Fragile X One gene, three very different disorders for which Genetic Technology is essential. Significance of Fragile X. Significance of Fragile X

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1 Fragile X One gene, three very different disorders for which Genetic Technology is essential Martin H. Israel Margaret E. Israel mhi@wustl.edu meisrael@sbcglobal.net uel L. Israel Association of Genetic Technologists June 16, 2017 Significance of Fragile X Fragile X Syndrome (FXS) is the most common inherited cause of cognitive impairment. ~1/3600 males and ~1/5000 females is affected. ~1/250 females is a carrier. ~1/800 males is a carrier. Equal opportunity all races and ethnic groups Single-gene disorder (FMR1) The allele that causes FXS is an unusual kind of mutation. This sort of mutation is important for several other disorders. Study of the protein (FMRP) is leading to new understanding of operation of central nervous system. Significance of Fragile X An allele of FMR1 that does not cause FXS does cause a different set of problems in carriers. Tremor Ataxia Syndrome (FXTAS) in older (mostly male) carriers. Premature Ovarian Insufficiency (FXPOI) in young female carriers. There are three forms of the gene Normal Premutation No FXS, but possible FXTAS or FXPOI Full mutation Usually results in FXS Clinical Molecular Genetics required for diagnosis 1

2 Origin of the name Fragile X Cytogenetics using folate deficient culture medium A fraction of the X chromosomes display a fragile site. These fragile sites were reliably identified in 1978, and regular diagnosis of FXS only began in the early 1980 s. was the first diagnosed in St. Louis, in January Characteristics of Fragile X Syndrome (None of these characteristics is unique to FXS, and individuals with FXS may not display all of these.) Cognitive Mild to moderate Cognitive Impairment in males Learning Disabilities to mild Cognitive Impairment in females Difficulty with sequencing, math, abstract reasoning Speech & language delays and disorders Characteristics of Fragile X Syndrome (None of these characteristics is unique to FXS, and individuals with FXS may not display all of these.) Behavioral Attention-deficit, hyperactivity (ADHD) Social anxiety Difficulty with transitions Autisim-like behaviors Poor eye contact Hand flapping when excited. Biting back of hand when upset. Tactile avoidance Repetitive motions (~5% of males with autism have FXS) 2

3 Characteristics of Fragile X Syndrome (None of these characteristics is unique to FXS, and individuals with FXS may not display all of these.) Physical (These typically become more apparent after puberty.) Long, narrow face Prominent ears Poor muscle tone Macrocephaly Macroorchidism (in males) age 18 Age 20 Age 4 1 /2 Age 27 Age 37 History of Fragile-X Genetics Before 1979 Some cognitive impairment noted as X-linked 1980s Cytogenetic Fragile X marker identifies individuals with FXS 1990s FMR-1 gene identified Clinical Molecular Genetics permits identification of affected individuals and also carriers 2000s Beginning to understand FMR Protein function Recognition of disorders different from FXS in carriers Phase-1 clinical trials of targeted treatments of FXS 2010s Promising results of Phase-2 clinical trials Beginning of Phase-3 clinical trials 3

4 A typical Fragile-X pedigree FXS does not display typical X- linked inheritance Male Female Affected A typical Fragile-X pedigree FXS does not display typical X- linked inheritance Male Female Affected Unaffected carrier Unaffected male carrier! A typical Fragile-X pedigree FXS does not display typical X- linked inheritance Male Female Affected Unaffected carrier 4

5 Fragile X syndrome Caused by a large CGG-repeat expansion in the leader section of the Fragile X (FMR1) gene Typical development: < 55 CGG repeats FMR1 gene Promoter (CGG) N Protein coding Premutation (Carrier) 55 to 200 CGG repeats Normal Full mutation > 200 CGG repeats // CpG methylation Gene shuts off fragile X syndrome Inheritance of the FMR1 gene Individuals with the premutation (55 N 200) do not have Fragile X syndrome, but the premutation may grow to full mutation (N>200) when the gene passes from mother to child. Males with premutation have daughters with about same N. So all daughters of premutation males carry the premutation. Females with the premutation: 55 N 69 have <~10% chance that children who get that X will have full mutation. 70 N 89 ~ to 60% chance. 90 N 99 ~80% chance N 100 >~95% chance. Results of Southern and PCR analysis of DNA of s family ~1 31 ~120 ~110 ~400 ~600 Clinical Molecular Genetics tell s sister she is not a carrier. 5

6 What good is FXS diagnosis if there is (now) no cure? There are effective treatments of symptoms. Speech therapy Occupational therapy with sensory integration Medication for serious ADHD or serious anxiety Teaching and testing techniques Avoid unnecessary diagnostic procedures Relieve parental guilt Counsel relatives More effective parenting E.g., know to prepare child for transitions. Opportunity to participate in clinical trials of targeted treatments What good is FXS diagnosis if there is (now) no cure? It turns out that although premutation carriers (those with 55 to 200 CGG) are not affected by Fragile X Syndrome, they may experience other effects for which they should be alert. The premutation is not completely benign. ~20% of premutation females have Primary Ovarian Insufficiency (POI) Menopause before age 40 (sometimes before ) Also very irregular periods and difficulty getting pregnant before end of menopause Now fertility clinics may order Clinical Molecular Genetics test for Fragile X in young women who are having trouble getting pregnant. 6

7 The premutation is not completely benign. Many (not all) premutation males, and a few females, between age ~50 and 80 develop tremors, ataxia, and in some cases dementia. Fragile-X-associated Tremor Ataxia Syndrome This is not just normal aging; post-mortem examination of brains indicate unique inclusions, and MRI imaging shows brain atrophy. Prior to identification of FXTAS some men have been misdiagnosed as having Parkinson s Disease. Clinical Molecular Genetics distinguish FXTAS from Parkinson. Triplet repeat amplification disorders identifiable with Molecular Genetics. Fragile X Syndrome (FXS) 1991 X CGG 5 UTR 7-55 >200 Spinobulbar Muscular Atrophy 1991 X CAG ORF Myotonic Dystrophy CTG 3 UTR 5- >50 Huntington Chorea (HD) CAG ORF >100 At least six more. Thank you! More information National Fragile X Foundation 7