from patients with DM1 to create a reference material panel. The CTG repeats in genomic DNA samples from 10 DM1 cell lines were characterized in three clinical genetic testing laboratories using PCR and Southern blot analysis. DMPK alleles in the samples cover four of five DM1 clinical categories: normal (5 to 34 repeats), mild (50 to 100 repeats), classical (101 to 1000 repeats), and congenital (>1000 repeats). We did not identify or establish Coriell cell lines in the premutation range (35 to 49 repeats). These samples are publicly available for quality control, proficiency testing, test development, and research and should help improve the accuracy of DM1 testing., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Few studies exist of developmental trajectories in children with intellectual disability, and none for those with subtelomeric deletions. We compared developmental trajectories of children with Wolf-Hirschhorn syndrome to other genetic disorders. We recruited 106 children diagnosed with fragile X, Williams-Beuren syndrome, or Wolf-Hirschhorn syndrome, assessing their intellectual and adaptive behavior abilities. We retested 61 children 2 years later. We compared Time 1 and Time 2 difference scores related to genetic disorder, age, initial IQ, or adaptive behavior composite. Results show genetic disorder and initial IQ score were significant factors for IQ differences, but only genetic disorder affected adaptive behavior differences. Results suggest different gene-brain-behavior pathways likely exist for these genetic disorders. Different developmental trajectories will influence the type and intensity of intervention implemented by caregivers.

Duchenne and Becker muscular dystrophies (DMD/BMD) are allelic X-linked recessive disorders that affect approximately 1 in 3500 and 1 in 20,000 male individuals, respectively. Approximately 65% of patients with DMD have deletions, 7% to 10% have duplications, and 25% to 30% have point mutations in one or more of the 79 exons of the dystrophin gene. Most clinical genetics laboratories test for deletions, and some use technologies that can detect smaller mutations and duplications. Reference and quality control materials for DMD/BMD diagnostic and carrier genetic testing are not commercially available. To help address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing and the DMD/BMD patient communities and the Coriell Cell Repositories, have characterized new and existing cell lines to create a comprehensive DMD/BMD reference material panel. Samples from 31 Coriell DMD cell lines from male probands and female carriers were analyzed using the Affymetrix SNP Array 6.0 and Multiplex Ligation-Dependent Probe Amplification (MRC-Holland BV, Amsterdam, the Netherlands), a multiplex PCR assay, and DNA sequence analysis. Identified were 16 cell lines with deletions, 9 with duplications, and 4 with point mutations distributed throughout the dystrophin gene. There were no discordant results within assay limitations. These samples are publicly available from Coriell Institute for Medical Research (Camden, NJ) and can be used for quality assurance, proficiency testing, test development, and research, and should help improve the accuracy of DMD testing., (Copyright © 2011 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

The course of cognitive-behavioral development in children with intellectual disabilities produced by genetic disorders has only recently begun to be examined systematically. Unfortunately, these studies are few in number. Previously, we examined cognitive-behavioral development in children with the fragile X (FMR1) mutation and found longitudinal decreases in both IQ and adaptive behavior (DQ) scores in most males and females with the full mutation. In this study, we examine longitudinal changes in IQ and DQ in children with neurofibromatosis type 1 (NF1) and Williams-Beuren Syndrome (WBS) by examining differences in composite IQ and DQ scores between the first test (T1) and retest (T2), and compare their developmental trajectory to children with the FMR1 mutation. Sixty-five children with the FMR1 mutation, or NF1, or WBS, ages 4-16 years, were retested two years after initial testing with the Stanford-Binet 4th Edition (SBFE) and the Vineland Adaptive Behavior Scale (VABS). In addition to significant longitudinal declines in IQ and DQ noted previously in children with the FMR1 mutation, we found significant decreases in IQ in males compared to females in the remainder of our sample. We also observed statistically significant decreases in DQ scores among children the FMR1 mutation, as noted previously, but not among children with NF1 or WBS. Moreover, significant declines were found only among males with the FMR1 mutation. Unlike declines in IQ scores, decreases in DQ were not significantly different between males and females., ((c) 2010 Wiley-Liss, Inc.)

