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

References

• Coffee B, Keith K, Albizua I, et al. Incidence of Fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet. 2009;85(4):503–514. doi:10.1016/j.ajhg.2009.09.007
   PubMed Web of Science ®Google Scholar
• Saldarriaga W, Tassone F, González-Teshima LY, Forero-Forero JV, Ayala-Zapata S. Fragile X Syndrome. Colomb Med. 2014;190–198. doi:10.25100/cm.v45i4.1810
   Web of Science ®Google Scholar
• Bagni C, Tassone F, Neri G, Fragile HR. X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest. 2012;122(12):4314–4322. doi:10.1172/JCI63141
   PubMed Web of Science ®Google Scholar
• Salcedo-Arellano MJ, Dufour B, McLennan Y, Martinez-Cerdeno V, Hagerman R. Fragile X syndrome and associated disorders: clinical aspects and pathology. Neurobiol Dis. 2020;136:104740. doi:10.1016/j.nbd.2020.104740
   PubMed Web of Science ®Google Scholar
• Sitzmann AF, Hagelstrom RT, Tassone F, Hagerman RJ, Butler MG. Rare FMR1 gene mutations causing fragile X syndrome: a review. Am J Med Genet Part A. 2018;176(1):11–18. doi:10.1002/ajmg.a.38504
   Web of Science ®Google Scholar
• Coffee B, Ikeda M, Budimirovic DB, Hjelm LN, Kaufmann WE, Warren ST. Mosaic FMR1 deletion causes fragile X syndrome and can lead to molecular misdiagnosis: a case report and review of the literature. Am J Med Genet Part A. 2008;146A(10):1358–1367. doi:10.1002/ajmg.a.32261
   PubMed Web of Science ®Google Scholar
• Tassanakijpanich N, Hagerman RJ, Worachotekamjorn J. Fragile X premutation and associated health conditions: a review. Clin Genet. 2021;99(6):751–760. doi:10.1111/cge.13924
   Web of Science ®Google Scholar
• Hagerman RJ, Berry-Kravis E, Hazlett HC, et al. Fragile X syndrome. Nat Rev Dis Prim. 2017. doi:10.1038/nrdp.2017.65
   Web of Science ®Google Scholar
• Taha MS, Haghighi F, Stefanski A, et al. Novel FMRP interaction networks linked to cellular stress. FEBS J. 2021;288(3):837–860. doi:10.1111/febs.15443
   Web of Science ®Google Scholar
• Siomi H, Siomi MC, Nussbaum RL, Dreyfuss G. The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell. 1993;74(2):291–298. doi:10.1016/0092-8674(93)90420-U
   PubMed Web of Science ®Google Scholar
• Ashley CT Jr, Wilkinson KD, Reines D, Warren ST. FMR1 protein contains conserved RNP-family domains and demonstrates selective RNA binding. Science (80-). 1993;262(5133):563–566. doi:10.1126/science.7692601
   PubMed Web of Science ®Google Scholar
• Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27(7):370–377. doi:10.1016/j.tins.2004.04.009
   PubMed Web of Science ®Google Scholar
• Gatto CL, Broadie K. Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models. Front Synaptic Neurosci. 2010. doi:10.3389/fnsyn.2010.00004
   Google Scholar
• Budimirovic DB, Haas-Givler B, Blitz R, et al. Consensus of the fragile X clinical and research consortium on clinical practices: autism Spectrum Disorder in Fragile X Syndrome. 2014;1–15.
