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A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 56707

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Special Issue Editors

Dr. David E. Godler

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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
Special Issues, Collections and Topics in MDPI journals

Dr. Olivia J. Veatch

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Guest Editor

Department of Psychiatry and Behavioral Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA
Interests: human genetics; bioinformatics; machine learning; neurodevelopment; sleep/circadian rhythms

Special Issue Information

Dear Colleagues,

This Special Issue of the International Journal of Molecular Sciences is dedicated to Professor Merlin G. Butler, in recognition of his retirement and to commemorate his substantial contributions to the field of genetics and genomics-driven medical care. Dr. Butler has been a pioneer in the expansion of our understanding of how genetics can help inform healthcare professionals regarding individuals with neurodevelopmental syndromes and conditions. For more than four decades, throughout his career as a physician scientist and laboratory and medical geneticist, he has cared for thousands of patients seeking genetic services in the clinical setting, also having performed extensive research, specifically, regarding Prader–Willi, Angelman, Burnside–Butler and fragile X syndromes, the genetics of autism and obesity, and the characterization, delineation and natural history of rare genetic disorders using advanced genomic and pharmacogenetic methods. Rapid advancements in genomic technologies are continuing to improve the diagnosis, disease surveillance, counseling, research and treatment of rare genetic diseases, chromosomal and neurodevelopmental disorders, autism, and congenital abnormalities. This commemorative Special Issue focuses on original research and review articles evaluating innovative molecular and computational approaches for studying the mechanisms underlying the expression and development of both common and rare genetic conditions.

Dr. David E. Godler
Dr. Olivia J. Veatch
Guest Editors

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Keywords

whole exome/genome sequencing
epigenetics
epigenomics
pharmacogenomics
transcriptomics
non-coding RNAs
biomarkers
patient stratification
bioinformatics
rare genetic diseases
genotype–phenotype correlations
chromosomal and neurodevelopmental disorders
congenital abnormalities
newborn screening

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Published Papers (14 papers)

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Editorial

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3 pages, 178 KiB

Open AccessEditorial

The Arduous Path to Drug Approval for the Management of Prader–Willi Syndrome: A Historical Perspective and Call to Action

by Deepan Singh, Jennifer L. Miller, Edward Robert Wassman, Merlin G. Butler, Allison Foley Shenk, Monica Converse and Maria Picone

Int. J. Mol. Sci. 2023, 24(14), 11574; https://doi.org/10.3390/ijms241411574 - 18 Jul 2023

Cited by 2 | Viewed by 2131

Abstract

Prader–Willi syndrome (PWS) is a neuroendocrine genetic disorder resulting from the loss of paternally expressed imprinted genes in chromosome 15q11-q13 [...] Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

Research

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17 pages, 4535 KiB

Open AccessArticle

Defining the 3′Epigenetic Boundary of the FMR1 Promoter and Its Loss in Individuals with Fragile X Syndrome

by David E. Godler, Yoshimi Inaba, Minh Q. Bui, David Francis, Cindy Skinner, Charles E. Schwartz and David J. Amor

Int. J. Mol. Sci. 2023, 24(13), 10712; https://doi.org/10.3390/ijms241310712 - 27 Jun 2023

Cited by 1 | Viewed by 1307

Abstract

This study characterizes the DNA methylation patterns specific to fragile X syndrome (FXS) with a full mutation (FM > 200 CGGs), premutation (PM 55–199 CGGs), and X inactivation in blood and brain tissues at the 3′ boundary of the FMR1 promoter. Blood was analyzed from 95 controls and 462 individuals (32% males) with FM and PM alleles. Brain tissues (62% males) were analyzed from 12 controls and 4 with FXS. There was a significant increase in intron 1 methylation, extending to a newly defined 3′ epigenetic boundary in the FM compared with that in the control and PM groups (p < 0.0001), and this was consistent between the blood and brain tissues. A distinct intron 2 site showed a significant decrease in methylation for the FXS groups compared with the controls in both sexes (p < 0.01). In all female groups, most intron 1 (but not intron 2 sites) were sensitive to X inactivation. In all PM groups, methylation at the 3′ epigenetic boundary and the proximal sites was significantly decreased compared with that in the control and FM groups (p < 0.0001). In conclusion, abnormal FMR1 intron 1 and 2 methylation that was sensitive to X inactivation in the blood and brain tissues provided a novel avenue for the detection of PM and FM alleles through DNA methylation analysis. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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16 pages, 1193 KiB

