Autosomal & Allosomes (Sex Chr) PDF

Module E: Genitourinary tract, fertility Autosomal aberrations: Down syndrome, translocation Down syndrome, Patau syndrome, Edward`s syndrome, cat`s cry syndrome, Allosomal (sex chromosomes) aberrations: fragile X...

Module E: Genitourinary tract, fertility Autosomal aberrations: Down syndrome, translocation Down syndrome, Patau syndrome, Edward`s syndrome, cat`s cry syndrome, Allosomal (sex chromosomes) aberrations: fragile X syndrome - sex chromosome) Karol P. Ruszel, 27-28/03/23 Down syndrome Bunt CW, Bunt SK. Role of the family physician in the care of children with Down syndrome. Am Fam Physician. 2014 Dec 15;90(12):851-8. PMID: 25591185. Papavassiliou P, Charalsawadi C, Rafferty K, Jackson-Cook C. Mosaicism for trisomy 21: a review. Am J Med Genet A. 2015 Jan;167A(1):26-39. doi: 10.1002/ajmg.a.36861. Epub 2014 Nov 20. PMID: 25412855. Mazurek D, Wyka J. Down syndrome--genetic and nutritional aspects of accompanying disorders. Rocz Panstw Zakl Hig. 2015;66(3):189-94. PMID: 26400113. Whooten R, Schmitt J, Schwartz A. Endocrine manifestations of Down syndrome. Curr Opin Endocrinol Diabetes Obes. 2018 Feb;25(1):61-66. doi: 10.1097/MED.0000000000000382. PMID: 29135488; PMCID: PMC6382276. Flores-Ramírez F, Palacios-Guerrero C, García-Delgado C, Morales-Jiménez AB, Arias-Villegas CM, Cervantes A, Morán-Barroso VF. Cytogenetic profile in 1,921 cases of trisomy 21 syndrome. Arch Med Res. 2015 Aug;46(6):484-9. doi: 10.1016/j.arcmed.2015.08.001. Epub 2015 Aug 24. PMID: 26314225. Down syndrome Chen CP, Wang YL, Chern SR, Wu PS, Chen YN, Chen SW, Chen LF, Lee MS, Yang CW, Wang W. Prenatal diagnosis and molecular cytogenetic characterization of low-level true mosaicism for trisomy 21 using uncultured amniocytes. Taiwan J Obstet Gynecol. 2016 Apr;55(2):285-7. doi: 10.1016/j.tjog.2016.02.014. PMID: 27125416. Hultén MA, Jonasson J, Iwarsson E, Uppal P, Vorsanova SG, Yurov YB, Iourov IY. Trisomy 21 mosaicism: we may all have a touch of Down syndrome. Cytogenet Genome Res. 2013;139(3):189-92. doi: 10.1159/000346028. Epub 2013 Jan 10. PMID: 23306383. Translocational Translocational down syndrome Victorino DB, Godoy MF, Goloni-Bertollo EM, Pavarino EC. Meta-analysis of Methylenetetrahydrofolate reductase maternal gene in Down syndrome: increased susceptibility in women carriers of the MTHFR Down syndrome 677T allele. Mol Biol Rep. 2014 Aug;41(8):5491-504. doi: 10.1007/s11033-014-3424-y. Epub 2014 Jun 10. PMID: 24913031. Polipalli SK, Karra VK, Jindal A, Puppala M, Singh P, Rawat K, Kapoor S. Cytogenetic Analysis for Suspected Chromosomal Abnormalities; A Five Years Experience. J Clin Diagn Res. 2016 Sep;10(9):GC01-GC05. doi: 10.7860/JCDR/2016/19926.8494. Epub 2016 Sep 1. PMID: 27790464; PMCID: PMC5071964. Bornstein E, Lenchner E, Donnenfeld A, Jodicke C, Keeler SM, Kapp S, Divon MY. Complete trisomy 21 vs translocation Down syndrome: a comparison of modes of ascertainment. Am J Obstet Gynecol. 2010 Oct;203(4):391.e1-5. doi: 10.1016/j.ajog.2010.06.019. Epub 2010 Aug 5. PMID: 20691415. Hartway S. A parent's guide to the genetics of Down syndrome. Adv Neonatal Care. 2009 Feb;9(1):27-30. doi: 10.1097/01.ANC.0000346092.50981.c0. PMID: 19212162. Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Down syndrome, +21 Common Physical Characteristics in Feet Newborns with Down Syndrome Widened gap between first and second Head/neck toes (sandal gap) Arched palate Global Brachycephaly (flattened head, Hyperflexibility usually posterior aspect) ❑ Muscular hypotonia Brushfield spots (hypopigmented Mental iris spot) intellectual disability in Down syndrome Ear abnormalities (low-set/folded) mild (IQ of 50 to 69), moderate (IQ of 35 ❑ Epicanthal folds to 49), and occasionally severe (IQ of 20 ❖ Excessive skin on nape of neck to 34) Flat facial profile prevalence of 10.3 per 10,000 Macroglossia Short neck and microcephaly 1 in every 787 liveborn babies Small nose 1:600-700 newborns ❑ Upward slant to the eyes Hands metabolic disorders, tissue dimorphism, Clinodactyly (curved fifth finger) Short, internal organ abnormalities, intellectual broad hands disabilities and characteristic phenotype Short fifth finger features Karol P. Ruszel, PhD Chair of Medical Genetics Single palmar crease [email protected] Department of Clinical Genetics  Down syndrome Karyotypes for girls are 47, XX, +21 Translocation involves transferring a and 47, XY, +21 for boys. Simple chromosome fragment to another. In DS such Trisomy constitutes the most translocation occurs between chromosomes 14 common form of DS in children and 21, 21 and 22 and 22 and 21 (5-6% of all (90-95%). DS cases). The karyotypes for girls are 46, XX, der (21;21), Mosaic Trisomy occurs when the +21 extra chromosome 21 is present in or 46, XX, der (14;21), +21 some, but not all cells, of the boys 46, XY, der (21;21), +21 or 46, XY, der individual. (14;21), +21. Mosaic Trisomy Single cell type In patients with Down syndrome, Organism composed of normal and trisomic approximately 90% to 95% of cells individuals have free trisomy for Tissue Mosaic Trisomy Some tissues affected by the chromosome 21 chromosome 21, 2% to 4% of trisomy individuals have unbalanced Chimerism Robertsonian translocations Two organisms are fused together into a whole involving chromosome 21, and 2% early in development, giving rise to a single to 4% of individuals have organism (one of them has trisomy) mosaicism Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Translocation Down syndrome CURIOSITIES Infertility should not be assumed. Both men and women with DS have fathered/mothered children Low-level true mosaicism for trisomy 21 can be associated with a 21 14 -21 -14 +14 favorable fetal outcome- no phenotype of syndrome Translocational rob (14q21q) Down syndrome Robertsonian translocation chromosome Robertsonian translocations are among comprises the long arm elements of two the most common balanced structural different acrocentric chromosomes rearrangements, with a frequency in newborn surveys of about 1 in 1,000 Translocation Down syndrome is due to centric fusion between the long rob(13q14q) and the rob(14q21q) arm of chromosome 21 and one are predominant 46,XY,rob(13;14) (q10;q10) chromosome of the group 13–15 or 21– 46,XX,rob(13;14)(q10;q10) 22 (D or G group) 45,XX,rob(13;14) (q12.1;q11.2) Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Down syndrome Other types of mutations: Whole region duplication region der(21;21) duplication Treatment and life planning for persons and caregivers: Many options accordingly to needs, due to relatively long lifespan of people with Down syndrome. Detailed discussion on this topic vastly exceeds the volume of this class Further reading is recommended Bunt CW, Bunt SK. Role of the family physician in the care of children with Down syndrome. Am Fam Physician. 2014 Dec 15;90(12):851-8. PMID: 25591185 Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics Patau syndrome Babay LÉ, Horányi D, Győrffy B, Nagy GR. Evidence for the Oocyte Mosaicism Selection model on the origin of Patau syndrome (trisomy 13). Acta Obstet Gynecol Scand. 2019 Dec;98(12):1558-1564. doi: 10.1111/ aogs.13694. Epub 2019 Aug 29. PMID: 31464342. Abuzenadah A, Al-Saedi S, Karim S, Al-Qahtani M. Role of Overexpressed Transcription Factor FOXO1 in Fatal Cardiovascular Septal Defects in Patau Syndrome: Molecular and Therapeutic Strategies. Int J Mol Sci. 2018 Nov 10;19(11):3547. doi: 10.3390/ijms19113547. PMID: 30423812; PMCID: PMC6274780. Nanjiani A, Hossain A, Mahgoub N. Patau syndrome. J Neuropsychiatry Clin Neurosci. 2007 Patau Spring;19(2):201-2. doi: 10.1176/jnp.2007.19.2.201. PMID: 17431076. Williams GM, Brady R. Patau Syndrome. [Updated 2020 Jun 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538347/ and Satgé D, Nishi M, Sirvent N, Vekemans M, Chenard MP, Barnes A. A tumor profile in Patau syndrome (trisomy 13). Am J Med Genet A. 2017 Aug;173(8):2088-2096. doi: 10.1002/ajmg.a.38294. Epub 2017 May 25. PMID: 28544599. Edwards syndromes Edward`s syndrome Mudaliyar US, Mudaliyar SU. Strawberry skull in Edwards syndrome. BJR Case Rep. 2017 Jun 10;3(4):20170045. doi: 10.1259/bjrcr.20170045. PMID: 30363185; PMCID: PMC6159170. Rosa RF, Rosa RC, Zen PR, Graziadio C, Paskulin GA. Trisomy 18: review of the clinical, etiologic, prognostic, and ethical aspects. Rev Paul Pediatr. 