   Google Scholar
• Budimirovic DB, Subramanian M. Neurobiology of Autism and Intellectual Disability: fragile X Syndrome. 2 ed. In: Johnston M, Adams H, Fatemi A, editors. London: Oxford University Press;2016.doi:10.1093/med/9780199937837.001.0001
   Google Scholar
• Saldarriaga W, Payán-Gómez C, González-Teshima LY, Rosa L, Tassone F, Hagerman RJ. Double genetic hit: fragile X syndrome and partial deletion of protein patched homolog 1 antisense as cause of severe autism spectrum disorder. J Dev Behav Pediatr. 2020;41(9):724–728. doi:10.1097/DBP.0000000000000850
   Web of Science ®Google Scholar
• Sherman SL, Kidd SA, Riley C, et al. Forward: a registry and longitudinal clinical database to study fragile X syndrome. Pediatrics. 2017;139(Supplement 3):S183–S193. doi:10.1542/peds.2016-1159E
   Web of Science ®Google Scholar
• Loehr JP, Synhorst DP, Wolfe RR, Hagerman RJ. Aortic root dilatation and mitral valve prolapse in the fragile X syndrome. Am J Med Genet. 1986;23(1–2):189–194. doi:10.1002/ajmg.1320230113
   Web of Science ®Google Scholar
• Rahit KMTH, Tarailo-Graovac M. Genetic modifiers and rare mendelian disease. Genes (Basel). 2020;11(3):239. doi:10.3390/genes11030239
   Web of Science ®Google Scholar
• Li D, Yu J, Gu F, et al. The roles of two novel FBN1 gene mutations in the genotype–phenotype correlations of marfan syndrome and ectopia lentis patients with marfanoid habitus. Genet Test. 2008;12(2):325–330. doi:10.1089/gte.2008.0002
   PubMedGoogle Scholar
• Fahed AC, Wang M, Homburger JR, et al. Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions. Nat Commun. 2020;11(1). doi:10.1038/s41467-020-17374-3
   Web of Science ®Google Scholar
• Kim M, Costello J. DNA methylation: an epigenetic mark of cellular memory. Exp Mol Med. 2017;49(4):e322–e322. doi:10.1038/emm.2017.10
   PubMed Web of Science ®Google Scholar
• Kraan CM, Baker EK, Arpone M, et al. Dna methylation at birth predicts intellectual functioning and autism features in children with fragile x syndrome. Int J Mol Sci. 2020;21(20):7735. doi:10.3390/ijms21207735
   Web of Science ®Google Scholar
• Pieretti M, Zhang F, Fu YH, et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell. 1991;66(4):817–822. doi:10.1016/0092-8674(91)90125-I
   PubMed Web of Science ®Google Scholar
• Nolin SL, Glicksman A, Houck GE, Brown WT, Dobkin CS. Mosaicism in fragile X affected males. Am J Med Genet. 1994;51(4):509–512. doi:10.1002/ajmg.1320510444
   PubMed Web of Science ®Google Scholar
• Stöger R, Genereux DP, Hagerman RJ, Hagerman PJ, Tassone F, Laird CD. Testing the FMR1 promoter for mosaicism in dna methylation among cpg sites, strands, and cells in FMR1-expressing males with fragile x syndrome. PLoS One. 2011;6(8):e23648. doi:10.1371/journal.pone.0023648
   Web of Science ®Google Scholar
• Pretto DI, Mendoza-Morales G, Lo J, et al. CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles. J Med Genet. 2014;51(5):309–318. doi:10.1136/jmedgenet-2013-102021
   PubMed Web of Science ®Google Scholar
• Jiraanont P, Kumar M, Tang H-T, et al. Size and methylation mosaicism in males with Fragile X syndrome. Expert Rev Mol Diagn. 2017;17(11):1023–1032. doi:10.1080/14737159.2017.1377612
   PubMed Web of Science ®Google Scholar
• Budimirovic DB, Schlageter A, Filipovic-Sadic S, et al. A genotype-phenotype study of high-resolution FMR1 nucleic acid and protein analyses in fragile X patients with neurobehavioral assessments. Brain Sci. 2020;10(10):694. doi:10.3390/brainsci10100694
   PubMed Web of Science ®Google Scholar
• Tassone F, Hagerman RJ, Loesch DZ, Lachiewicz A, Taylor AK, Hagerman PJ. Fragile X males with unmethylated, full mutation trinucleotide repeat expansions have elevated levels of FMR1 messenger RNA. Am J Med Genet. 2000;94(3):232–236. doi:10.1002/1096-8628(20000918)94:3<232::aid-ajmg9>3.0.CO;2-H
   PubMed Web of Science ®Google Scholar
