Abstract
Asymptomatic female carriers of the FMR1 premutation at childbearing age have been mostly identified through prenatal genetic testing, which is routinely proposed in Israel. During the last few years, a premutation phenotype in males and females has been defined—FXAND, including neuropsychiatric disorder, learning difficulties, endocrine dysfunction, and premature ovarian failure. So when a family at risk is identified, should individuals be tested for premutation even if minors? In order to understand what professionals’ views are with regard to testing FMR1 premutation in minors, we performed a questionnaire testing both ethical attitudes and knowledge. Eighty-two percent of professionals would positively consider fragile X testing in minors, and an additional 15.4% would consider it in boys only. The specific phenotype of full mutation is recognized well by health professionals, while the premutation phenotype is not well known. There is a need to expand awareness on the fragile X premutation phenotype through better information. Testing of fragile X premutation status in minors should be considered, when at risk due to family history.
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References
Allen EG, Sullivan AK, Marcus M, Small C, Dominguez C, Epstein MP et al (2007) Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum Reprod 22(8):2142–2152
Bailey DB Jr, Skinner D, Davis AM, Whitmarsh I, Powell C (2008) Ethical, legal, and social concerns about expanded newborn screening: fragile X syndrome as a prototype for emerging issues. Pediatrics 121(3)
Bailey DB Jr, Hatton DD, Tassone F, Skinner M, Taylor AK (2001) Variability in FMRP and early development in males with fragile X syndrome. Am J Ment Retard 106(1):16–27
Bailey DB, Berry-Kravis E, Gane LW, Guarda S, Hagerman R, Powell CM et al (2017) Fragile X newborn screening: lessons learned from a multisite screening study. Pediatrics 139(Supplement 3):S216–S225
Berry-Kravis E, Abrams L, Coffey SM, Hall DA, Greco C, Gane LW et al (2007) Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord
Binedell J, Soldan JR, Scourfield J, Harper PS (1996) Huntington’s disease predictive testing: the case for an assessment approach to requests from adolescents. J Med Genet 33:912–918
Borry P, Fryns JP, Schotsmans P, Dierickx K (2005) Attitudes towards carrier testing in minors: a systematic review. Genet Couns 16:341–352
Botkin JR, Belmont JW, Berg JS, Berkman BE, Bombard Y, Holm IA, Levy HP, Ormond KE, Saal HM, Spinner NB, Wilfond BS, McInerney J (2015) Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet 97(1):6–21
Botta-Orfila T, Tartaglia GG, Michalon A (2016) Molecular pathophysiology of fragile X-associated tremor/ataxia syndrome and perspectives for drug development. Cerebellum 15:599–610
Bourgeois JA, Coffey SM, Rivera SM, Hessl D, Gane LW, Tassone F et al (2009) A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry 70:852–862
Chiang PW, Carpenter LE, Hagerman PJ (2001) The 5′-untranslated region of the FMR1 message facilitates translation by internal ribosome entry. J Biol Chem 276(41):37916–37921
Cozaru GC, Aschie M, Mitroi AF, Poinareanu I, Gorduza EV (2016) Ethical and genetic aspects regarding presymptomatic testing for neurodegenerative diseases. Rev Med Chir Soc Med Nat Iasi 120(1):15–22
D’Amanda CS, Peay HL, Wheeler AC, Turbitt E, Biesecker BB (2019) Fragile X syndrome clinical trials: exploring parental decision-making. J Intellect Disabil Res
Farzin F, Perry H, Hessl D, Loesch D, Cohen J, Bacalman S, Gane L, Tassone F, Hagerman P, Hagerman R (2006) Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X premutation. J Dev Behav Pediatr 27(2 Suppl):S137–S144
Gabis L, Raz R (2010) The knowledge base of Israeli pediatricians in the area of child development. Harefuah 149(1)
Gabis L V, Kesner Baruch Y, Jokel A, Raz R (2011) Psychiatric and autistic comorbidity in fragile X syndrome across ages. J Child Neurol. 2011/04/30
Gabis LV, Hochberg O, Leon Attia O, Banet-Levi Y, Topf D, Shefer S (2017) Prolonged time lag to final diagnosis of fragile X syndrome. J Pediatr
Godard B, ten Kate L, Evers-Kiebooms G, Aymé S (2003) Population genetic screening programmes: principles, techniques, practices, and policies. Eur J Hum Genet 11