2013 Jan-Mar;31(1):111-20. English, Portuguese. doi: 10.1590/ s0103-05822013000100018. PMID: 23703053. Cereda A, Carey JC. The trisomy 18 syndrome. Orphanet J Rare Dis. 2012 Oct 23;7:81. doi: 10.1186/1750-1172-7-81. PMID: 23088440; PMCID: PMC3520824. Satgé D, Nishi M, Sirvent N, Vekemans M. A tumor profile in Edwards syndrome (trisomy 18). Am J Med Genet C Semin Med Genet. 2016 Sep;172(3):296-306. doi: 10.1002/ajmg.c.31511. Epub 2016 Jul 30. PMID: 27474103. Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Patau syndrome +13 Severe numerous anomalies!!! The least common congenital anomalies including central nervous The severest of all autosomal system (CNS) defects, midline abnormalities, trisomies eye and ear anomalies, cardiac defects, apnea, Prevalence rate of 1:5000 to orofacial flaws, gastrointestinal and 1:20,000 genitourinary aberrations, limb deformations, 1.4, 1.9 to 2.8/10000 births and developmental retardation Presence of an extra copy of dysmorphic features, polydactyly of hands and/or feet, cryptorchidism, abnormal chromosome 13 auricles/low-set ears, microphthalmia, Other changes in chromosome 13, neurological disorders/microcephaly, such as translocation, can also result micrognathia, scalp defects, oral clefts, in the characteristics classified as Patau microphthalmia/anophthalmia, duplication of syndrome. the hallux Multiple congenital abnormalities associated Life expectancy is severely with poor prognosis. Along with CNS disorders, limited; more than 80% of PS patients heart ailments, especially septal defects are do not survive long, and according to leading cause of deaths some estimates have median survival of 2.5 days The cumulative 5-year survival is about 7% There is no specific treatment recommended for PS. Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Edwards syndrome +18 4.8 to 7 per 10,000 births / liveborns as 1 in 6,000 / 2.63 per 10,000 births POOR PREGNANCY OUTCOME most live born infants die within the first few days or weeks of life. The median survival of live born cases of T13/T18 is reported as 10–14 days with 1-year survival around 8– 10%. There is limited comparative population prevalence and survival data for T13/T18 on an international basis. Almost half of the mortality in LB occurred within the first week and 87–88% by the first year in both T13 and T18 Most recent studies report a median survival of 3-14.5 days, a percentage of survival at 24 hours of 60%-75%, at 1 week of 40%-60%, at 1 month of 22%-44%, at 6 months of 9%-18%, and after 1 year of 5%-10% The cumulative 5-year survival was 7.7% Many cases are detected during antenatal screening for down syndrome and through free fetal DNA tests. The screening by assessment of nuchal fold and nasal bone identifies 66.7% of cases with trisomy 18 (and 13). By including the evaluation of reversed flow in the ductus venosus and the tricuspid valve regurgitation, the detection rate increases to 83.3% Growing evidence has shown that medical and Horseshoe kidney is common finding surgical interventions can prolong survival in trisomy 18 Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Edwards syndrome +18 PRENATAL growth deficiency, characteristic craniofacial features, distinctive hand posture (overriding fingers), nail hypoplasia, short hallux, short sternum, and major malformations (particularly involving the heart). The prenatal sonographic pattern of trisomy 18: Growth retardation, polyhydramnios, “strawberry-shaped” cranium (brachycephaly and narrow frontal cranium), choroid plexus cyst, overlapping of hands fingers (second and fifth on third and fourth respectively), congenital heart defects, omphalocele, and single umbilical artery MARKERS IN MOTHER’S BLOOD The levels of human chorionic