The number of different laboratories that perform genetic testing for cystic fibrosis is increasing. However, there are a limited number of quality control and other reference materials available, none of which cover all of the alleles included in commercially available reagents or platforms. The alleles in many publicly available cell lines that could serve as reference materials have neither been confirmed nor characterized. The Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community as well as Coriell Cell Repositories, have characterized an extended panel of publicly available genomic DNA samples that could serve as reference materials for cystic fibrosis testing. Six cell lines [containing the following mutations: E60X (c.178G>T), 444delA (c.312delA), G178R (c.532G>C), 1812-1G>A (c.1680-1G>A), P574H (c.1721C>A), Y1092X (c.3277C>A), and M1101K (c.3302T>A)] were selected from those existing at Coriell, and seven [containing the following mutations: R75X (c.223C>T), R347H (c.1040G>A), 3876delA (c.3744delA), S549R (c.1646A>C), S549N (c.1647G>A), 3905insT (c.3773_3774insT), and I507V (c.1519A>G)] were created. The alleles in these materials were confirmed by testing in six different volunteer laboratories. These genomic DNA reference materials will be useful for quality assurance, proficiency testing, test development, and research and should help to assure the accuracy of cystic fibrosis genetic testing in the future. The reference materials described in this study are all currently available from Coriell Cell Repositories.

This case report describes a young man referred for electrodiagnostic evaluation for hand stiffness and intermittent numbness. His needle electromyography revealed diffusely increased insertional and spontaneous motor activity in the form of myotonic discharges. Given the finding of symptomatic myotonia also in his mother, Thomsen myotonia was suspected. Investigations not only confirmed Thomsen myotonia, but also led to the identification of a previously reported heterozygous Becker mutation in both the proband and his mother.

Myotonia congenita (MC) is a rare disorder of skeletal muscle caused by mutations in the CLCN1 gene,(1,2) which encodes the chloride ion channel found in the t-tubule of skeletal muscle. MC is characterized by impaired relaxation of voluntary muscle after sudden contraction that diminishes with muscle activity, known as the "warm-up effect." Individuals with MC can develop muscular hypertrophy despite little physical activity. Esotropia and reduced saccadic velocities have been reported in the dominant form of MC. We report two cases in which orbital magnetic resonance imaging (MRI) imaging showed extraocular muscle hypertrophy.

Studies of age-related features of cognitive-behavioral deficits produced by genetic mutations permit us to draw inferences about how brain development may be related cognitive ability as the child ages. Except for Down syndrome (DS) and the fragile X mutation (FRAXA), little is known about the longitudinal changes in cognitive-behavioral development in individuals with genetic abnormalities producing learning disabilities (LD) or mental retardation (MR). The purpose of this prospective study was to compare and contrast age related to cognitive abilities, adaptive and maladaptive behaviors in children and adolescents in the same age range, diagnosed with one of three genetic disorders: the FRAXA mutation, Neurofibromatosis type 1 (NF1) or Williams-Beuren syndrome (WBS). We also sought to examine whether cognitive-behavioral abilities associated with these three genetic disorders were related systematically to age. We examined 108 children, ages 4-15 years, with FRAXA, WBS, or NF1. Results show that there is a significant negative correlation between age and IQ, and between age and adaptive behavior (DQ) scores, in children with FRAXA and WBS, but not in children with NF1. All three groups of children have unusually high proportions of maladaptive behavior, ranging from 1/6 children with NF1 to 2/3 children with FRAXA. Cognitive and adaptive behavior profiles of children with FRAXA and WBS were also surprisingly similar. Our findings suggest the need for examining longitudinal developmental cognitive-behavioral changes in children and adolescents with all genetic disorders that produce LD or MR., (Copyright (c) 2007 Wiley-Liss, Inc.)

The Angelman (AS) and Prader-Willi syndromes (PWS) are clinically distinct neurobehavioural syndromes resulting from loss of maternal (AS) or paternal contributions (PWS) of imprinted genes within the chromosomal 15q11-q13 region. The molecular diagnosis of both syndromes can be made by a variety of techniques, including DNA methylation, DNA polymorphism and molecular cytogenetic analyses. DNA methylation analysis at three major loci (ZNF127, PW71 and 5' SNRPN) has been successfully used for the postnatal diagnosis of AS and PWS. Methylation analysis, in contrast to other techniques, can reliably be used to diagnose all three major molecular classes (deletion, uniparental disomy and imprinting mutation) of PWS, and three of the four major classes of AS. In this study we demonstrate that methylation analysis can also be successfully used in prenatal diagnosis, by examining specimens obtained from amniocentesis and chorionic villus sampling. Correct prenatal diagnoses were obtained in 24 out of 24 samples using the 5' SNRPN locus; 4 out of 15 using the ZNF127 locus; and 10 out of 18 using the PW71 locus. Therefore, our data indicate that although the DNA methylation imprints of ZNF127 and 5' SNRPN arise in the germline and are present in brain, only 5' SNRPN maintains the imprint in tissues suitable for the prenatal diagnosis of AS and PWS., (Copyright 2000 John Wiley & Sons, Ltd.)