Open AccessArticle

Evaluation of Autonomic Nervous System Dysfunction in Childhood Obesity and Prader–Willi Syndrome

by Lawrence P. Richer, Qiming Tan, Merlin G. Butler, Hayford M. Avedzi, Darren S. DeLorey, Ye Peng, Hein M. Tun, Arya M. Sharma, Steven Ainsley, Camila E. Orsso, Lucila Triador, Michael Freemark and Andrea M. Haqq

Int. J. Mol. Sci. 2023, 24(9), 8013; https://doi.org/10.3390/ijms24098013 - 28 Apr 2023

Cited by 2 | Viewed by 2159

Abstract

The autonomic nervous system (ANS) may play a role in the distribution of body fat and the development of obesity and its complications. Features of individuals with Prader–Willi syndrome (PWS) impacted by PWS molecular genetic classes suggest alterations in ANS function; however, these have been rarely studied and presented with conflicting results. The aim of this study was to investigate if the ANS function is altered in PWS. In this case-control study, we assessed ANS function in 20 subjects with PWS (6 males/14 females; median age 10.5 years) and 27 body mass index (BMI) z-score-matched controls (19 males/8 females; median age 12.8 years). Standardized non-invasive measures of cardiac baroreflex function, heart rate, blood pressure, heart rate variability, quantitative sudomotor axon reflex tests, and a symptom questionnaire were completed. The increase in heart rate in response to head-up tilt testing was blunted (p < 0.01) in PWS compared to controls. Besides a lower heart rate ratio with Valsalva in PWS (p < 0.01), no significant differences were observed in other measures of cardiac function or sweat production. Findings suggest possible altered sympathetic function in PWS. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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15 pages, 3940 KiB

Open AccessArticle

Chromosomal Microarray Study in Prader-Willi Syndrome

by Merlin G. Butler, Waheeda A. Hossain, Neil Cowen and Anish Bhatnagar

Int. J. Mol. Sci. 2023, 24(2), 1220; https://doi.org/10.3390/ijms24021220 - 7 Jan 2023

Cited by 2 | Viewed by 3631

Abstract

A high-resolution chromosome microarray analysis was performed on 154 consecutive individuals enrolled in the DESTINY PWS clinical trial for Prader-Willi syndrome (PWS). Of these 154 PWS individuals, 87 (56.5%) showed the typical 15q11-q13 deletion subtypes, 62 (40.3%) showed non-deletion maternal disomy 15 and five individuals (3.2%) had separate unexpected microarray findings. For example, one PWS male had Klinefelter syndrome with segmental isodisomy identified in both chromosomes 15 and X. Thirty-five (40.2%) of 87 individuals showed typical larger 15q11-q13 Type I deletion and 52 individuals (59.8%) showed typical smaller Type II deletion. Twenty-four (38.7%) of 62 PWS individuals showed microarray patterns indicating either maternal heterodisomy 15 subclass or a rare non-deletion (epimutation) imprinting center defect. Segmental isodisomy 15 was seen in 34 PWS subjects (54.8%) with 15q26.3, 15q14 and 15q26.1 bands most commonly involved and total isodisomy 15 seen in four individuals (6.5%). In summary, we report on PWS participants consecutively enrolled internationally in a single clinical trial with high-resolution chromosome microarray analysis to determine and describe an unbiased estimate of the frequencies and types of genetic defects and address potential at-risk genetic disorders in those with maternal disomy 15 subclasses in the largest PWS cohort studied to date. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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17 pages, 1194 KiB

