Fragile X syndrome in the largest world clustering. I. Genetic epidemiology and founder effect outline.

The FMR1 5' regulation gene region harbors a CGG trinucleotide repeat expansion (CGG-TRE) that causes Fragile X syndrome (FXS) when it expands to more than 200 repetitions. Ricaurte is a small village in southwestern Colombia, with an FXS prevalence of 1 in 38 men and 1 in 100 women (~100 times higher than the worldwide reported prevalence), defining Ricaurte as the largest FXS cluster in the world. In the present study, using next-generation sequencing of whole exome capture, we genotype 55 individuals from Ricaurte (49 with either full mutation or with premutation), four individuals from neighboring villages (with either the full mutation or with the premutation), and one unaffected woman, native of Ricaurte, who did not belong to any of the affected families. With advanced clustering and haplotype reconstruction, we modeled a common haplotype of 33 SNPs spanning 83,567,899 bp and harboring the FMR1 gene. This reconstructed haplotype was found in all the men from Ricaurte who carried the expansion, demonstrating that the genetic conglomerate of FXS in this population is due to a founder effect. The definition of this founder effect and its population outlining will allow a better prediction, follow-up, precise and personalized characterization of epidemiological parameters, better knowledge of the disease's natural history, and confident improvement of the clinical attention, life quality, and health interventions for this community.

Mosaicism in Fragile X syndrome: A family case series.

Fragile X syndrome (FXS) has a classic phenotype, however its expression can be variable among full mutation males. This is secondary to variable methylation mosaicisms and the number of CGG triplet repeats in the non-coding region of the Fragile X Mental Retardation 1 (FMR1) gene, producing a variable expression of the Fragile X Mental Retardation Protein (FMRP). Here we report a family with several individuals affected by FXS: a boy with a hypermethylated FMR1 mutation and a classic phenotype; a man with an FMR1 gene mosaicism in the range of premutation (PM) and full mutation (FM), who has a mild phenotype due to which FXS was initially disregarded; and the cases of four women with a FM and mosaicism. This report highlights the importance of DNA molecular testing for the diagnosis of FXS in patients with developmental delay, intellectual disability and/or autism due to the variable phenotype that occurs in individuals with FMR1 mosaicisms.

Raising Knowledge and Awareness of Fragile X Syndrome in Serbia, Georgia, and Colombia: A Model for Other Developing Countries?

Fragile X syndrome is the most common monogenetic cause of inherited intellectual disability and syndromic autism spectrum disorder. Fragile X syndrome is caused by an expansion (full mutation ≥200 CGGs repeats, normal 10-45 CGGs) of the fragile X mental retardation 1 (FMR1) gene, epigenetic silencing of the gene, which leads to reduction or lack of the gene's product: the fragile X mental retardation protein. In this cross-sectional study, we assessed general and pharmacotherapy knowledge (GK and PTK) of fragile X syndrome and satisfaction with education in neurodevelopmental disorders (NDDs) among senior medical students in Serbia (N=348), Georgia (N=112), and Colombia (N=58). A self-administered 18-item questionnaire included GK (8/18) and PTK (7/18) components and self-assessment of the participants education in NDDs (3/18). Roughly 1 in 5 respondents had correct answers on half or more facts about fragile X syndrome (GK>PTK), which ranged similarly 5-7 in Serbia, 6-8 in Georgia, and 5-8 in Colombia, respectively. No cohort had an average value greater than 9 (60%) that would represent passing score "cut-off." None of the participants answered all the questions correctly. More than two-thirds of the participants concluded that they gained inadequate knowledge of NDDs during their studies, and that their education in this field should be more intense. In conclusion, there is a major gap in knowledge regarding fragile X syndrome among senior medical students in these three developing countries. The finding could at least in part be generalized to other developing countries aimed toward increasing knowledge and awareness of NDDs and fostering an institutional collaboration between developed and developing countries.

C-reactive protein, interleukin-6 and pre-eclampsia: large-scale evidence from the GenPE case-control study.

