Pain and gain of predictive genetic testing: Particular case of fragile X syndrome

TL;DR

This paper discusses the psychological and medical implications of predictive genetic testing in a family affected by fragile X syndrome.

Contribution

The study highlights the genetic counseling process and outcomes in an Arab family with fragile X syndrome.

Findings

The boy was found to have a full mutation in the FMR1 gene, while his mother had a premutation.

Fragile X premutation is associated with various physical and psychological health symptoms.

Fragile X syndrome patients may have an unusually low risk of cancers due to over-expression of FMRP in cancer tissues.

Abstract

The purpose of predictive genetic tests is to identify carriers or the onset of a disease in pre-symptomatic individuals. Prediction is linked to a negative psychological impact (anxiety, depression, etc.), depending on the perception of risk, the severity of the disease, and the availability and effectiveness of treatments.

Here, we report on genetic counselling during predictive genetic testing offered to an Arab family affected by fragile X condition (FXS) caused by the unstable expansion of a CGG repeat (CGGR) in the FMR1 gene.

A 10-year-old boy who harbored a mental retardation was referred to our genetic counselling for genetic testing as he was suspected to be affected by FXS. Screening of FMR1 gene mutations was conducted for the index case and his mother. A predictive genetic testing for the family members (brothers, sisters and others) was offered, focusing on knowledge of genetics and medical risks of FXS.

FMR1 molecular analysis showed a full mutation (300 to 2000 CGGR) for the boy and a large premutation (100 CGGR) for the mother. During genetic counselling, the family was informed about the significance of the genetic results. In FXS initiated by an expansion of over 200 CGGR. While mental retarded males usually harbor the full mutation, the mother carry a premutation (70 to 200 CGGR). The deficiency of FMR protein (FMRP) in the neurons of affected males leads to brain developmental abnormalities. Some pre-mutated children may show signs of the autism spectrum disorder and females may develop FMR1-related premature ovarian insufficiency. An increased risk of a late onset fragile X tremor ataxia syndrome is identified in pre-mutated men (55 to 200 CGGR) and less in women.

The reduction or loss of FMRP leads to multisystem damage. Neuropsychiatric disorders such as mental retardation, speech and language delay, autism spectrum disorder, sensory hyperexcitation, social anxiety, abnormal eye contact, shyness and aggressive behaviour are common in individuals with the mutation. Affected women are often under-diagnosed because mental retardation is not constant, but minor disorders including a borderline IQ with learning difficulties and emotional disturbances have been reported. Conditions associated with fragile X premutation, a term proposed by the European Fragile X Network (FXPAC), seem to be characterized by many physical and psychological health symptoms. Anxiety, depression, sleep disorders and mood disorders are more common in permutated individuals. However, new reports suggested that FXS patients could be at unusually low risk of cancers, because FMRP is over-expressed in multiple cancer tissues.

None Declared