Open AccessArticle

Comparison of Body Composition, Muscle Strength and Cardiometabolic Profile in Children with Prader-Willi Syndrome and Non-Alcoholic Fatty Liver Disease: A Pilot Study

by Diana R. Mager, Krista MacDonald, Reena L. Duke, Hayford M. Avedzi, Edward C. Deehan, Jason Yap, Kerry Siminoski and Andrea M. Haqq

Int. J. Mol. Sci. 2022, 23(23), 15115; https://doi.org/10.3390/ijms232315115 - 1 Dec 2022

Cited by 1 | Viewed by 2226

Abstract

Syndromic and non-syndromic obesity conditions in children, such as Prader-Willi syndrome (PWS) and non-alcoholic fatty liver disease (NAFLD), both lower quality of life and increase risk for chronic health complications, which further increase health service utilization and cost. In a pilot observational study, we compared body composition and muscle strength in children aged 7–18 years with either PWS (n = 9), NAFLD (n = 14), or healthy controls (n = 16). Anthropometric and body composition measures (e.g., body weight, circumferences, skinfolds, total/segmental composition, and somatotype), handgrip strength, six minute-walk-test (6MWT), physical activity, and markers of liver and cardiometabolic dysfunction (e.g., ALT, AST, blood pressure, glucose, insulin, and lipid profile) were measured using standard procedures and validated tools. Genotyping was determined for children with PWS. Children with PWS had reduced lean body mass (total/lower limb mass), lower handgrip strength, 6MWT and increased sedentary activity compared to healthy children or those with NAFLD (p < 0.05). Children with PWS, including those of normal body weight, had somatotypes consistent with relative increased adiposity (endomorphic) and reduced skeletal muscle robustness (mesomorphic) when compared to healthy children and those with NAFLD. Somatotype characterizations were independent of serum markers of cardiometabolic dysregulation but were associated with increased prevalence of abnormal systolic and diastolic blood pressure Z-scores (p < 0.05). Reduced lean body mass and endomorphic somatotypes were associated with lower muscle strength/functionality and sedentary lifestyles, particularly in children with PWS. These findings are relevant as early detection of deficits in muscle strength and functionality can ensure effective targeted treatments that optimize physical activity and prevent complications into adulthood. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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11 pages, 428 KiB

Open AccessArticle

Preserved Sleep for the Same Level of Respiratory Disturbance in Children with Prader-Willi Syndrome

by Qiming Tan, Xiao Tian (Tim) He, Sabrina Kang, Andrea M. Haqq and Joanna E. MacLean

Int. J. Mol. Sci. 2022, 23(18), 10580; https://doi.org/10.3390/ijms231810580 - 13 Sep 2022

Cited by 3 | Viewed by 1883

Abstract

Debate remains as to how to balance the use of recombinant human growth hormone (rhGH) as an important treatment in Prader-Willi syndrome (PWS) with its potential role in obstructive sleep apnea. This single-center, retrospective study assessed differences in overnight polysomnography results between children with and without PWS and changes in respiratory parameters before and after the initiation of rhGH treatment in those with PWS. Compared with age-, sex-, and body-mass-index-matched controls (n = 87), children with PWS (n = 29) had longer total sleep time (434 ± 72 vs. 365 ± 116 min; p < 0.01), higher sleep efficiency (86 ± 7 vs. 78 ± 15%; p < 0.05), and lower arousal events (8.1 ± 4.5 vs. 13.0 ± 8.9 events/h; p < 0.05). Mean oxygen saturation was lower in PWS children (94.3 ± 6.0 vs. 96.0 ± 2.0%; p < 0.05), with no other differences in respiratory parameters between groups. Eleven children with PWS (38%) met the criteria for further analyses of the impact of rhGH; polysomnography parameters did not change with treatment. Compared with other children undergoing polysomnography, children with PWS had more favorable markers of sleep continuity and lower oxygen saturation for the same level of respiratory disturbance. rhGH administration was not associated with changes in respiratory parameters in PWS. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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Review