Multiple small studies have suggested that women with pre-eclampsia present elevated levels of C-reactive protein (CRP) and interleukin-6 (IL-6). However, little is known regarding the source of this CRP and IL-6 increase. Therefore, the aim of this study was to evaluate the relationship between CRP and IL-6 levels with pre-eclampsia considering different confounding factors. Using data from a large Colombian case-control study (3,590 cases of pre-eclampsia and 4,564 normotensive controls), CRP and IL-6 levels were measured in 914 cases and 1297 controls. The association between maternal serum levels of CRP and IL-6 with pre-eclampsia risk was evaluated using adjusted logistic regression models. Pre-eclampsia was defined as presence of blood pressure ≥140/90 mmHg and proteinuria ≥300mg/24 h (or ≥1 + dipstick). There was no evidence of association between high levels of CRP and IL-6 with pre-eclampsia after adjusting for the following factors: maternal and gestational age, ethnicity, place and year of recruitment, multiple-pregnancy, socio-economic position, smoking, and presence of infections during pregnancy. The adjusted OR for 1SD increase in log-CRP and log-IL-6 was 0.96 (95%CI 0.85, 1.08) and 1.09 (95%CI 0.97, 1.22), respectively. Although previous reports have suggested an association between high CRP and IL-6 levels with pre-eclampsia, sample size may lack the sufficient power to draw robust conclusions, and this association is likely to be explained by unaccounted biases. Our results, the largest case-control study reported up to date, demonstrate that there is not a causal association between elevated levels of CRP and IL-6 and the presence of pre-eclampsia.

Optic nerve coloboma as extension of the phenotype of 22q11.23 duplication syndrome: a case report.

BACKGROUND: 22q11.2 duplication syndrome (Dup22q11.2) has reduced penetrance and variable expressivity. Those affected may have intellectual disabilities, dysmorphic facial features, and ocular alterations such as ptosis, hypertelorism, nystagmus, and chorioretinal coloboma. The prevalence of this syndrome is unknown, there are only approximately 100 cases reported. However Dup22q11.2 should have a similar prevalence of DiGeorge syndrome (1 in each 4000 new-borns), in which the same chromosomal region that is duplicated in Dup22q11.2 is deleted. CASE PRESENTATION: We report a patient with intellectual disability, psychomotor development delay, hearing loss with disyllable pronunciation only, hyperactivity, self-harm, hetero-aggressive behaviour, facial dysmorphism, left facial paralysis, post-axial polydactyly, and for the first time in patients with Dup22q11.2, optic nerve coloboma and dysplasia in optic nerve. Array comparative genomic hybridization showed a 22q11.23 duplication of 1.306 million base pairs. CONCLUSIONS: New ocular findings in Dup22q11.2 syndrome, such as coloboma and dysplasia in the optic nerve, are reported here, contributing to the phenotypic characterization of a rarely diagnosed genetic syndrome. A complete characterization of the phenotype is necessary to increase the rate of clinical suspicion and then the genetic diagnostic. In addition, through bioinformatics analysis of the genes mapped to the 22q11.2 region, it is proposed that deregulation of the SPECC1L gene could be implicated in the development of ocular coloboma.

Genetic cluster of fragile X syndrome in a Colombian district.

BACKGROUND: Fragile X syndrome (FXS) is the most common cause of inherited intellectual disabilities and autism. The reported prevalence of the full mutation (FM) gene FMR1 in the general population is 0.2-0.4 per 1000 males and 0.125-0.4 per 1000 females. Population screening for FMR1 expanded alleles has been performed in newborns and in an adult population. However, it has never been carried out in an entire town. Ricaurte is a Colombian district with 1186 habitants, with a high prevalence of FXS, which was first described by cytogenetic techniques in 1999. METHODS: Using a PCR-based approach, screening for FXS was performed on blood spot samples obtained from 926 (502 males and 424 females) inhabitants from Ricaurte, accounting for 78% of total population. RESULTS: A high prevalence of carriers of the expanded allele was observed in all FXS mutation categories. Using the Bayesian methods the carrier frequency of FM was 48.2 (95% Credibility Region CR: 36.3-61.5) per 1000 males and 20.5 (95% CR:13.5-28.6) per 1000 females; the frequency of premutation carrier was 14.1 (95% RC: 8.0-21.7) per 1000 males (95% RC: 8.0-21.7 per 1000 males) and 35.9 (95% RC: 26.5-46.2) per 1000 for females (95% RC: 26.5-46.2 per 1000 females), and gray zone carrier was 13.4 (95% RC: 7.4-20.7) per 1000 males (95% RC: 7.4-20.7 per 1000 males) and 42.2 (95% RC: 32.2-53.8) per 1000 for females (95% RC: 32.2-53.8 per 1000 females). Differences in carrier frequencies were observed for premutation and FM alleles between natives and non-natives. CONCLUSIONS: This study shows that in Ricaurte the carrier frequencies of FMR1 expanded alleles (premutations and FMs) are higher than those reported in the literature, suggesting that Ricaurte constitutes a genetic cluster of FXS.

