Fragile X Syndrome Genetics

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (10 August 2022) | Viewed by 34861

Special Issue Editors


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Guest Editor
1. Diagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville 3052, Australia
2. Faculty of Medicine, Dentistry and Health Sciences, Department of Paediatrics, University of Melbourne, Parkville 3052, Australia
Interests: genomics; fragile X syndrome; FMR1; FMRP; CGG; epigenetics; imprinting disorders; cohort studies; clinical trials
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Co-Guest Editor
1. Central Clinical School, Sydney Medical School, University of Sydney, New South Wales, Australia
2. Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA
Interests: developmental disabilities; fragile X syndrome; FMR1; FMRP; autism; progeria; aging; treatment trials

Special Issue Information

Dear Colleagues,

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading single-gene cause of autism. FXS is usually caused by a CGG trinucleotide expansion to greater than 200 repeats, inducing epigenetic silencing of the fragile X gene, FMR1, and loss of its protein product, FMRP, essential for normal neurodevelopment. Since the discovery of the causative mechanism of FXS around 1991, there has been rapid progress in better understanding FXS neurogenetics and developing improved diagnostic and screening techniques, as well as potential targeted therapies. Preclinical trials that assessed treatments for pathways dysregulated due to loss of FMRP were highly successful in FMR1 knockout mouse models. Unfortunately, successful treatment trials in mice have not had similar improved outcomes in FXS patient trials. One possible explanation for the lack of translation of the preclinical success is that KO mouse models do not fully reflect the underlying biology of FXS in humans where mosaicism for active and inactive alleles plays a significant role.  

This Special Issue will comprise reviews and original research articles focused on the recent advances in genetics/genomics testing; the contribution of mosaicism and epigenetic processes; and the clinical description, co-morbidities, biomarkers, and natural history of FXS. Current and future directions with a focus on improved screening, diagnosis, and treatment will be addressed in this issue.

Prof. David E. Godler
Prof. Dr. William Ted Brown
Guest Editors

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Keywords

  • fragile X syndrome
  • FMR1
  • FMRP
  • mosaicism
  • fragile X intellectual disability
  • autism and fragile X
  • fragile X biomarkers
  • fragile X treatment trials

Published Papers (12 papers)

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Editorial

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4 pages, 185 KiB  
Editorial
Editorial for the Fragile X Syndrome Genetics Special Issue: May 2023
by David E. Godler and William T. Brown
Genes 2023, 14(6), 1148; https://doi.org/10.3390/genes14061148 - 25 May 2023
Viewed by 1061
Abstract
Fragile X syndrome (FXS) is the leading single-gene cause of inherited intellectual disability and autism [...] Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)