Myotonic dystrophy (DM), the most common inherited muscle disorder, is caused by a CTG expansion in the 3"-untranslated region of a protein kinase gene ( DMPK ). The complex and variable phenotype is most likely caused by a complex molecular pathogenesis, including deficiency of the DMPK protein, a trans -dominant misregulation of RNA homeostasis and haploinsufficiency of a neighboring homeobox gene [DM locus-associated homeodomain protein (DMAHP )]. Here, we study the allele-specific transcriptional activity of the DMAHP/SIX5 gene in DM patient tissues. Using a quantitative fluorescent RT-PCR assay, we tested allele-specific accumulation of DMAHP/SIX5 transcripts in both total and poly(A)+pools. In muscle biopsies, we found that transcript reductions of DMAHP/SIX5 alleles in cis with CTG expansions correlated with the extent of expansion. A patient with approximately 90 CTG repeats in muscle DNA (normal n < 37) showed a 20% reduction of allele-specific transcript levels, while four other DM patients with larger expansions showed 80% reductions. The effects of the CTG expansions on DMAHP transcription were tissue specific: autopsy tissues from a patient with 1500 repeats showed 80% reductions in muscle and liver; however, RNA from other tissues (lung, aorta, heart conduction tissue, cerebellum) showed 0-20% reductions. Our results suggest that the effect of the CTG repeat on the DMAHP/SIX5 promoter is variable and tissue-specific. Our data are consistent with abnormalities of DMAHP/SIX5 probably having a more prominent role in disease pathogenesis in muscle, liver and brain, but being less important in other tissues.

Unstable trinucleotide repeat DNA contained in numerous genes has been proposed as the underlying mechanism in the clinical phenomenon of genetic anticipation in fragile X syndrome and other neurodegenerative diseases. No clear evidence has been found for the role of these abnormal trinucleotide repeat expansion-containing genes in schizophrenia or other psychiatric disorders. This report describes an adult male with psychosis who was later found to have methylation mosaicism of the FMR1 gene. We discuss history, examination, and investigation which led to the diagnosis and treatment response of this patient.

A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.

The fragile X syndrome phenotype of mental retardation is almost always caused by abnormal CGG trinucleotide amplification within the FMR1 gene. Occasionally fragile X syndrome results from point mutations or deletions within or around the FMR1 locus. We have identified a mentally retarded African American male with typical fragile X phenotype and a 300-400 base pair intragenic deletion near the CGG repeat segment, present in his peripheral blood lymphocytes with no apparent mosaicism. His mother, who is not retarded, has a full FMR1 CGG expansion mutation with 700-900 repeats. A review of 23 published cases with FMR1 gene deletions shows full FMR1 mutation in the mother of only 1 other propositus, a male with FMR1 full mutation/premutation/deletion mosaicism of his cultured skin fibroblasts and peripheral blood lymphocytes. The various deletions within FMR1 and their clinical significance are reviewed.

Individuals with translocation Down syndrome (DS) often inherit the rearranged chromosome from a carrier parent. DS due to inheritance of one Robertsonian or derivative (14q21q) from one parent and a second der(14q21q) in addition to a free chromosome 21 from the other parent are rarely documented in liveborn infants. Presented here is such a propositus with DS and with a unique karyotype 45,XY,der(14;21) (p11.1;p11.1)pat,der(14;21)(p11.1;q11.1)mat, +21mat. Using conventional chromosome heteromorphisms, fluorescent in situ hybridization (FISH), and microsatellite polymorphism analyses, we established the biparental origin of the 2 der(14q21q) and the maternal origin of the extra chromosome 21 in the patient. A combination of both cytogenetic and molecular genetic techniques also enabled us to show that the 2 der(14q21q) were not identical by descent and hence the parents were nonconsanguineous. It has been a well-established fact that mothers with Robertsonian translocations have higher risk for nondisjunction than do carrier fathers. Our case, wherein the nondisjunctional event occurred in the mother, even though both parents are carriers of a 14;21 Robertsonian translocation, is yet another example of this.

Fragile X syndrome results from the expansion of the CGG repeat in the FMR1 gene. Expansion has been suggested to be a postzygotic event with the germline protected. From an analysis of intact ovaries of full mutation fetuses, we now show that only full expansion alleles can be detected in oocytes (but in the unmethylated state). Similarly, the testes of a 13-week full mutation fetus show no evidence of premutations while a 17-week full mutation fetus exhibits some germ cells with attributes of premutations. These data discount the hypothesis that the germline is protected from full expansion and suggest full mutation contraction in the immature testis. Thus, full expansion may already exist in the maternal oocyte, or postzygotic expansion, if it occurs, arises quite early in development prior to germline segregation.