Down Syndrome and Fragile X Syndrome in a Colombian Woman: Case Report.

BACKGROUND: Down syndrome (DS) and Fragile X syndrome (FXS) are the major genetic causes of intellectual disabilities. Here, we present a case of a 32-year-old woman with the diagnosis of both FXS and DS. She is the daughter of a 47-year-old pre-mutation woman who also has three sons with FXS. METHODS: Cytogenetic testing detected the presence of a complete trisomy 21. A combination of PCR and Southern blot analysis was utilized to document the presence of the FMR1 full mutation. RESULTS: The patient has physical characteristics and behavioural disturbances typical of both FXS and DS, which were confirmed by molecular testing. Her treatment plan included a trial of sertraline because of the severity of her shyness and lack of language. She had an excellent response to sertraline with improvement in shyness and social interactions, particularly with family members. CONCLUSIONS: In this study, we report the case of a woman with both FXS and DS, which is the fifth case of FXS and DS in the world's literature. The patient is from Ricaurte, a small town in Colombia, South America, where there is the world's highest prevalence for FXS.

[Trisomy 18 syndrome: A case report]. / Síndrome de trisomía 18. Reporte de un caso clínico.

INTRODUCTION: The trisomy 18 syndrome occurs due to the presence of an extra chromosome 18 in most cases. The prevalence in infants is estimated at 1:6000 to 1:8000. Those affected have a high mortality rate, only 4% may survive their first year of life. There are few reported cases exceeding five years of age. OBJECTIVE: The aim of this paper is to report a case of trisomy 18 of long survival with oral cavity features not described in the literature, and to provide information to physicians and paediatricians about aetiology, phenotype, survival and genetic counselling. CASE REPORT: A 7 year-old female patient with 2 karyotypes performed by lymphocyte culture showing 47XX+18 in all metaphases. She presented with growth deficiency, dysmorphic facies, severe psychomotor retardation and cognitive disability, inability to feed, lack of verbal language, sensorineural hearing loss, ataxia, cerebellar hypoplasia, and genitals with hypoplastic labia majora and minora. In the oral cavity: dome shaped palate, macroglossia, absence of upper central incisors and first upper and lower molars in mouth. X-ray findings showed formation of missing teeth, with late eruption being concluded. CONCLUSIONS: In cases of trisomy 18 syndrome there is an increased risk of neonatal and infant mortality. The clinical characteristics in utero and in neonates have been well described. Since few cases exceeding five years of age have been reported, the phenotype is yet to be established. In the case being reported we describe oral cavity findings not documented in the literature.

[Sotos syndrome diagnosed by comparative genomic hybridisation]. / Síndrome de Sotos diagnosticado por hibridación genómica comparativa.

UNLABELLED: Sotos Syndrome (SS) is a genetic disease with an autosomal dominant pattern caused by haplo-insufficiency of NSD1 gene secondary to point mutations or microdeletion of the 5q35 locus where the gene is located. It is a rare syndrome, occurring in 7 out of every 100,000 births. The objective of this report is to present the case of a 4 year-old patient with a global developmental delay, as well as specific physical findings suggesting a syndrome of genetic origin. CLINICAL CASE: Female patient, 4 years of age, thinning hair, triangular facie, long palpebral fissure, arched palate, prominent jaw, winged scapula and clinodactilia of the fifth finger both hands. The molecular test comparative genomic hybridisation test by microarray was subsequently performed, with the result showing 5q35.2 q35.3 region microdeletion of 2,082 MB, including the NSD1 gene. CONCLUSION: Finally, this article also proposes the performing of comparative genomic hybridisation as the first diagnostic option in cases where clinical findings are suggestive of SS.

[A case of partial 1p36.1 deletion and partial trisomy 6p diagnosed by karyotype]. / Un caso de deleción parcial 1p36.1 y trisomía parcial 6p diagnosticadas por cariotipo.