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13 pages, 1219 KiB

Open AccessReview

Prader–Willi Syndrome and Chromosome 15q11.2 BP1-BP2 Region: A Review

by Merlin G. Butler

Int. J. Mol. Sci. 2023, 24(5), 4271; https://doi.org/10.3390/ijms24054271 - 21 Feb 2023

Cited by 13 | Viewed by 6478

Abstract

Prader–Willi syndrome (PWS) is a complex genetic disorder with three PWS molecular genetic classes and presents as severe hypotonia, failure to thrive, hypogonadism/hypogenitalism and developmental delay during infancy. Hyperphagia, obesity, learning and behavioral problems, short stature with growth and other hormone deficiencies are identified during childhood. Those with the larger 15q11-q13 Type I deletion with the absence of four non-imprinted genes (NIPA1, NIPA2, CYFIP1, TUBGCP5) from the 15q11.2 BP1-BP2 region are more severely affected compared with those with PWS having a smaller Type II deletion. NIPA1 and NIPA2 genes encode magnesium and cation transporters, supporting brain and muscle development and function, glucose and insulin metabolism and neurobehavioral outcomes. Lower magnesium levels are reported in those with Type I deletions. The CYFIP1 gene encodes a protein associated with fragile X syndrome. The TUBGCP5 gene is associated with attention-deficit hyperactivity disorder (ADHD) and compulsions, more commonly seen in PWS with the Type I deletion. When the 15q11.2 BP1-BP2 region alone is deleted, neurodevelopment, motor, learning and behavioral problems including seizures, ADHD, obsessive-compulsive disorder (OCD) and autism may occur with other clinical findings recognized as Burnside–Butler syndrome. The genes in the 15q11.2 BP1-BP2 region may contribute to more clinical involvement and comorbidities in those with PWS and Type I deletions. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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15 pages, 458 KiB

Open AccessReview

Clinical Trials in Prader–Willi Syndrome: A Review

by Ranim Mahmoud, Virginia Kimonis and Merlin G. Butler

Int. J. Mol. Sci. 2023, 24(3), 2150; https://doi.org/10.3390/ijms24032150 - 21 Jan 2023

Cited by 11 | Viewed by 6356

Abstract

Prader–Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal 15q11-q13 deletion observed in about 60% of individuals. This is followed by maternal disomy 15 (both 15 s from the mother), found in approximately 35% of cases. the remaining individuals have a defect of the imprinting center that controls the activity of imprinted genes on chromosome 15. Mild cognitive impairment and behavior problems in PWS include self-injury, anxiety, compulsions, and outbursts in childhood, impacted by genetic subtypes. Food seeking and hyperphagia can lead to morbid obesity and contribute to diabetes and cardiovascular or orthopedic problems. The control of hyperphagia and improving food-related behaviors are the most important unmet needs in PWS and could be addressed with the development of a new therapeutic agent, as currently no approved therapeutics exist for PWS treatment. The status of clinical trials with existing results for the management of obesity and hyperphagia in PWS will be discussed in this review, including treatments such as beloranib, setmelanotide, a diazoxide choline controlled-release tablet (DCCR), an unacylated ghrelin analogue, oxytocin and related compounds, glucagon-like peptide 1 receptor agonists, surgical intervention, and transcranial direct-current stimulation. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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15 pages, 705 KiB

Open AccessReview

Genetics of Obesity in Humans: A Clinical Review

by Ranim Mahmoud, Virginia Kimonis and Merlin G. Butler

Int. J. Mol. Sci. 2022, 23(19), 11005; https://doi.org/10.3390/ijms231911005 - 20 Sep 2022

Cited by 51 | Viewed by 16036

Abstract

Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and developing countries. The development of genome-wide association studies (GWAS) and next-generation sequencing (NGS) has increased the discovery of genetic associations and awareness of monogenic and polygenic causes of obesity. The genetics of obesity could be classified into syndromic and non-syndromic obesity. Prader–Willi, fragile X, Bardet–Biedl, Cohen, and Albright Hereditary Osteodystrophy (AHO) syndromes are examples of syndromic obesity, which are associated with developmental delay and early onset obesity. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin. Monogenic obesity is caused by variants of single genes while polygenic obesity includes several genes with the involvement of members of gene families. New advances in genetic testing have led to the identification of obesity-related genes. Leptin (LEP), the leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PCSK1), the melanocortin 4 receptor (MC4R), single-minded homolog 1 (SIM1), brain-derived neurotrophic factor (BDNF), and the neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) have been reported as causative genes for obesity. NGS is now in use and emerging as a useful tool to search for candidate genes for obesity in clinical settings. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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19 pages, 1005 KiB