This study surveyed obligate carriers of the fragile X syndrome fra(X) to ascertain opinions and attitudes regarding carrier testing. Female carriers of fra(X) syndrome were recruited during their visits to the Fragile X Clinic at Duke University Medical Center. Twenty-eight obligate carriers completed a 48 question structured interview and a visual analog scale (VAS). Strong trends in the responses were identified. Fra(X) syndrome was viewed as a very serious problem and the risk to offspring high. Subjects reported that prior knowledge of carrier status would have changed their reproductive plans. All felt that relatives should be informed about the inheritance of fra(X) syndrome; the mean age given for preferred age to inform their children of the inheritance of fra(X) syndrome was 12 years, and mean age given for optimal timing of carrier testing was 10 years. The women interviewed indicated that growing up with knowledge of their carrier status would have been preferable to learning this information as adults and they endorsed an aggressive approach to informing and testing their children. Further investigation is warranted to determine the psychological consequences of carrier testing for fra(X) syndrome in order to develop appropriate guidelines for testing and informing individuals at risk for fra(X) syndrome.

Myotonic dystrophy (DM) is a trinucleotide repeat syndrome which can contain 50 to over 2,000 CTG repeats in affected individuals, but does not express a fragile site. Although one prior study [Jalal et al., Am J Med Genet 46:441-443, 1993] did not find evidence of fragility at 19q13.3 in six individuals affected with DM using induction protocols for folate sensitive fragile sites, other chemicals may induce fragile site expression at this site. In an attempt to induce fragile sites at 19q13.3, blood cultures from four congenital DM cases and four control individuals treated with fluorodeoxyuridine (folate-sensitive rare fragile sites), bromodeoxyurdine (rare and common fragile sites), aphidicolin (common fragile sites), and 5-azacytidine (common fragile sites) were harvested using routine cytogenetic technique. Slides were solid stained and 100 cells were examined for fragile site expression, particularly on F group chromosomes. The latter were photographed prior to destaining and G-banded to verify chromosome and band location of breakage. No culture conditions induced a fragile site at band 19q13.3 at > 1% expression in patients with congenital DM. Our results suggest that CTG repeats, even when present in > 1,000 copies, may behave differently from other large expansions which are associated with fragile sites. The CTG repeats in DM are not associated with a methylated CpG island, as are folate-sensitive fragile sites, which most likely plays a role in the expression of fragile sites at the trinucleotide repetitive site.

Retrospective longitudinal studies have noted declines in IQ scores in many but not all fra(X) (fragile X) males and females. We report on a prospective investigation of longitudinal changes in cognitive ability (IQ) and adaptive behavior (DQ) in 24 fra(X) males from four test sites. Individuals who were tested ranged in age from 3-15 years. To determine cognitive ability, all males were administered the Stanford-Binet test (4th Edition). To assess adaptive behavior, all males were evaluated using the Vineland Adaptive Behavior Scales. Mean interest interval was 2.3 years. Using identical DNA protocols, all subjects were identified as bearing the fra(X) mutation. Results showed declines in IQ scores in 18/24 (75%) males. Four males showed no change in scores. Declines in DQ scores were noted in 22/24 (92%) of those tested. DQ scores were higher than IQ scores in 20/24 (83%) subjects. From a descriptive cohort analysis, decreases in IQ scores appear to follow a well-defined, negatively decelerating function. Declines in DQ were steeper and more nearly linear. Declining scores are not indicative of regression of intellectual and/or social skills, but of a relative inability to keep pace with their age-normed cohort. We conclude that the fra(X) mutation affects cognitive abilities in a uniform, nonlinear manner comparable to outcomes observed in earlier retrospective studies. Adaptive behavior also declines, but in a more linear fashion.

Fragile X DNA studies were carried out on all obligate carriers of a large fragile X family with 10 mentally retarded individuals. One 64-year-old carrier man with an altered FMR-1 allele was not described as being mentally retarded or as having any limitations in function. He was married, raised 8 children, and worked as an auto mechanic. On examination, he had macrocephaly and mild macroorchidism but few of the other typical physical findings of males with fragile X syndrome. His Full Scale IQ is 73, and his Vineland Adaptive Behavior Composite is 73. On the Woodcock-Johnson Psycho-Educational Battery-Revised, he achieved standard scores of 64 in Reading, 55 in Math, and 83 in Knowledge. His DNA findings showed a broad smear on Southern blot analysis of 100-500 CGG repeats and no methylation at the EagI site upstream of the FMR-1 protein coding region. His FMR-1 protein production is 12% of normal. His daughters all have large premutations, with somatic instability in the size of the CGG repeat lengths. They all have evidence of academic underachievement and 2 have physical characteristics frequently described in individuals with fragile X.