The deletion of chromosomal region 1p36 is one of the most common sub-telomeric microdeletion syndromes and has distinctive dysmorphic features. On the other hand, partial trisomy of the short arm of chromosome 6 is a rare chromosomal abnormality with a variable phenotype. OBJECTIVE: To report a case with both chromosome abnormalities, and to highlight the importance of the karyotype as a diagnostic tool in dysmorphology. CLINICAL CASE: The case of is presented of a two month-old infant with several craniofacial anomalies, neck haemangioma, sacral pit, rhizomelic shortening, small hands and feet, left unilateral cryptorchidism, and hypotonia. The infant also suffered intrauterine growth restriction and is the product of the eighth pregnancy of a 28 years old woman. Due to the unspecific findings in phenotype, a karyotype was requested, which showed a partial deletion of 1p36.1 and a partial trisomy of chromosome 6. CONCLUSION: The development of new techniques in molecular biology has improved diagnostic possibilities in medical genetics. However, the traditional karyotype remains as an important diagnostic tool in patients with multiple congenital anomalies.

Karyotype versus genomic hybridization for the prenatal diagnosis of chromosomal abnormalities: a metaanalysis.

OBJECTIVE: The aim of this study was to determine the diagnostic accuracy of comparative genomic hybridization (CGH) compared with karyotyping for the detection of numerical and structural chromosomal alterations in prenatal diagnosis. STUDY DESIGN: A metaanalysis was performed using searches of PubMed, EMBASE, CENTRAL, Cochrane Register of Diagnostic Test Accuracy Studies, Google Scholar, gray literature, and reference manuals. No language restriction was imposed. We included cross-sectional, cohort, and case-control studies published from January 1980 through March 2014 in the analysis. Studies of pregnant women who received chorionic villus biopsies, amniocentesis, or cordocentesis and then underwent CGH and karyotype analysis were included. Two independent reviewers assessed each study by title, abstract, and full text before its inclusion in the analysis. Methodological quality was assessed using QUADAS2, and a third reviewer resolved any disagreement. Conclusions were obtained through tests (sensitivity, specificity, and likelihood ratios) for the presence of numerical and structural chromosomal abnormalities. The reference used for these calculations was the presence of any abnormalities in either of the 2 tests (karyotype or CGH), although it should be noted that in most cases, the karyotyping test had a lower yield compared with CGH. Statistical analysis was performed in RevMan 5.2 and the OpenMeta[Analyst] program. RESULTS: In all, 137 articles were found, and 6 were selected for inclusion in the systematic review. Five were included in the metaanalysis. According to the QUADAS2 analysis of methodology quality, there is an unclear risk for selection bias and reference and standard tests. In the other elements (flow, time, and applicability conditions), a low risk of bias was found. CGH findings were as follows: sensitivity 0.939 (95% confidence interval [CI], 0.838-0.979), I(2) = 82%; specificity 0.999 (95% CI, 0.998-1.000), I(2) = 0%; negative likelihood ratio 0.050 (95% CI, 0.015-0.173), I(2) = 0%; and positive likelihood ratio 1346.123 (95% CI, 389-4649), I(2) = 0%. Karyotype findings were as follows: sensitivity 0.626 (95% CI, 0.408-0.802), I(2) = 93%; specificity 0.999 (95% CI, 0.998-1.000), I(2) = 0%; negative likelihood ratio 0.351 (95% CI, 0.101-1.220), I(2) = 0%; and positive likelihood ratio 841 (95% CI, 226-3128), I(2) = 10%. CONCLUSION: This systematic review provides evidence of the relative advantage of using CGH in the prenatal diagnosis of chromosomal and structural abnormalities over karyotyping, demonstrating significantly higher sensitivity with similar specificity.

Two extraordinarily severe cases of Treacher Collins syndrome.