• Dolskiy AA, Yarushkin AA, Grishchenko IV, et al. miRNA expression and interaction with the 3′UTR of FMR1 in FRAXopathy pathogenesis. Non-Coding RNA Res. 2021;6(1):1–7. doi:10.1016/j.ncrna.2020.11.006
   Web of Science ®Google Scholar
• Primerano B, Tassone F, Hagerman RJ, Hagerman P, Amaldi F, Bagni C. Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations. RNA. 2002;8(12):1482–1488. doi:10.1017/S1355838202020642
   PubMed Web of Science ®Google Scholar
• Kaufmann WE, Abrams MT, Chen W, Reiss AL. Genotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome. Am J Med Genet. 1999. doi:10.1002/(SICI)1096-8628(19990402)83:4<286::aid-ajmg10>3.0.CO;2-H
   Web of Science ®Google Scholar
• Loesch DZ, Bui QM, Dissanayake C, et al. Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X. Neurosci Biobehav Rev. 2007. doi:10.1016/j.neubiorev.2006.09.007
   Web of Science ®Google Scholar
• Backes M, Genç B, Schreck J, Doerfler W, Lehmkuhl G, Von Gontard A. Cognitive and behavioral profile of fragile X boys: correlations to molecular data. Am J Med Genet. 2000;95(2):150–156. doi:10.1002/1096-8628(20001113)95:2<50::aid-ajmg11><50::aid-ajmg11>3.0.CO;2-1
   PubMed Web of Science ®Google Scholar
• Tassone F, Hagerman RJ, Iklé DN, et al. FMRP expression as a potential prognostic indicator in fragile X syndrome. Am J Med Genet. 1999;84(3):250–261. doi:10.1002/(SICI)1096-8628(19990528)84:3<250::aid-ajmg17>3.0.CO;2-4
   PubMed Web of Science ®Google Scholar
• Hall S, DeBernardis M, Reiss A. Social escape behaviors in children with fragile X syndrome. J Autism Dev Disord. 2006;36(7):935–947. doi:10.1007/s10803-006-0132-z
   PubMed Web of Science ®Google Scholar
• Bagni C, Zukin RS, Synaptic A. Perspective of Fragile X syndrome and autism spectrum disorders. Neuron. 2019. doi:10.1016/j.neuron.2019.02.041
   Web of Science ®Google Scholar
• Kim K, Hessl D, Randol JL, et al. Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions. PLoS One. 2019;14(12):e0226811. doi:10.1371/journal.pone.0226811
   PubMed Web of Science ®Google Scholar
• Aliaga SM, Slater HR, Francis D, et al. Identification of males with cryptic fragile x alleles by methylation-Specific quantitative melt analysis. Clin Chem. 2016;62(2):343–352. doi:10.1373/clinchem.2015.244681
   Web of Science ®Google Scholar
• Baker EK, Arpone M, Aliaga SM, et al. Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features. Mol Autism. 2019;10(1). doi:10.1186/s13229-019-0271-7
   Web of Science ®Google Scholar
• Baker EK, Arpone M, Vera SA, et al. Intellectual functioning and behavioural features associated with mosaicism in fragile X syndrome. J Neurodev Disord. 2019;11(1). doi:10.1186/s11689-019-9288-7
   Web of Science ®Google Scholar
• Kraan CM, Godler DE, Amor DJ. Epigenetics of fragile X syndrome and fragile X-related disorders. Dev Med Child Neurol. 2019;61(2):121–127. doi:10.1111/dmcn.13985
   PubMed Web of Science ®Google Scholar
• Rousseau F, Heitz D, Biancalana V, et al. Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. Obstet Gynecol Surv. 1992;47(5):306–308. doi:10.1097/00006254-199205000-00008
   Google Scholar
• Loesch DZ, Sherwell S, Kinsella G, et al. Fragile X-associated tremor/ataxia phenotype in a male carrier of unmethylated full mutation in the FMR1 gene. Clin Genet. 2012;82(1):88–92. doi:10.1111/j.1399-0004.2011.01675.x
   Web of Science ®Google Scholar
• Santa María L, Pugin A, Alliende MA, et al. FXTAS in an unmethylated mosaic male with fragile X syndrome from Chile. Clin Genet. 2014;86(4):378–382. doi:10.1111/cge.12278
   Web of Science ®Google Scholar
• Baker EK, Arpone M, Kraan C, et al. FMR1 mRNA from full mutation alleles is associated with ABC-CFX scores in males with fragile X syndrome. Sci Rep. 2020;10(1). doi:10.1038/s41598-020-68465-6
   Web of Science ®Google Scholar
