1. Screening for Intellectual Disability: Lessons from Fragile X
Kruti Acharya MD, Abigail Schindler, MS
Department of Disability and Human Development, University of Illinois at Chicago
Illinois LEND Program
Background
Stakeholder Opinions
Although FXAD do not meet traditional public health screening criteria, pilot programs are underway because a broader definition of benefit has been adopted and the screening technology exists. Based on stakeholder preferences, an ideal FXS NBS program would be voluntary, universally offered and able to identify both FMR-1 FM and PM; that is identify newborns at risk for FXS as well as adult-onset FXAD, FXPOI and FXTAS. Screening children for adult onset disorders is prohibited by many professional guidelines because of concerns of the child’s future privacy and confidentiality. Follow-up studies are necessary to understand the long-term psychological impact on individuals and families of learning this type of information in childhood.
NBS for FXAD is additionally complicated by complex genetic presentation. Mutations in a single gene lead to 3 distinct conditions. Even when the genotype is confirmed, there is uncertainty to develop the condition. As technology continues to evolve, instances of genetic pleiotropy (ie. ApoE in Down Syndrome and Alzheimer disease) will be increasingly recognized. Professional and patient education will be integral to any population screening program to ensure consent is informed and genetic counseling is effective and accurate for all families whose children screen positive.
Fragile X Newborn Screening
An Ideal FMR-1 NBS program would …
Be Mandatory or Voluntary?
Mandatory- Acceptable if benefits outweigh risks
Lower refusal rate if the screening is “opt out” as opposed to “voluntary”
Voluntary- Reasons why “reasonable” people would not want to know
Increase anxiety
Results reveal potential risks of adult-onset FXAD for parents and other relatives
Screen for full mutation only or both full and premutations?
Full mutation- Focuses only on genetic conditions that present in childhood
Premutation - reveals increased risk of adult-onset conditions
May be useful for family cascade testing, though ethically debatable
Predictive genetic testing in childhood-not supported by many professional organizations
Screen males only or both genders?
Males only- Virtually all males with FM are affected and could benefit; additional cost to separate samples
Both Genders- 2/3 of females with FM will have some disability and could benefit from screening (like males), however 1/3 of females with FM will be normal, but labeled with FXS from birth which could inadvertently limit expectations
The ongoing development of new genetic technologies has shed light on genetic variations associated with intellectual disability
Our knowledge about the clinical implications of these genetic variations is constantly evolving
The case of Fragile X Associated Disorders (FXAD) highlights complexities of genetic screening for intellectual disability
In 2005, FXS considered and rejected for inclusion in uniform newborn screening panel because no cost-effective population test
Test has since been developed
Pilot programs for Fragile X NBS underway
TABLE 1: Support for FXS NBS
Mandatory
Voluntary
Genetic Health Professionals (GHP)2*
20%
80%
Developmental Behavioral Pediatricians (DBP) 3*
35%
65%
Genetic counselors (GC)4
Pediatricians6
31%
69%
*of those who supported universal NBS
Should we screen newborns for FXS
Traditional Newborn Screening Criteria:
Diagnosis of conditions appropriate for screening should directly benefit the individual being treated by reducing morbidity and/or mortality
Who benefits from Newborn Screening for FXS?
Newborns do not directly benefit
No specific treatment or cure for FXS
They can receive therapies without diagnosis based on developmental delays
Parents benefit
Enhanced future reproductive decision-making
Family benefit
Avoid diagnostic odyssey
Societal benefit
Scientific knowledge (ie. Natural history)
Proponents support notion that expanded benefit (i.e. to family and society) sufficient to warrant population screening1.
Fragile X Associated Disorders
TABLE 2: What FMR-1 mutation should FXAD NBS identify?
FM Only
FM and PM
Unsure
Pediatricians6 8%
65%
27%
Parents7 6%
94%
N/A
Fragile X associated disorders (FXAD) are multigenerational lifespan disorders.
In one family, multiple family members can be affected by distinct disorders
Genotype (genetic code) does not correlate 1:1 with phenotype (clinical presentation)
TABLE 3: What genders should FXAD NBS screen?
Males
Female
Both Genders
Genetic Health Professionals2*
91%
89% -
Developmental Behavioral Pediatricians3*
98%
96%
Pediatricians5
15% (males only)
85%
*percentages who found it at least moderately important to identify males & females in a newborn screening program
Fragile X Syndrome (FXS)
Fragile X Tremor Ataxia Syndrome (FXTAS)
Fragile X Primary Ovarian Insufficiency (FXPOI)
FMR-1 Genotype
Full Mutation (FM)
Premutation
(PM)
Premutation (PM)
Symptoms
Intellectual Disability/ Autism
Neuro-
degenerative disorder
Early menopause
Onset of Symptoms
Childhood
Adult
Gender
M>F
Female only
Prevalence
1: males
1: females
30-40% males with PM
8-16% females with PM
20-28%
females with PM
Treatment
Developmental therapies
Supportive
Reproductive Technology
Does not meet traditional NBS criteria since the individual being screened do not directly benefit
According to stakeholders’ preferences, an ideal Fragile X NBS program would be: 1) Universally offered, 2) Require parental consent, 3) Screen both male and female infants and 4) Screen for both FM and PM
References
Discussion
1 Bailey, DB, Bishop, E, Raspa, & Skinner, D (2011). Caregiver opinions about expanded Fragile X population screening. Genet in Med, 14(1),
2Acharya, K & Ross , LF (2009) Fragile X Screening: Views of Genetic Health Professionals. Am J Med Genet A. 10(4): 626–632.
3 Acharya, K & Schindler, A (2013). Developmental and behavioral pediatricians' attitudes toward screening for fragile X. Am J Intellect Dev Disabil. 118(4):
4 Hiraki S, Ormond KE, Kim K, & Ross LF (2006). Attitudes of genetic counselors towards expanding newborn screening and offering predictive genetic testing to children. Am J Med Genet.140A:2312–2319. 
5 Acharya K, Ackerman PD, & Ross LF (2005). Pediatricians' attitudes toward expanding newborn screening. Pediatrics. 116(4):e
6 Kemper, AR; Bailey, DB. Pediatricians' knowledge of and attitudes toward fragile X syndrome screening. Academic Pediatrics. 2009;9:
7 Skinner D, Sparkman KL, Bailey DB Jr. Screening for fragile X syndrome: parent attitudes and perspectives. Genet Med 2003;5:378–384.
Full Mutation FMR-I gene
Boys
Fragile X Syndrome
Girls
½ Mild Impairment
½ Unaffected
Acknowledgements
This study was funded by NIH 5 K23 MH The authors would like to thank Michael Msall, Lainie Ross, and colleagues in the section of Developmental and Behavioral Pediatrics at the University of Chicago for their assistance in this research.