Open AccessReview

DNA Methylation Episignatures in Neurodevelopmental Disorders Associated with Large Structural Copy Number Variants: Clinical Implications

by Kathleen Rooney and Bekim Sadikovic

Int. J. Mol. Sci. 2022, 23(14), 7862; https://doi.org/10.3390/ijms23147862 - 16 Jul 2022

Cited by 11 | Viewed by 3430

Abstract

Large structural chromosomal deletions and duplications, referred to as copy number variants (CNVs), play a role in the pathogenesis of neurodevelopmental disorders (NDDs) through effects on gene dosage. This review focuses on our current understanding of genomic disorders that arise from large structural chromosome rearrangements in patients with NDDs, as well as difficulties in overlap of clinical presentation and molecular diagnosis. We discuss the implications of epigenetics, specifically DNA methylation (DNAm), in NDDs and genomic disorders, and consider the implications and clinical impact of copy number and genomic DNAm testing in patients with suspected genetic NDDs. We summarize evidence of global methylation episignatures in CNV-associated disorders that can be used in the diagnostic pathway and may provide insights into the molecular pathogenesis of genomic disorders. Finally, we discuss the potential for combining CNV and DNAm assessment into a single diagnostic assay. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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Other

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23 pages, 2662 KiB

Open AccessCase Report

Mowat–Wilson Syndrome: Case Report and Review of ZEB2 Gene Variant Types, Protein Defects and Molecular Interactions

by Caroline St. Peter, Waheeda A. Hossain, Scott Lovell, Syed K. Rafi and Merlin G. Butler

Int. J. Mol. Sci. 2024, 25(5), 2838; https://doi.org/10.3390/ijms25052838 - 29 Feb 2024

Cited by 1 | Viewed by 2593

Abstract

Mowat–Wilson syndrome (MWS) is a rare genetic neurodevelopmental congenital disorder associated with various defects of the zinc finger E-box binding homeobox 2 (ZEB2) gene. The ZEB2 gene is autosomal dominant and encodes six protein domains including the SMAD-binding protein, which functions as a transcriptional corepressor involved in the conversion of neuroepithelial cells in early brain development and as a mediator of trophoblast differentiation. This review summarizes reported ZEB2 gene variants, their types, and frequencies among the 10 exons of ZEB2. Additionally, we summarized their corresponding encoded protein defects including the most common variant, c.2083 C>T in exon 8, which directly impacts the homeodomain (HD) protein domain. This single defect was found in 11% of the 298 reported patients with MWS. This review demonstrates that exon 8 encodes at least three of the six protein domains and accounts for 66% (198/298) of the variants identified. More than 90% of the defects were due to nonsense or frameshift changes. We show examples of protein modeling changes that occurred as a result of ZEB2 gene defects. We also report a novel pathogenic variant in exon 8 in a 5-year-old female proband with MWS. This review further explores other genes predicted to be interacting with the ZEB2 gene and their predicted gene–gene molecular interactions with protein binding effects on embryonic multi-system development such as craniofacial, spine, brain, kidney, cardiovascular, and hematopoiesis. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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8 pages, 1429 KiB

Open AccessCase Report

A Complex Genomic Rearrangement Resulting in Loss of Function of SCN1A and SCN2A in a Patient with Severe Developmental and Epileptic Encephalopathy

by Valeria Orlando, Silvia Di Tommaso, Viola Alesi, Sara Loddo, Silvia Genovese, Giorgia Catino, Licia Martucci, Maria Cristina Roberti, Marina Trivisano, Maria Lisa Dentici, Nicola Specchio, Bruno Dallapiccola, Alessandro Ferretti and Antonio Novelli