Here, we report two extraordinarily severe cases of Teacher Collins syndrome. Initially, amniotic bands and plical fold disruption were considered, but downslanting eyes made us consider severe Treacher Collins syndrome. A TCOF1 mutation in exon 24 was identified in Patient 1 (c.4355_4356ins14, resulting in p.1456Thrfs*18). Patient 2, who expired on day 4, is so similar to Patient 1 that severe Treacher Collins syndrome may be inferred in this instance. Neither the TCOF1 mutation nor the well-known variability in the expression in affected families with Treacher Collins syndrome (∼40% of reported cases) can explain the severity of these cases; otherwise, we would be aware of such cases within families from time to time. We are unaware of any recent sporadic cases (∼60% of reported cases) exactly like ours either with a single exception in the case reported by Writzl et al. [2008] with a TCOF1 mutation. The case described by Otto in 1841 is spectacular. We propose several hypotheses to be considered in explaining this developmental amplification, including some promoter effect on the gene, some position effect on the gene, a polymorphism elsewhere in the gene, a point mutation elsewhere in the gene, a polymorphism in another gene, or a point mutation in another gene, such as POLR1C (which maps to 6p21.1) or POLR1D (which maps to13q12.2). We also review the etiology and pathogenesis of Treacher Collins syndrome, and discuss several other severe cases from the past.

Fragile X Syndrome in children.

Fragile X syndrome is caused by the expansion of CGG triplets in the FMR1 gene, which generates epigenetic changes that silence its expression. The absence of the protein coded by this gene, FMRP, causes cellular dysfunction, leading to impaired brain development and functional abnormalities. The physical and neurologic manifestations of the disease appear early in life and may suggest the diagnosis. However, it must be confirmed by molecular tests. It affects multiple areas of daily living and greatly burdens the affected individuals and their families. Fragile X syndrome is the most common monogenic cause of intellectual disability and autism spectrum disorder; the diagnosis should be suspected in every patient with neurodevelopmental delay. Early interventions could improve the functional prognosis of patients with Fragile X syndrome, significantly impacting their quality of life and daily functioning. Therefore, healthcare for children with Fragile X syndrome should include a multidisciplinary approach.

El síndrome de X frágil es causado por la expansión de tripletas CGG en el gen FMR1, el cual genera cambios epigenéticos que silencian su expresión. La ausencia de la proteína codificada por este gen, la FMRP, causa disfunción celular, llevando a deficiencia en el desarrollo cerebral y anormalidades funcionales. Las manifestaciones físicas y neurológicas de la enfermedad aparecen en edades tempranas y pueden sugerir el diagnóstico. Sin embargo, este debe ser confirmado por pruebas moleculares. El síndrome afecta múltiples aspectos de la vida diaria y representa una alta carga para los individuos afectados y para sus familias. El síndrome de C frágil es la causa monogénica más común de discapacidad intelectual y trastornos del espectro autista; por ende, el diagnóstico debe sospecharse en todo paciente con retraso del neurodesarrollo. Intervenciones tempranas podrían mejorar el pronóstico funcional de pacientes con síndrome de X frágil, impactando significativamente su calidad de vida y funcionamiento. Por lo tanto, la atención en salud de niños con síndrome de X frágil debe incluir un abordaje multidisciplinario.

Hearing Loss in Patients With Morquio Syndrome: Protocol for a Scoping Review.

BACKGROUND: Mild to moderate hearing loss is common in patients with mucopolysaccharidosis (MPS) IVA. The hearing loss can be conductive, sensorineural, or mixed. However, in these patients, the mixed form is frequent, attributed to the combination of conductive and neurosensory elements, with slowly progressive evolution. Conductive hearing loss may be secondary to recurrent upper respiratory tract infections, serous otitis media, and deformities of the ear ossicles due to the accumulation of glycosaminoglycans (GAGs). Meanwhile, the sensorineural form is mainly attributed to the accumulation of GAGs in the auditory system. OBJECTIVE: The aim of this scoping review is to understand the extent and type of evidence in relation to the physiopathology, classification, epidemiology, and clinical management of hearing loss and the effect of therapy for hearing loss in patients with MPS IVA. METHODS: This scoping review includes participants across all genders and of no particular age group who are diagnosed with MPS IVA and develop hearing loss as a comorbidity. No exclusion criteria (country, language, or document type) will be applicable. The information sources will include experimental and quasi-experimental, analytical observational, observational, and qualitative studies. Unpublished literature will not be covered. Grey literature will be covered. A total of 2 independent reviewers will participate in the process of screening the literature, paper selection, and data extraction, and this process will be performed blindly. When all manuscripts have been selected, disagreements that arise between the 2 reviewers at each stage of the selection process will be resolved through discussion or with an additional reviewer. Results will be reported with descriptive statistics and information will be displayed in a diagrammatic or tabular manner, as explained in the JBI guidelines. RESULTS: The literature search was performed in November 2021 in MEDLINE, LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde), the Cochrane Library, ScienceDirect, Google Scholar, and OpenGrey; a total of 780 results were retrieved. Completion of the review is expected in mid-2022. CONCLUSIONS: This scoping review will be the first to describe the extent of the information regarding the development of hearing loss in the MPS IVA population. The data gathered by this review may lead to an understanding of the grade of hearing loss in this population and allow for the assessment of possible interventions according to the disease pattern. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/32986.