Research

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12 pages, 2461 KiB  
Article
Efficient Delivery of FMR1 across the Blood Brain Barrier Using AAVphp Construct in Adult FMR1 KO Mice Suggests the Feasibility of Gene Therapy for Fragile X Syndrome
by Kathryn K. Chadman, Tatyana Adayev, Aishwarya Udayan, Rida Ahmed, Chun-Ling Dai, Jeffrey H. Goodman, Harry Meeker, Natalia Dolzhanskaya and Milen Velinov
Genes 2023, 14(2), 505; https://doi.org/10.3390/genes14020505 - 16 Feb 2023
Cited by 2 | Viewed by 2099
Abstract
Background Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism. Gene therapy may offer an efficient method to ameliorate the symptoms of this disorder. Methods An AAVphp.eb-hSyn-mFMR1IOS7 vector and an empty control were injected into the tail [...] Read more.
Background Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism. Gene therapy may offer an efficient method to ameliorate the symptoms of this disorder. Methods An AAVphp.eb-hSyn-mFMR1IOS7 vector and an empty control were injected into the tail vein of adult Fmr1 knockout (KO) mice and wildtype (WT) controls. The KO mice were injected with 2 × 1013 vg/kg of the construct. The control KO and WT mice were injected with an empty vector. Four weeks following treatment, the animals underwent a battery of tests: open field, marble burying, rotarod, and fear conditioning. The mouse brains were studied for levels of the Fmr1 product FMRP. Results: No significant levels of FMRP were found outside the CNS in the treated animals. The gene delivery was highly efficient, and it exceeded the control FMRP levels in all tested brain regions. There was also improved performance in the rotarod test and partial improvements in the other tests in the treated KO animals. Conclusion: These experiments demonstrate efficient, brain-specific delivery of Fmr1 via peripheral administration in adult mice. The gene delivery led to partial alleviation of the Fmr1 KO phenotypical behaviors. FMRP oversupply may explain why not all behaviors were significantly affected. Since AAV.php vectors are less efficient in humans than in the mice used in the current experiment, studies to determine the optimal dose using human-suitable vectors will be necessary to further demonstrate feasibility. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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17 pages, 2510 KiB  
Article
Observable Symptoms of Anxiety in Individuals with Fragile X Syndrome: Parent and Caregiver Perspectives
by Reymundo Lozano, Talia Thompson, Jayne Dixon-Weber, Craig A. Erickson, Elizabeth Berry-Kravis, Sara Williams, Elizabeth Smith, Jean A. Frazier, Hilary Rosselot, Cristan Farmer and David Hessl
Genes 2022, 13(9), 1660; https://doi.org/10.3390/genes13091660 - 16 Sep 2022
Cited by 8 | Viewed by 2186
Abstract
Caregiver reports, clinical observations, and diagnostic assessments indicate that most individuals with fragile X syndrome experience high levels of chronic anxiety. However, anxiety is a challenging endpoint for outcome measurement in FXS because most individuals cannot reliably report internal emotional or body states. [...] Read more.
Caregiver reports, clinical observations, and diagnostic assessments indicate that most individuals with fragile X syndrome experience high levels of chronic anxiety. However, anxiety is a challenging endpoint for outcome measurement in FXS because most individuals cannot reliably report internal emotional or body states. A comprehensive survey of the presence, frequency, and duration of anxiety-related symptoms and questions to elicit open-ended responses was completed by caregivers of 456 individuals with FXS, ages 2–81 years (87 female, 369 male) and 24 female and 2 male FXS self-advocates ages 15–66 years. Caregivers reported classic behavioral indicators of anxiety, such as avoidance, irritability, motor agitation, and physiological symptoms, as well as behavioral features in FXS such as repetitive behavior, aggression, and self-injury. Self-advocate accounts largely paralleled caregiver data. Factor analyses yielded four factors: (1) increased irritability, aggression, and self-injury; (2) increased physical movement, nervous activity, and restlessness; (3) physical and physiological features of anxiety; and (4) internalizing and gastrointestinal symptoms. Caregivers are capable of observing and reporting behaviors that are valid indicators of anxious states that are usually reported in self-report standardized assessments. These results support the development of an anxiety measure for FXS that minimizes problems with rater inference. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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13 pages, 960 KiB  
Article
Exploring Parents’ Concerns Regarding Long-Term Support and Living Arrangements for Their Children with Fragile X Syndrome
by Kaylynn Shuleski, Laura Zalles and Reymundo Lozano
Genes 2022, 13(9), 1654; https://doi.org/10.3390/genes13091654 - 15 Sep 2022
Cited by 1 | Viewed by 1720
Abstract
Given limited data regarding future planning specific to Fragile X Syndrome (FXS) individuals and the growing population of individuals within this community, this study sought to explore the concerns and challenges caregivers of individuals affected by FXS encounter when considering long-term support plans. [...] Read more.