Hagerman RJ, Protic D, Rajaratnam A, Salcedo-Arellano MJ, Aydin EY, Schneider A (2018) Fragile X-associated neuropsychiatric disorders (FXAND). Front Psychiatry 9
Hamlin AA, Sukharev D, Campos L, Mu Y, Tassone F, Hessl D et al (2012) Hypertension in FMR1 premutation males with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Am J Med Genet A 158A(6):1304–1309
Hantash FM, Goos DM, Crossley B, Anderson B, Zhang K, Sun W, Strom CM (2011) FMR1 premutation carrier frequency in patients undergoing routine population-based carrier screening: insights into the prevalence of fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency i. Genet Med 13(1):39–45
Jorde LB, Carey JC, Bamshad MJ (2015) Medical genetics. Elsevier. (Student consult)
Kraan CM, Hocking DR, Georgiou-Karistianis N, Metcalfe SA, Archibald AD, Fielding J et al (2014) Impaired response inhibition is associated with self-reported symptoms of depression, anxiety, and ADHD in female FMR1 premutation carriers. Am J Med Genet Part B Neuropsychiatr Genet 165(1):41–51
Kromberg JG, Wessels TM (2013) Ethical issues and Huntington’s disease. South African Med J 103(SUPPL. 1):1023–1026
Lidia G, Annick R. Online survey on the atitiudes towards genetic testing of Fragile X in minors [Internet]. surveymonkey. 2018 [cited 2018 Feb 6]. Available from: https://www.surveymonkey.com/r/Q2QMQD6
Loesch DZ, Huggins RM, Hagerman RJ (2004) Phenotypic variation and FMRP levels in fragile X. Ment Retard Dev Disabil Res Rev 10(1):31–41
Metcalfe SA, Delatycki MB, Cohen J, Archibald AD, Emery JD (2018) Fragile X population carrier screening. Genetics in Medicine 20:1091–1092
Quarrell OW, Clarke AJ, Compton C, de Die-Smulders CEM, Fryer A, Jenkins S et al (2018) Predictive testing of minors for Huntington’s disease: the UK and Netherlands experiences. Am J Med Genet Part B Neuropsychiatr Genet 177(1):35–39
Ross LF, Acharya K (2008) Policy considerations in designing a fragile X population screening program. Genetics in Medicine 10:711–713
Rousseau F, Rouillard P, Morel ML, Khandjian EW, Morgan K (1995) Prevalence of carriers of premutation-size alleles of the FMRI gene--and implications for the population genetics of the fragile X syndrome. Am J Hum Genet 57(5):1006–1018
Skinner D, Choudhury S, Sideris J, Guarda S, Buansi A, Roche M et al (2011) Parents decisions to screen newborns for FMR1 gene expansions in a pilot research project. Obstet Gynecol Surv 66:616–617
SurveyMonkey Inc. www.surveymonkey.com [Internet]. San Mateo, California, USA. 2018. Available from: https://www.surveymonkey.com/welcome/sem/?&opt=brand&iv_=__iv_p_1_a_173788055_g_8916172415_c_207770216800_k_servermonkey_m_b_w_kwd-6161441176_n_g_d_c_v__l__t__r_1t1_x__y__f__o__z__i__j__s__e__h_2376_ii__vi__&utm_source=adwords&utm_medium=ppc&utm_term=serv
Toledano-Alhadef H, Basel-Vanagaite L, Magal N, Davidov B, Ehrlich S, Drasinover V, Taub E, Halpern GJ, Ginott N, Shohat M (2001) Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel. Am J Hum Genet 69(2):351–360
Verkerk AJMH, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DPA, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 65(5):905–914
Welt CK, Smith PC, Taylor AE (2004) Evidence of early ovarian aging in fragile X premutation carriers. J Clin Endocrinol Metab 89(9):4569–4574
Wheeler AC, Bailey DB, Berry-Kravis E, Greenberg J, Losh M, Mailick M et al (2014) Associated features in females with an FMR1 premutation. J Neurodev Disord 6
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We are grateful to Leora Allen for editing at the time of manuscript submission. We are also grateful to Mrs. Meirav Shaham for the statistical contribution.
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The study and the questionnaire was approved by Helsinki committee 5018–18-SMC and was conducted in accordance with the provisions of the Declaration of Helsinki and GCP and adhered to ICMJE guidelines with regard to study registration.
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Gabis, L.V., Shefer, S. & Raas-Rothschild, A. Ethical Dilemmas Linked to Fragile X Testing of Minors—a Preliminary Survey Among Professionals. J Mol Neurosci 70, 254–259 (2020). https://doi.org/10.1007/s12031-019-01445-2
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DOI: https://doi.org/10.1007/s12031-019-01445-2