© 2017, GENASSIST, Inc.

By Keith S. Wexler, MBA, Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Case Study:  We were contacted by a mother with a 6 month old son who believed her son was failing to reach all of his developmental milestones. 

The parents had an appointment with the genetics department for evaluation of her son which would not be for several months.

The pediatrician in consult with the genetics department ordered blood chromosomes and Fragile X on the child.  The chromosomes returned as normal 46,XY. 

The son was found to have greater than 260 CGG repeats on the Fragile X DNA analysis and was diagnosed with Fragile X Syndrome.  There was no other family history of Fragile X. Familial studies were suggested. 

Testing of the mother showed 84 CGG repeats. Subsequently the maternal grandmother was tested and had 66 CGG repeats and the maternal great grandfather showed 59 CGG repeats. 

This testing demonstrated expansion of a premutation (55 to 200 repeats in 3 generations) resulting in a male child with Fragile X Syndrome.

The question parents always ask when they are referred is “why doesn’t routine prenatal screening test all pregnant women for that disease?” The main questions they have are:

  • What is the percentage chance of recurrence?
  • What preconception and/or prenatal testing options do they have to try to prevent having another “affected” child?

Fragile X, a fragile site on the distal end of an X chromosome was first described by Dr. Herbert Lubs at the University of Colorado in 1969, associated with male mental disability. Much of the work on Fragile X was done in Colorado by Dr. Randi J Hagerman among others. 

The syndrome sometimes called Escalante Syndrome may include intellectual disability, speech problems, social integration issues, repetitive movements, hypotonia in addition to some phenotypic findings including prominent ears, high arched palate, flat feet, elongated face and large testis. 

*It is believed that 2-6% of autistic-like behavior may be due to Fragile X.

  • Normal CGG Repeats: on an X chromosome are 6 to 44 repeats (average 29)
  • Grey Zone: 45-54 repeats
  • Premutation: 55-200 repeats
  • Full Mutation:   Greater than 200 repeats

As many as *1 in 130 to 1 in 150 females may be a carrier of one Fragile X chromosome and 1 in 1000 to 1 in 4000 males and 1 to 6000 female births may manifest symptoms of the syndrome.

*Reference: The National Fragile X Foundation quotes a “large Israeli study found approximately 1 in 130 women were FMR carriers” (National Fragile X Foundation and Paul, R et al Neurotoxicology 31 (2010) 399-402). Also the premutation carrier prevalence is quoted as 1 in 151 by the National Fragile X Foundation (several publications) and the CDC. Seltzer, MM in the Am J Medical Genetics B Neuropsychiatr Genet 159 B(5):589-597 (2012) also discussed grey (gray) zone (intermediate) prevalence as approximately 1 in 38.   Grey (gray) zone patients CGG repeats are usually stable but occasionally do expand though not usually in one generation.

To date, there have been no reports of expansion to a full mutation (greater than 200 CGG repeats) in a single generation from a carrier female with fewer that 56 repeats.

The estimated risk for expansion to a full mutation based on repeat size is approximately:

#Number of CGG Repeats of Maternal Allele                              Percentage Expansion to Full Mutation

55-59                                                                                                                     5.4%

60-69                                                                                                                     19%

70-79                                                                                                                     49.6%

80-89                                                                                                                     73%

90-99                                                                                                                     86.8%   

100-130                                                                                                                 >95%

>130                                                                                                                       100%

Reference: S.L. Nolin, et al Am. J. Hum Genetics 72:454,2003             

It appears that the number of CGG repeats is normally interrupted by AGG repeats. Loss of some AGG repeats result in a longer series of CGG and may explain the variable degree of expansion in some families.

Premutation Carrier Females: (55 to 200 repeats) may exhibit premature ovarian failure and possibly autoimmune disease but this is not reported in grey zone carriers.

Fragile X associated Tremor-Ataxia Syndrome has been reported in up to 40% of males and up to 8% of females who are carriers of a premutation but not in “grey zone” individuals.

Prenatal diagnosis by Chorionic Villus Sampling (CVS) and/or amniocentesis is available.  Preimplantation Generic Diagnosis (PGD) is available by a limited number of laboratories.

Analysis:  This case study helps illustrate the “screening” dilemmas that families face when deciding to have a child. 

There is currently no preconceptional or prenatal testing that can screen for all abnormalities.

Even if a patient tests negative for a disease that they are screened for, they can still have a child with the disease, often due to “unknown” mutations. We cannot test for “everything”, and still do not know what “everything” is. 

“Standard of Care” for testing in pregnancy means that a majority of healthcare providers are routinely performing the same prenatal screen on every patient.

There currently is no single genetic preconceptional screen or prenatal screen that all healthcare providers perform.

With carrier frequencies of 1 in 130 to 1 in 150 it may be time to recommend Fragile X carrier screening as part of a routine preconceptional or prenatal testing panel.