Int. J. Mol. Sci. 2022, 23(21), 12900; https://doi.org/10.3390/ijms232112900 - 26 Oct 2022

Cited by 2 | Viewed by 2248

Abstract

Complex genomic rearrangements (CGRs) are structural variants arising from two or more chromosomal breaks, which are challenging to characterize by conventional or molecular cytogenetic analysis (karyotype and FISH). The integrated approach of standard and genomic techniques, including optical genome mapping (OGM) and genome sequencing, is crucial for disclosing and characterizing cryptic chromosomal rearrangements at high resolutions. We report on a patient with a complex developmental and epileptic encephalopathy in which karyotype analysis showed a de novo balanced translocation involving the long arms of chromosomes 2 and 18. Microarray analysis detected a 194 Kb microdeletion at 2q24.3 involving the SCN2A gene, which was considered the likely translocation breakpoint on chromosome 2. However, OGM redefined the translocation breakpoints by disclosing a paracentric inversion at 2q24.3 disrupting SCN1A. This combined genomic high-resolution approach allowed a fine characterization of the CGR, which involves two different chromosomes with four breakpoints. The patient’s phenotype resulted from the concomitant loss of function of SCN1A and SCN2A. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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5 pages, 200 KiB

Open AccessHypothesis

Next Steps in Prader-Willi Syndrome Research: On the Relationship between Genotype and Phenotype

by Joyce Whittington and Anthony Holland

Int. J. Mol. Sci. 2022, 23(20), 12089; https://doi.org/10.3390/ijms232012089 - 11 Oct 2022

Viewed by 1623

Abstract

This article reviews what we know of the phenotype and genotype of Prader-Willi syndrome and hypothesizes two possible paths from phenotype to genotype. It then suggests research that may strengthen the case for one or other of these hypotheses. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

10 pages, 572 KiB

Open AccessCase Report

Connective Tissue Disorders and Fragile X Molecular Status in Females: A Case Series and Review

by Merlin G. Butler, Waheeda A. Hossain, Jacob Steinle, Harry Gao, Eleina Cox, Yuxin Niu, May Quach and Olivia J. Veatch

Int. J. Mol. Sci. 2022, 23(16), 9090; https://doi.org/10.3390/ijms23169090 - 13 Aug 2022

Viewed by 2174

Abstract

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and the second most common cause after Down syndrome. FXS is an X-linked disorder due to a full mutation of the CGG triplet repeat of the FMR1 gene which codes for a protein that is crucial in synaptogenesis and maintaining functions of extracellular matrix-related proteins, key for the development of normal neuronal and connective tissue including collagen. In addition to neuropsychiatric and behavioral problems, individuals with FXS show physical features suggestive of a connective tissue disorder including loose skin and joint laxity, flat feet, hernias and mitral valve prolapse. Disturbed collagen leads to hypermobility, hyperextensible skin and tissue fragility with musculoskeletal, cardiovascular, immune and other organ involvement as seen in hereditary disorders of connective tissue including Ehlers–Danlos syndrome. Recently, FMR1 premutation repeat expansion or carrier status has been reported in individuals with connective tissue disorder-related symptoms. We examined a cohort of females with features of a connective tissue disorder presenting for genetic services using next-generation sequencing (NGS) of a connective tissue disorder gene panel consisting of approximately 75 genes. In those females with normal NGS testing for connective tissue disorders, the FMR1 gene was then analyzed using CGG repeat expansion studies. Three of thirty-nine females were found to have gray zone or intermediate alleles at a 1:13 ratio which was significantly higher (p < 0.05) when compared with newborn females representing the general population at a 1:66 ratio. This association of connective tissue involvement in females with intermediate or gray zone alleles reported for the first time will require more studies on how the size variation may impact FMR1 gene function and protein directly or in relationship with other susceptibility genes involved in connective tissue disorders. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Merlin G. Butler's Retirement: Unlocking Genetic Mysteries)

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