• Schneider A, Winarni TI, Cabal-Herrera AM, et al. Elevated FMR1-mRNA and lowered FMRP – a double-hit mechanism for psychiatric features in men with FMR1 premutations. Transl Psychiatry. 2020;10(1). doi:10.1038/s41398-020-00863-w
   Web of Science ®Google Scholar
• Dipple KM, McCabe ERB. Phenotypes of patients with “Simple” mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet. 2000;66(6):1729–1735. doi:10.1086/302938
   Web of Science ®Google Scholar
• Schäffer AA. Digenic inheritance in medical genetics. J Med Genet. 2013;50(10):641–652. doi:10.1136/jmedgenet-2013-101713
   Web of Science ®Google Scholar
• Mineur YS, Sluyter F, De Wit S, Oostra BA, Crusio WE. Behavioral and neuroanatomical characterization of the Fmr1 knockout mouse. Hippocampus. 2002;12(1):39–46. doi:10.1002/hipo.10005
   Web of Science ®Google Scholar
• Bakker CE, Verheij C; The Dutch-Belgian Fragile X Consorthium, et al. Fmr1 knockout mice: a model to study fragile X mental retardation. Cell. 1994. doi:10.1016/0092-8674(94)90569-X
   Web of Science ®Google Scholar
• Errijgers V, Kooy RF. Genetic modifiers in mice: the example of the fragile X mouse model. Cytogenet Genome Res. 2004;105(2–4):448–454. doi:10.1159/000078218
   Web of Science ®Google Scholar
• Crawford H, Scerif G, Wilde L, et al. Genetic modifiers in rare disorders: the case of fragile X syndrome. Eur J Hum Genet. 2021;29(1):173–183. doi:10.1038/s41431-020-00711-x
   Web of Science ®Google Scholar
• Hessl D, Tassone F, Cordeiro L, et al. Brief report: aggression and stereotypic behavior in males with fragile X syndrome - Moderating secondary genes in a “single gene” disorder. J Autism Dev Disord. 2008;38(1):184–189. doi:10.1007/s10803-007-0365-5
   PubMed Web of Science ®Google Scholar
• Louhivuori V, Arvio M, Soronen P, Oksanen V, Paunio T, Castrén ML. The Val66Met polymorphism in the BDNF gene is associated with epilepsy in fragile X syndrome. Epilepsy Res. 2009;85(1):114–117. doi:10.1016/j.eplepsyres.2009.01.005
   PubMed Web of Science ®Google Scholar
• Stepniak B, Kästner A, Poggi G, et al. Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes. EMBO Mol Med. 2015;7(12):1565–1579. doi:10.15252/emmm.201505696
   Web of Science ®Google Scholar
• Tondo M, Poo P, Naudó M, et al. Predisposition to epilepsy in fragile X syndrome: does the Val66Met polymorphism in the BDNF gene play a role? Epilepsy Behav. 2011;22(3):581–583. doi:10.1016/j.yebeh.2011.08.003
   Web of Science ®Google Scholar
• Wassink TH, Hazlett HC, Davis LK, Reiss AL, Piven J. Testing for association of the monoamine oxidase a promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome. J Neurodev Disord. 2014;6(1). doi:10.1186/1866-1955-6-6
   Web of Science ®Google Scholar
• Chen ZY, Patel PD, Sant G, et al. Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci. 2004;24(18):4401–4411. doi:10.1523/JNEUROSCI.0348-04.2004
   PubMed Web of Science ®Google Scholar
• Szeszko PR, Lipsky R, Mentschel C, et al. Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry. 2005;10(7):631–636. doi:10.1038/sj.mp.4001656
   PubMed Web of Science ®Google Scholar
• Chen ZY, Jing D, Bath KG, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science (80-). 2006;314(5796):140–143. doi:10.1126/science.1129663
   PubMed Web of Science ®Google Scholar
• Gratacòs M, González JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry. 2007;61(7):911–922. doi:10.1016/j.biopsych.2006.08.025
   Web of Science ®Google Scholar
• AlOlaby RR, Sweha SR, Silva M, et al. Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome. Brain Dev. 2017;39(6):483–492. doi:10.1016/j.braindev.2017.01.012
   Web of Science ®Google Scholar
• Duy PQ, Budimirovic DB. Fragile X syndrome: lessons learned from the most translated neurodevelopmental disorder in clinical trials. Transl Neurosci. 2017;8(1). doi:10.1515/tnsci-2017-0002
   Web of Science ®Google Scholar