Hispano-American Brain Bank on Neurodevelopmental Disorders: An initiative to promote brain banking, research, education, and outreach in the field of neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) are conditions that present with brain dysfunction due to alterations in the processes of brain development. They present with neuropsychiatric, cognitive, and motor symptoms. Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are two of the most common NDDs. Human brain tissue is a scarce resource that is obtained from postmortem donations. In the case of NDDs, specifically autism, the reduced donation rate of brains prevents researchers to investigate its pathology and fine anatomy. The Hispano-American Brain Bank of Neurodevelopmental Disorders (Banco Hispanoamericano de CErebros de trastornos del NEurodesarrollo) or CENE is a large-scale brain bank for neurodevelopmental disorders in Hispano-America and the US. CENE's objectives are to collect and distribute brains of patients with NDDS, with a focus on ASD and FXS, to perform research, promote education of future scientists, and enhance public awareness about the importance of human tissue availability for scientific research on brain function and disease. CENE has thus far established a bilingual system of nodes and teams in several American countries including California-US, Pennsylvania-US, México, Puerto Rico, Colombia, and Dominican Republic. CENE ensures that postmortem NDD samples used in research better match the world's genetic and ethnic diversity. CENE enables and expands NDD brain research worldwide, particularly with respect to ASD and FXS.

Myasis in uterine prolapse, successful treatment.

We describe the case of an elderly female with total genital prolapse and superinfected uterine myasis. The successful treatment included mechanical extraction of the larvae, antibiotics, and ivermectin (this last one reported for the first time); along with the surgical correction of the prolapse.

Variable Expressivity in Fragile X Syndrome: Towards the Identification of Molecular Characteristics That Modify the Phenotype.

Fragile X syndrome (FXS), is an X-linked inherited genetic disease. FXS is the leading cause of inherited intellectual disability and autism in the world. Those affected are characterized by intellectual disability, language deficit, typical facies, and macroorchidism. Alterations in the FMR1 gene have been associated with FXS. The majority of people with this condition have an allele with an expansion of more than 200 repeats in a tract of CGGs within the 5' untranslated region, and this expansion is associated with a hypermethylated state of the gene promoter. FXS has incomplete penetrance and variable expressivity. Intellectual disability is present in 100% of males and 60% of females. Autism spectrum disorder symptoms appear in 50% to 60% of males and 20% of females. Other characteristics such as behavioral and physical alterations have significant variations in presentation frequency. The molecular causes of the variable phenotype in FXS patients are becoming clear: these causes are related to the FMR1 gene itself and to secondary, modifying gene effects. In FXS patients, size and methylation mosaicisms are common. Secondary to mosaicism, there is a variation in the quantity of FMR1 mRNA and the protein coded by the gene Fragile Mental Retardation Protein (FMRP). Potential modifier genes have also been proposed, with conflicting results. Characterizing patients according to CGG expansion, methylation status, concentration of mRNA and FMRP, and genotypification for possible modifier genes in a clinical setting offers an opportunity to identify predictors for treatment response evaluation. When intervention strategies become available to modulate the course of the disease they could be crucial for selecting patients and identifying the best therapeutic intervention. The purpose of this review is to present the information available about the molecular causes of the variability of the expression incomplete penetrance and variable expressivity in FXS and their potential clinical applications.

Fragile X Syndrome Secondary to in Vitro Fertilization With a Family Egg Donor: A Case Report and Review of the Literature.

