Family Testing May Help Bring the Diagnostic Odyssey Closer to an End

When a variant of unknown significance turns up in a genetic test, a family study may help clarify whether the variant is more likely to be pathogenic or benign. The added value of a family study in a difficult case of hereditary spastic paraplegia type 4 (HSP4) was the topic of a recent webinar by Meagan Krasner, MS, LCGC, one of Athena’s team of genetic counselors.

HSP is characterized by gait unsteadiness due to progressive lower extremity spastic weakness. It usually presents in childhood as “clumsiness,” with frequent falling or an abnormal stride. Symptoms may begin at any age, and both penetrance and progression may be variable, even within a single family, said Ms. Krasner, which can make recognizing the inherited nature of the disease more difficult.

HSP4 is the most common cause of autosomal dominant HSP, accounting for about 40% of the cases, she explained. It has a worldwide prevalence of between 2 and 6 per 100,000 population. Sequence variants account for up to 80% of cases, with deletions accounting for the remainder. Reduced penetrance means that carriers may be asymptomatic on examination, while subtle symptoms may account for the fact that some affected patients are unaware they are affected.


There are a large number of variants in the gene responsible for HSP4, called SPAST or SPG4, which can make the genetic diagnosis challenging. Ms. Krasner outlined a recent case in which the diagnostic odyssey for the family stretched over seven years, until, using samples from multiple family members, Athena Insight, the variant scientist team, was able to reclassify a variant as predicted pathogenic which had originally been determined to be of uncertain significance (VUS).

The proband, a two-and-a-half year-old boy, was seen in 2007, and his younger sister in 2008. His mother was seen shortly thereafter, and all were found to be carrying the same variant. But too little was known about the potential pathogenicity of the variant to classify it as predicted pathogenic at the time.

A second sample from the mother arrived for testing in 2014, which was flagged by Athena’s duplicate control system. “They were still trying to figure out what was going on seven years later,” Ms. Krasner said. She worked with the family’s genetic counselor to obtain a pedigree and further records. “We wanted to see if we could help further classify the variant with our current analysis team.” Updated clinical information indicated that the disease had progressed in all three family members over the ensuing years.

The pedigree showed that the proband had an affected uncle, two affected aunts, and an affected grandmother, as well an unaffected great-aunt. Athena’s team requested samples from each, as well as an unaffected aunt, and offered free testing in order to make a more definitive determination of the significance of the variant. The Athena Insight team analyzed information from both public and internal sources to make assessments about the variant’s likely effect on the properties of the protein, as well as the population frequency of the variant.

“Based on the segregation data, we were able to change the variant’s classification from VUS to Predicted Pathogenic,” Ms. Krasner said. This may be especially helpful for understanding the risks for other children in the proband’s extended family, whether they are currently unaffected or have begun to display subtle symptoms associated with HSP. “This information can help the families begin to develop a treatment plan.” Prenatal testing, which is only offered for variants that are predicted or known pathogenic, is now also an option.

“In the best case, family testing can help end the diagnostic odyssey so many families remain on for too long,” Ms. Krasner said. “With more information from other family members, and with the detailed analysis provided by the Athena team, we may be able to provide a more definitive answer for families about this most important question.”

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