gonadotropin, unconjugated estriol, and alpha-fetoprotein are significantly lower in pregnancies with trisomy 18 compared to normal pregnancy CYTOGENETICS The demonstration of an extra chromosome 18, or less commonly a partial trisomy of the long arm of chromosome 18. In the partial trisomy form only a segment of the chromosome 18 long arm is present in triplicate, often resulting from a balanced translocation or inversion carried by one parent. This type of trisomy accounts for approximately 2% of cases presenting with the Edwards phenotype. Standard G-banded karyotype allows for confirmation of the clinical diagnosis. A small portion of patients (less than 5% in population) have mosaicism of trisomy 18; they show an extremely variable phenotype. Karol P. Ruszel, PhD [email protected] Chair of Medical Genetics Department of Clinical Genetics  Cat’s cry syndrome (CdCS) Cri du chat Cri du chat syndrome Vado Y, Errea-Dorronsoro J, Llano-Rivas I, Gorria N, Pereda A, Gener B, Garcia-Naveda L, Perez de Nanclares G. Cri-du-chat syndrome mimics Silver-Russell syndrome depending on the size of the deletion: a case report. BMC Med Genomics. 2018 Dec 27;11(1):124. doi: 10.1186/s12920-018-0441-z. PMID: 30587166; PMCID: PMC6307281. Zhang B, Willing M, Grange DK, Shinawi M, Manwaring L, Vineyard M, Kulkarni S, Cottrell CE. Multigenerational autosomal dominant inheritance of 5p chromosomal deletions. Am J Med Genet A. 2016 Mar;170(3):583-93. doi: 10.1002/ajmg.a.37445. Epub 2015 Nov 24. PMID: 26601658. Espirito Santo LD, Moreira LM, Riegel M. Cri-Du-Chat Syndrome: Clinical Profile and Chromosomal Microarray Analysis in Six Patients. Biomed Res Int. 2016;2016:5467083. doi: 10.1155/2016/5467083. Epub 2016 Apr 7. PMID: 27144168; PMCID: PMC4838791. Rodríguez-Caballero A, Torres-Lagares D, Rodríguez-Pérez A, Serrera-Figallo MA, Hernández-Guisado JM, Machuca-Portillo G. Cri du chat syndrome: a critical review. Med Oral Patol Oral Cir Bucal. 2010 May 1;15(3):e473-8. doi: 10.4317/medoral.15.e473. PMID: 20038906. Nandhagopal R, Udayakumar AM. Cri-du-chat syndrome. Indian J Med Res. 2014 Oct;140(4):570-1. PMID: 25488457; PMCID: PMC4277150. Cerruti Mainardi P. Cri du Chat syndrome. Orphanet J Rare Dis. 2006 Sep 5;1:33. doi: 10.1186/1750-1172-1-33. PMID: 16953888; PMCID: PMC1574300. Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Cri du chat de novo deletion (around 80%) cri du chat syndrome (CdCS) a little more than 10%- parental resulting from a partial or total deletion on translocation the short arm of chromosome 5 (5p-). The size of the less than 10% -cytogenetic rare deletion could affect from region 5p15.3 to the aberrations complete loss of the short arm. ❑ specific chromosomal region is involved in CdCS Various chromosomal aberrations (5p 15.1-5p 15.3) 77.5% of the patients showed a terminal ❑ main clinical feature of the syndrome, a deletion high-pitched monochromatic cat-like crying, that 8.75% an interstitial deletion usually disappears in the first years of life. 5% a de novo translocation CdCS is one of the most common chromosomal 3.75% a familiar translocation deletion syndromes in humans, with an 3.75% a mosaic with two cellular lines incidence of 1:15.000-1:50.000 live-births 1% a pericentric inversion. In mentally retarded population CdCS represents less than 1 percent This deletion often has a paternal origin (80-90% of the cases) The breakpoints have a range from p13 to p15.2 Two distinct regions: associated with the typical crying of the CdCS (located in 5p 15.3) associated with dysmorphism, microcephaly and mental handicap (located in 5p 15.2) Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Cri du chat partial aneusomy syndromes like CdCS result from abnormal gene dosage (haploinsufficiency) involving a large number of contiguous genes human δ-catenin (CTNND2) mapped to 5p15.2 δ-catenin is a protein involved in cell motility and is expressed early in neuronal development. δ-catenin deletion seems to correlate with mental retardation in patients with a terminal deletion in this area The human Semaphorin F gene (SEMAF) -role in guiding axons or migrating neuronal precursors during cortical development telomerase reverse transcriptase (hTERT) is located in 5p15.33 LOC340094, ADAMTS16, KIAA0947, FLJ33360, MED10, UBE2QL1, LOC255167, NSUN2, SRD5A1, PAPD7, MIR4278 Cerruti Mainardi P. Cri du Chat syndrome. Orphanet J Rare Dis. 2006 Sep 5;1:33. doi: 10.1186/1750-1172-1-33. PMID: 16953888; PMCID: PMC1574300 Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Cri du chat In addition to the crying, the newborn with CdCS Among the main craniofacial alterations we can presents a low birth weight (below 20th percentile, emphasize microcephaly (especially evident during 2.614 g average weight), and small size (always the first two years of life), facial dysmorphism with below 50th percentile) despite a gestational age vertical growth pattern, severe asymmetry, moon close to the norm. During the first two years of life, face (83.5% of the patients affected) that their growth and development is remarkably slow disappears in adolescence and adulthood to turn because of the feeding difficulties (weak and into elongated and narrow faces. impaired suction, dysphagia, muscle hypotonia, gastroesophageal and nasal reflux) Other facial alterations widely described in CdCS include the presence of epicanthal folds (90.2% of the patients), down-turned corners of the Among the cardiac pathology we found cyanosis, mouth (81%), large nasal bridge (87.2%), short cutaneous hemangioma, cutis marmorata, philtrum (87.8%), convex facial profile with tetralogy of Fallot, cardiac congenital defects mandibular microretrognathia (96.7%), abnormal (frequently ductus associated with a septal dermatoglyphics (92%) ventricular defect and less often ductus with a septal atrial defect) Metabolism impairment non-cetonic hyperglycemia and deficit in Cryptorchidism is prevalent in youth and the synthesis of purine hypogonadism in adulthood. Girls in pubertal age present menarche and normal sexual secondary Senses impairment: hypersensibility development, but irregular menstrual periods. to sounds, auditive discomfort and strabismus Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Cri du chat Both survival rate and life expectation are high, having been registered cases of Regarding the social profile, many of the individuals who were over 50 years of children with CdCS live at home and interact age. with society, eventually achieving communication and coordination Most of the reported cases indicate that improvements‚ being able to express their the individuals with CdCS generally have needs, establishing relationships with other a nice and loving personality people and developing different levels of but….. motor activity hyperactivity, loss of attention, uneasiness, aggressive and self-injured REMARKS ON DIAGNOSIS behavior might be present a proper clinical diagnosis will depend more on the ability to recognize the combination of a Not all the individuals are able to collection of more or less specific situations develop spoken language and (microcephaly, facial dismorphism, typical cry, occasionally they use sign language low weight in birth, etc…) with success. Invariably, receptive language and comprehension is Once the suspected diagnosis is established, the remarkably better than expressive first complimentary test is a kariotype analysis. If language the results are apparently normal however do not correspond with the clinic supposition, it is CURIOSITY necessary to do more precise cytogenetic Currently there is only one molecular analysis (FISH, CGH or quantitative PCR case of procreation between or even NGS). two individuals with CdCS Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Fragile X syndrome Fragile X syndrome Riley C, Wheeler A. Assessing the Fragile X Syndrome Newborn Screening Landscape. Pediatrics. 2017 Jun;139(Suppl 3):S207-S215. doi: 10.1542/peds.2016-1159G. PMID: 28814541; PMCID: PMC5599128. Garber KB, Visootsak J, Warren ST. Fragile X syndrome. Eur J Hum Genet. 