Objective: To evidence the need for screening fragile X syndrome (FXS) in egg donors in assisted reproduction protocols. Case report : This is the report of a boy with FXS who inherited the mutated allele from an ovule donated by the mother´s sister through an assisted reproduction protocol. Identifying premutation (PM) carriers of FXS amongst gamete donors isn't part of the obligatory genetic analysis for donors and is only considered by most of the in vitro fertility societies and guidelines as part of the extension screening tests. Conclusion: It is cost-effective to do pre-conceptional screening for the PM or full mutation (FM) of the FMR1 gene affected in FXS in every woman undergoing assisted reproductive methods, including gamete donors even without a positive family history of intellectual disabilities. This case supports the need of rethinking the guidelines on the necessary gamete donor screening tests in assisted reproduction protocols.

Double Genetic Hit: Fragile X Syndrome and Partial Deletion of Protein Patched Homolog 1 Antisense as Cause of Severe Autism Spectrum Disorder.

BACKGROUND: Fragile X syndrome (FXS) is an X-linked genetic disorder caused by the absence of the fragile X mental retardation 1 protein. FXS is the most common inherited cause of intellectual disability and autism spectrum disorder (ASD). Approximately 60% of subjects with FXS present with ASD, and 2% to 4% of individuals diagnosed with ASD have FXS. Most individuals with ASD have a genetic disorder, so detailed molecular testing of individuals with ASD is medically indicated. Deletions of the protein patched homolog 1 antisense (PTCHD1-AS) gene have been associated with ASD. Here, we describe, for the first time, a boy with FXS because of a point mutation in the FMR1 gene and autism, and the latter comorbidity of ASD is likely because of a deletion of PTCHD1-AS. Thus, the observed phenotype of FXS with severe autism symptoms is likely caused by a double hit of genetic mutations. CASE PRESENTATION: The case is a 5-year-old boy with phenotypic characteristics of FXS. The psychological assessment based on parent report and the Autism Diagnostic Observation Schedule, Second Edition identified severe difficulties on every item of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnostic criteria for ASD, with language impairment, anxiety, attention, and affective problems. Exome sequencing identified a de novo pathogenic variant in the FMR1 gene c.229delT (p.Cys77Alafs*5) and, coupled with comparative genomic hybridization, also diagnosed a maternally inherited partial deletion of the PTCHD1-AS gene. CONCLUSION: Fragile X syndrome presents with clinical features in virtually all affected men, predominantly intellectual disability. However, there are other comorbidities present in a subset of patients, including ASD. We propose that the variable expressivity in FXS could be partially explained by the additive effect of a second genetic mutation that increases the individual susceptibility to the unique phenotypic findings, as is the case of the patient described here.

Pentraxin-3 is a candidate biomarker on the spectrum of severity from pre-eclampsia to HELLP syndrome: GenPE study.

Pentraxin-3 has been reported as a promising biomarker of pre-eclampsia and its severity; however, available studies have small sample sizes, and analyses are not always adjusted for confounders. The aim of this study is to establish the strength of the association between maternal Pentraxin-3 level and pre-eclampsia or HELLP syndrome. It was a case-control study. Women with pre-eclampsia or HELLP syndrome were defined as cases, and women with healthy pregnancies at term (>37 weeks) were classified as controls. Plasma concentrations of Pentraxin-3 were determined at the time of delivery by quantitative enzyme immunoassay. Associations between Pentraxin-3 and pre-eclampsia and HELLP syndrome were assessed by multinomial logistic regression. Subsidiary analysis for the time of disease onset was also carried out. Odds ratios and 95% confidence intervals are reported. A total of 1024 pregnant women were included (461 controls, 368 pre-eclampsia, 195 HELLP). A positive log-linear relationship was found between the top pentraxin-3 quintile and HELLP syndrome. After adjustment for confounders (maternal age, ethnicity, socioeconomic position, date and place of recruitment, family history of pre-eclampsia, smoking, body mass index at beginning of pregnancy, gestational age and multiple pregnancy), the strength of the association was higher for HELLP syndrome [OR 1.13 (95% CI 1.08; 1.18)] than for pre-eclampsia [OR 1.03 (95% CI 1.03; 1.10)]. No difference according to time of onset or pentraxin-3 level was found. In summary, pentraxin-3 level was associated with pre-eclampsia, but it was more strongly associated with HELLP syndrome. Longitudinal studies with a lower probability of residual confounding are necessary to improve our knowledge about the role of pentraxin-3 in pre-eclampsia.