Given limited data regarding future planning specific to Fragile X Syndrome (FXS) individuals and the growing population of individuals within this community, this study sought to explore the concerns and challenges caregivers of individuals affected by FXS encounter when considering long-term support plans. This involved identifying the reasons individuals with FXS continue to reside with family and the reservations caregivers have regarding future supports and living arrangements. We administered an anonymous online survey consisting of 34 questions assessing eligibility, living arrangements/supports, and future concerns. We found that most individuals with FXS were affected with moderate Intellectual and Developmental Disabilities (IDD) and co-occurring behavioral conditions but had overall good health. The majority of individuals with FXS currently resided with family due to parental desire, their own desire, and the inability to live independently. For one-third of caregivers, the plan for future living arrangements is to continue residing with family members long-term. A large proportion of caregivers had not considered alternative arrangements or were unsure. More than 70% of caregivers of individuals with FXS are concerned about multiple aspects of the individual’s future. Caregivers of younger individuals are the most concerned, but also believe they have time before they need to plan or are unable to currently assess the future need for support. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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11 pages, 1696 KiB  
Article
Co-Occurrence of Fragile X Syndrome with a Second Genetic Condition: Three Independent Cases of Double Diagnosis
by Elisabetta Tabolacci, Maria Grazia Pomponi, Laura Remondini, Roberta Pietrobono, Daniela Orteschi, Veronica Nobile, Cecilia Pucci, Elisa Musto, Marika Pane, Eugenio M. Mercuri, Giovanni Neri, Maurizio Genuardi, Pietro Chiurazzi and Marcella Zollino
Genes 2021, 12(12), 1909; https://doi.org/10.3390/genes12121909 - 27 Nov 2021
Cited by 4 | Viewed by 3127
Abstract
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism caused by the instability of a CGG trinucleotide repeat in exon 1 of the FMR1 gene. The co-occurrence of FXS with other genetic disorders has only been occasionally [...] Read more.
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism caused by the instability of a CGG trinucleotide repeat in exon 1 of the FMR1 gene. The co-occurrence of FXS with other genetic disorders has only been occasionally reported. Here, we describe three independent cases of FXS co-segregation with three different genetic conditions, consisting of Duchenne muscular dystrophy (DMD), PPP2R5D--related neurodevelopmental disorder, and 2p25.3 deletion. The co-occurrence of DMD and FXS has been reported only once in a young boy, while in an independent family two affected boys were described, the elder diagnosed with FXS and the younger with DMD. This represents the second case in which both conditions coexist in a 5-year-old boy, inherited from his heterozygous mother. The next double diagnosis had never been reported before: through exome sequencing, a girl with FXS who was of 7 years of age with macrocephaly and severe psychomotor delay was found to carry a de novo variant in the PPP2R5D gene. Finally, a maternally inherited 2p25.3 deletion associated with a decreased level of the MYT1L transcript, only in the patient, was observed in a 33-year-old FXS male with severe seizures compared to his mother and two sex- and age-matched controls. All of these patients represent very rare instances of genetic conditions with clinical features that can be modified by FXS and vice versa. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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24 pages, 1104 KiB  
Article
Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes
by Cedrik Tekendo-Ngongang, Angela Grochowsky, Benjamin D. Solomon and Sho T. Yano
Genes 2021, 12(11), 1669; https://doi.org/10.3390/genes12111669 - 22 Oct 2021
Cited by 10 | Viewed by 3351
Abstract
FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and [...] Read more.
FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing FMR1 variation, with clinical and functional evidence supporting pathogenicity of five splicing, five missense, one in-frame deletion, one nonsense, and four frameshift variants. In addition, FMR1 deletions occur in both mosaic full mutation patients and as constitutional pathogenic alleles. De novo deletions arise not only from full mutation alleles but also alleles with normal-sized CGG repeats in several patients, suggesting that the CGG repeat region may be prone to genomic instability even in the absence of repeat expansion. We conclude that clinical tests for potentially FMR1-related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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17 pages, 1985 KiB  
Article
Development of a Quantitative FMRP Assay for Mouse Tissue Applications
by Tatyana Adayev, Giuseppe LaFauci, Weimin Xu, Carl Dobkin, Richard Kascsak, W. Ted Brown and Jeffrey H. Goodman
Genes 2021, 12(10), 1516; https://doi.org/10.3390/genes12101516 - 26 Sep 2021
Cited by 2 | Viewed by 1964
Abstract
Fragile X syndrome results from the absence of the FMR1 gene product—Fragile X Mental Retardation Protein (FMRP). Fragile X animal research has lacked a reliable method to quantify FMRP. We report the development of an array of FMRP-specific monoclonal antibodies and their application [...] Read more.
Fragile X syndrome results from the absence of the FMR1 gene product—Fragile X Mental Retardation Protein (FMRP). Fragile X animal research has lacked a reliable method to quantify FMRP. We report the development of an array of FMRP-specific monoclonal antibodies and their application for quantitative assessment of FMRP (qFMRPm) in mouse tissue. To characterize the assay, we determined the normal variability of FMRP expression in four brain structures of six different mouse strains at seven weeks of age. There was a hierarchy of FMRP expression: neocortex > hippocampus > cerebellum > brainstem. The expression of FMRP was highest and least variable in the neocortex, whereas it was most variable in the hippocampus. Male C57Bl/6J and FVB mice were selected to determine FMRP developmental differences in the brain at 3, 7, 10, and 14 weeks of age. We examined the four structures and found a developmental decline in FMRP expression with age, except for the brainstem where it remained stable. qFMRPm assay of blood had highest values in 3 week old animals and dropped by 2.5-fold with age. Sex differences were not significant. The results establish qFMRPm as a valuable tool due to its ease of methodology, cost effectiveness, and accuracy. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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Review