2008 Jun;16(6):666-72. doi: 10.1038/ejhg.2008.61. Epub 2008 Apr 9. PMID: 18398441; PMCID: PMC4369150. Meijer H, de Graaff E, Merckx DM, Jongbloed RJ, de Die-Smulders CE, Engelen JJ, Fryns JP, Curfs PM, Oostra BA. A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome. Hum Mol Genet. 1994 Apr;3(4):615-20. doi: 10.1093/hmg/3.4.615. PMID: 8069307. Baker EK, Arpone M, Aliaga SM, Bretherton L, Kraan CM, Bui M, Slater HR, Ling L, Francis D, Hunter MF, Elliott J, Rogers C, Field M, Cohen J, Cornish K, Santa Maria L, Faundes V, Curotto B, Morales P, Trigo C, Salas I, Alliende AM, Amor DJ, Godler DE. Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features. Mol Autism. 2019 May 3;10:21. doi: 10.1186/ s13229-019-0271-7. PMID: 31073396; PMCID: PMC6499941. Salcedo-Arellano MJ, Hagerman RJ, Martínez-Cerdeño V. Fragile X syndrome: clinical presentation, pathology and treatment. Gac Med Mex. 2020;156(1):60-66. English. doi: 10.24875/GMM.19005275. PMID: 32026885. Loesch DZ, Bui QM, Dissanayake C, Clifford S, Gould E, Bulhak-Paterson D, Tassone F, Taylor AK, Hessl D, Hagerman R, Huggins RM. Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X. Neurosci Biobehav Rev. 2007;31(3):315-26. doi: 10.1016/j.neubiorev.2006.09.007. Epub 2006 Nov 9. PMID: 17097142; PMCID: PMC2145511. Pandelache A, Baker EK, Aliaga SM, Arpone M, Forbes R, Stark Z, Francis D, Godler DE. Clinical and Molecular Differences between 4-Year-Old Monozygous Male Twins Mosaic for Normal, Premutation and Fragile X Full Mutation Alleles. Genes (Basel). 2019 Apr 5;10(4):279. doi: 10.3390/genes10040279. PMID: 30959842; PMCID: PMC6523498. Loesch D, Hagerman R. Unstable mutations in the FMR1 gene and the phenotypes. Adv Exp Med Biol. 2012;769:78-114. doi: 10.1007/978-1-4614-5434-2_6. PMID: 23560306; PMCID: PMC4124039. Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Fragile X syndrome Fragile X syndrome X-linked dominant disorder with reduced penetrance the most common inherited cause of mental retardation with approximately 1 in 4000 males affected caused by expansions of a CGG repeat in the 5ʹ-untranslated (UTR) region of the FMR1 Physical features: Elongated face, prominent ears, joint Salcedo-Arellano MJ, Hagerman RJ, Martínez-Cerdeño V. hypermobility, macroorchidism Fragile X syndrome: clinical presentation, pathology and treatment. Gac Med Mex. 2020;156(1):60-66. English. doi: Mental features: Individuals with 10.24875/GMM.19005275. PMID: 32026885. FXS may present with anything from learning problems and a Diagnosis is made based upon the detection of normal IQ to severe mental alterations to FMR1 retardation and autistic behaviors Individuals with FXS usually do not have significant medical issues Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics  Fragile X syndrome The FMR1 allele sizes are variable and can be classified into distinct repeat sizes: Females with the full normal size (NS: 200 CGG full mutation (FM), FXS causative. withdrawal, language deficits, mood lability, Hypermethylation of this expanded repeat tract and the and depression upstream CpG island extends from FMR1 promoter into FMR1 intron 1 what silences FMR1 expression causing loss of its product, fragile X mental retardation protein (FMRP) The fragile X-associated The majority of individuals with the premutation tremor/ataxia syndrome have normal intelligence, but males are prone to (FXTAS) causes intentional have attentional problems, executive dysfunction, tremors, balance problems, social deficits, and obsessive-compulsive behavior. frequent falls, neuropathy, Autistic-like features are common in individuals with autonomic dysfunction, FM (FXS): hand flapping, hand biting, gaze cognitive decline, and avoidance, tactile defensiveness, and hyperarousal to dementia, which may sensory stimuli. Anxiety and mood disorders, progressively worsen over hyperactivity, impulsivity, and aggressive behavior time can also be present. Karol P. Ruszel, PhD Chair of Medical Genetics [email protected] Department of Clinical Genetics Thank You for Your attention!