The "Critical Element of Genetic Evaluation and Genetic Counseling" was written and approved by genetic professionals and perinatologists within the state of Washington. The document is to act as an aid to medical geneticists, genetic counselors, and perinatologists who practice within our state. This Critical Element of Genetic Evaluation and Genetic Counseling does not define the applicable standard of care, nor is it intended to dictate an exclusive course for the diagnosis, counseling, treatment or management of genetic conditions or birth defects. The authors acknowledge that appropriate clinical practices may vary depending upon a number of factors including, among others, the needs and choices of the individual patient, the resources available, and limitations unique to the particular institution or type of practice.

1. Review patient/family questions; reason for referral; knowledge base; perception of disease status and/or risk; what diagnoses have been considered; perceived notion about causation; assess need for professional interpreter: which individuals in the family are perceived to be affected, carriers, or at risk.

2a. Using standard symbols, obtain family history (1st and 2nd degree relatives to consultand, and further removed as appropriate). Note ethnic background, consanguinity, ongoing pregnancies, and other significant family history.

b. Additional directed family history: maternal relatives with developmental delay/mental retardation, special education, behavior problems and/ or autism.

c. Obtain relevant medical records on patient, including records of 1).appropriate tests/evaluations: Fragile X DNA testing, Fragile X cytogenetics, and past genetic evaluations 2). records bearing on management: developmental testing/psychometric and school evaluations and 3). on other family members as needed: Fra X test results.

3. Obtain prenatal and perinatal history of patient, including prenatal exposures, pregnancy complications and prenatal testing, when appropriate.

4. Obtain past medical history (including environmental/occupational exposures) focusing on: Behavior issues (e.g. hand flapping, avoidance of eye contact).

5. Obtain information on growth and development, including school placement. For adult, also obtain information on education, employment and social functioning.

6. Assess family functioning and use of community resources. Assess personal, social, religious, ethnocultural issues.

7. Assess possible ethical concerns, such as confidentiality, non-paternity, insurability, discrimination, prenatal diagnosis: informing at risk family members about risk and availability of diagnostic, carrier and prenatal testing/counseling.

8 Perform general physical examination of patient and/or other family members present if indicated, with attention to: ht, wt, OFC, facial features, testicular size in adolescent and older males, scoliosis, evaluation of joint mobility especially laxity, informal assessment of social skills.

9. Other issues to consider:

(this may occur in a series of multiple patient visits)

1. Summarize information obtained and discuss with patient/family the (possible) diagnosis and the degree of certainty of the diagnosis based on available information.

2. a). Recommend relevant tests/evaluations on patient and/or on other relatives which may include:

b). Discuss sensitivity/specificity of test(s)/evaluation(s): ): diagnostic sensitivity of full mutation in males vs. females; predictive aspects of premutation size for expansion in the offspring of females.

3. Discuss the following issues related to natural history: prognosis, developmental outcome/intellectual functioning, anticipated possible medical complications, including pregnancy related risks for affected women if indicated, and preventive measures: males with full mutation: usually moderate MR. Females with full mutation: range of abilities (mild MR to learning difficulties to normal). Premutation carriers are asymptomatic.

4. Review inheritance pattern (including penetrance and expressivity): X-linked, trinucleotide repeat

5. Assess and discuss recurrence risk for future pregnancies, for affected and at risk individuals. Discuss general background risk for birth defects and recommendations for preconceptional and prenatal use of 0.4 mg folate per day. Including any additional risk based on family history/ethnicity/maternal age/maternal disease/maternal exposure/others; discuss recommendations for preconceptional folic acid supplementation: Males with the full mutation are unlikely to reproduce. Transmitting males have no risk of occurrence; risk to offspring of females with premutation depends on the size of the expansion; females with full mutation have a 50% risk of transmission of full expansion.

6a. Discuss reproductive options (e.g. assisted reproductive technologies, adoption, taking risk and no additional pregnancies) when appropriate:

b. Discuss prenatal diagnostic options/issues: amniocentesis for Fragile X DNA mutation analysis; CVS may not be as reliable because of variation in methylation. Risk of mental retardation in female fetuses with the full expansion is 50%.

(or referral for discussion of)

7. Review management recommendations/options including screening protocols: pharmalocologic intervention for behavioral problems; special education.

8. Consider referral to: (medical specialties)developmental pediatrician, OT/PT, psychologist, psychiatrist

9. Address psychosocial issues including anticipatory guidance, patient and family reaction to diagnosis, need for community support services.

10. Address follow-up issues, such as genetic counseling for extended family members, including a plan for relaying test results: Genetic counseling should be offered to those members of the extended family determined to be at risk by pedigree analysis.