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32 pages, 1118 KiB  
Review
Behavior Problems and Social Competence in Fragile X Syndrome: A Systematic Review
by Olga Cregenzán-Royo, Carme Brun-Gasca and Albert Fornieles-Deu
Genes 2022, 13(2), 280; https://doi.org/10.3390/genes13020280 - 30 Jan 2022
Cited by 10 | Viewed by 6494
Abstract
Fragile X syndrome (FXS) causes intellectual disability and is the known leading cause of autism. Common problems in FXS include behavior and social problems. Along with syndromic characteristics and autism comorbidity, environmental factors might influence these difficulties. This systematic review focuses on the [...] Read more.
Fragile X syndrome (FXS) causes intellectual disability and is the known leading cause of autism. Common problems in FXS include behavior and social problems. Along with syndromic characteristics and autism comorbidity, environmental factors might influence these difficulties. This systematic review focuses on the last 20 years of studies concerning behavior and social problems in FXS, considering environmental and personal variables that might influence both problems. Three databases were reviewed, leading to fifty-one studies meeting the inclusion criteria. Attention deficit hyperactivity disorder (ADHD) problems remain the greatest behavior problems, with behavioral problems and social competence being stable during the 20 years. Some developmental trajectories might have changed due to higher methodological control, such as aggressive behavior and attention problems. The socialization trajectory from childhood to adolescence remains unclear. Comorbidity with autism in individuals with FXS increased behavior problems and worsened social competence profiles. At the same time, comparisons between individuals with comorbid FXS and autism and individuals with autism might help define the comorbid phenotype. Environmental factors and parental characteristics influenced behavior problems and social competence. Higher methodological control is needed in studies including autism symptomatology and parental characteristics. More studies comparing autism in FXS with idiopathic autism are needed to discern differences between conditions. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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14 pages, 1393 KiB  
Review
Mechanisms of Genome Instability in the Fragile X-Related Disorders
by Bruce E. Hayward and Karen Usdin
Genes 2021, 12(10), 1633; https://doi.org/10.3390/genes12101633 - 17 Oct 2021
Cited by 6 | Viewed by 3756
Abstract
The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that [...] Read more.
The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological FMR1 allele size classes are distinguished. Premutation (PM) alleles have 54–200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are prone to both somatic and germline expansion, with female PM carriers being at risk of having a child with >200+ repeats. Inheritance of such full mutation (FM) alleles causes FXS. Contractions of PM and FM alleles can also occur. As a result, many carriers are mosaic for different sized alleles, with the clinical presentation depending on the proportions of these alleles in affected tissues. Furthermore, it has become apparent that the chromosomal fragility of FXS individuals reflects an underlying problem that can lead to chromosomal numerical and structural abnormalities. Thus, large numbers of CGG-repeats in the FMR1 gene predisposes individuals to multiple forms of genome instability. This review will discuss our current understanding of these processes. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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Other

7 pages, 1344 KiB  
Case Report
Fragile X Syndrome Caused by Maternal Somatic Mosaicism of FMR1 Gene: Case Report and Literature Review
by Maria Jose Gómez-Rodríguez, Montserrat Morales-Conejo, Ana Arteche-López, Maria Teresa Sánchez-Calvín, Juan Francisco Quesada-Espinosa, Irene Gómez-Manjón, Carmen Palma-Milla, Jose Miguel Lezana-Rosales, Ruben Pérez de la Fuente, Maria-Luisa Martin-Ramos, Manuela Fernández-Guijarro, Marta Moreno-García and Maria Isabel Alvarez-Mora
Genes 2022, 13(9), 1609; https://doi.org/10.3390/genes13091609 - 8 Sep 2022
Cited by 1 | Viewed by 2277
Abstract
Fragile X syndrome (FXS) is caused by an abnormal expansion of the number of trinucleotide CGG repeats located in the 5′ UTR in the first exon of the FMR1 gene. Size and methylation mosaicisms are commonly observed in FXS patients. Both types of [...] Read more.
Fragile X syndrome (FXS) is caused by an abnormal expansion of the number of trinucleotide CGG repeats located in the 5′ UTR in the first exon of the FMR1 gene. Size and methylation mosaicisms are commonly observed in FXS patients. Both types of mosaicisms might be associated with less severe phenotypes depending on the number of cells expressing FMRP. Although this dynamic mutation is the main underlying cause of FXS, other mechanisms, including point mutations or deletions, can lead to FXS. Several reports have demonstrated that de novo deletions including the entire or a portion of the FMR1 gene end up with the absence of FMRP and, thus, can lead to the typical clinical features of FXS. However, very little is known about the clinical manifestations associated with FMR1 gene deletions in mosaicism. Here, we report an FXS case caused by an entire hemizygous deletion of the FMR1 gene caused by maternal mosaicism. This manuscript reports this case and a literature review of the clinical manifestations presented by carriers of FMR1 gene deletions in mosaicism. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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6 pages, 221 KiB  
Case Report
Case Reports of Aortic Aneurism in Fragile X Syndrome
by Sivan Lewis, Andrew DePass, Randi J. Hagerman and Reymundo Lozano
Genes 2022, 13(9), 1560; https://doi.org/10.3390/genes13091560 - 30 Aug 2022
Cited by 2 | Viewed by 1611
Abstract
Fragile X syndrome (FXS) is an inherited genetic condition that is the leading known cause of inherited intellectual developmental disability. Phenotypically, individuals with FXS also present with distinct physical features including, elongated face, prominent ears, pectus excavatum, macroorchidism, and joint laxity, which suggests [...] Read more.
Fragile X syndrome (FXS) is an inherited genetic condition that is the leading known cause of inherited intellectual developmental disability. Phenotypically, individuals with FXS also present with distinct physical features including, elongated face, prominent ears, pectus excavatum, macroorchidism, and joint laxity, which suggests connective tissue dysplasia. In addition to mitral valve prolapse, aortic dilatation has been identified within individuals with FXS. Abnormal elastin fiber networks have been found in the skin, valves, and aorta in individual cases. Aortic dilatation has been described in other connective tissue disorders, particularly Marfan syndrome. However, while aortic aneurysms are characteristic of Marfan syndrome, no similar cases have been reported in FXS patients to date. This case report details the presentation of two patients with FXS and aortic aneurysm. Our two cases highlight the risks of aortic pathology in FXS, and the need for monitoring in asymptomatic patients with significant aortic dilatation. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
9 pages, 2214 KiB  
Case Report
Detection of Cryptic Fragile X Full Mutation Alleles by Southern Blot in a Female and Her Foetal DNA via Chorionic Villus Sampling, Complicated by Mosaicism for 45,X0/46,XX/47,XXX
by Alison Pandelache, David Francis, Ralph Oertel, Rebecca Dickson, Rani Sachdev, Ling Ling, Dinusha Gamage and David E. Godler
Genes 2021, 12(6), 798; https://doi.org/10.3390/genes12060798 - 24 May 2021
Cited by 2 | Viewed by 2787
Abstract
We describe a female with a 72 CGG FMR1 premutation (PM) (CGG 55–199) and family history of fragile X syndrome (FXS), referred for prenatal testing. The proband had a high risk of having an affected pregnancy with a full mutation allele (FM) (CGG [...] Read more.
We describe a female with a 72 CGG FMR1 premutation (PM) (CGG 55–199) and family history of fragile X syndrome (FXS), referred for prenatal testing. The proband had a high risk of having an affected pregnancy with a full mutation allele (FM) (CGG > 200), that causes FXS through hypermethylation of the FMR1 promoter. The CGG sizing analysis in this study used AmplideX triplet repeat primed polymerase chain reaction (TP-PCR) and long-range methylation sensitive PCR (mPCR). These methods detected a 73 CGG PM allele in the proband’s blood, and a 164 CGG PM allele in her male cultured chorionic villus sample (CVS). In contrast, the Southern blot analysis showed mosaicism for: (i) a PM (71 CGG) and an FM (285–768 CGG) in the proband’s blood, and (ii) a PM (165 CGG) and an FM (408–625 CGG) in the male CVS. The FMR1 methylation analysis, using an EpiTYPER system in the proband, showed levels in the range observed for mosaic Turner syndrome. This was confirmed by molecular and cytogenetic karyotyping, identifying 45,X0/46,XX/47,XXX lines. In conclusion, this case highlights the importance of Southern blot in pre- and postnatal testing for presence of an FM, which was not detected using AmplideX TP-PCR or mPCR in the proband and her CVS. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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