11. Document clinic visit, including persons present, and subsequent substantive contacts (e.g. clinic note, +/- letter to referral source, +/- letter to family; other). Contact referring health care provider as appropriate.

12. Other issues to consider: Ethical concerns in prenatal diagnosis due to inability to predict phenotype (i.e. MR) in female fetus with full expansion.

13. References and/or other protocols:

The "Critical Element of Genetic Evaluation and Genetic Counseling" was written and approved by genetic professionals and perinatologists within the state of Washington. The document is to act as an aid to medical geneticists, genetic counselors, and perinatologists who practice within our state. This Critical Element of Genetic Evaluation and Genetic Counseling does not define the applicable standard of care, nor is it intended to dictate an exclusive course for the diagnosis, counseling, treatment or management of genetic conditions or birth defects. The authors acknowledge that appropriate clinical practices may vary depending upon a number of factors including, among others, the needs and choices of the individual patient, the resources available, and limitations unique to the particular institution or type of practice.

1. Review patient/family questions; reason for referral; knowledge base; perception of disease status and/or risk; what diagnoses have been considered; perceived notion of causation; assess need for professional interpreter: which individuals in the family are perceived to be affected, carriers, or at risk.

2a. Using standard symbols, obtain family history (1st and 2nd degree relatives to consultand, and further removed as appropriate). Note ethnic background, consanguinity, ongoing pregnancies, and other significant family history.

b. Additional directed family history: maternal relatives with developmental delay/mental retardation, special education, behavior problems and/ or autism.

c. Obtain relevant medical records on patient/affected family member(s), including records on appropriate diagnostic testing/evaluation: Fragile X DNA analysis; Fragile X cytogenetics and on other family members as needed: either Fragile X DNA analysis or Fragile X cytogenetics on at least one affected individual and Fragile X DNA testing on consultand if he/she is determined to be at risk by pedigree analysis.

3. Obtain patient's past and current pregnancy history; documenting gestational age, Rh, prenatal exposures, pregnancy complications and pertinent prenatal testing to date.

4. Obtain patient's past medical history.

5. Obtain information on education, employment and social functioning as appropriate.

6. Assess family functioning and use of community resources, as appropriate. Assess personal (e.g. social, ethnocultural, religious) issues, including feelings about prenatal testing and consequences.

7. Assess ethical issues, such as confidentiality, insurability, discrimination and non-paternity.

8. Other issues to consider:

(this may occur in a series of multiple patient visits)

1a). Discuss risk of specific condition occurring in current pregnancy based on information available. Arrange for additional tests/evaluations on consultand and/or father of the baby if indicated: Fragile X DNA analysis on consultand or father of the baby as appropriate

b). Discuss sensitivity/specificity of test(s)/evaluation(s): diagnostic sensitivity of full mutation in males vs. females; predictive aspects of premutation size for expansion in the offspring of females.

c). Discuss referral of other family members for genetic testing/evaluation if inheritable disease is suspected and confirmation is necessary.

2a). Discuss general background risk for birth defects, including any additional risk based on family history/ethnicity/maternal age/maternal disease/maternal exposure/others:

b). Discuss inheritance pattern of disorder, including risk for future pregnancies:

3. Discuss the following issues related to natural history: prognosis, developmental outcome/intellectual functioning, anticipated possible medical complications, including pregnancy related risks for affected women if indicated, and preventive measures: males with full mutation: usually moderate MR. Females with full mutation: range of abilities (mild MR to learning difficulties to normal). Premutation carriers are asymptomatic.

4a). Review prenatal testing options as indicated:

b). Discuss risks and limitations of prenatal testing options, including sensitivity/specificity of test method(s): Risk of MR in females fetuses with the full expansion is 50%.

5. Explore psychosocial impact of testing vs. non-testing, ethical issues, and discuss the decision making process. Refer to outside resources as appropriate to help with decision making. (Process includes the discussion of outcomes/results; additional testing; option of termination of pregnancy; grief and supportive counseling; pediatric follow up; and support groups).

6. Document status of decision making by patient/family.

7. Make arrangements for testing if desired and plan for relaying results and for follow-up.

8. Consider referral to specific community resources and support groups.

9. Document the clinic visit, including persons present, and subsequent substantive contacts (e.g. clinic note, +/- letter to referring source, +/- letter to family, other). Contact referring health care provider as appropriate.

10. Other issues to consider: * controversy regarding CVS reliability in prenatal diagnosis of Fra X due to variation in methylation. Phenotype of female with full expansion.

11. References and/or other protocols: