#ScienceSaturday posts share exciting scientific developments and educational resources with the KAND community. Each week, Dr. Dominique Lessard and Dr. Dylan Verden of KIF1A.ORG summarize newly published KIF1A-related research and highlight progress in rare disease research and therapeutic development.

KIF1A-Related Research

Prenatal isolated clubfoot increases the risk for clinically significant exome sequencing results

Several recent studies have identified KIF1A mutations in people who were undiagnosed or diagnosed with another disorder based on symptoms. Because KAND diagnosis requires a genetic assessment, an important question is when to look for KIF1A mutations. It would be great to perform genetic screening for every child, but due to cost or limited availability this may only happen if symptoms are present.

As our community knows, time is precious and finding leads for earlier diagnosis is invaluable. In this week’s article, researchers performed genetic screening for children with foot deformities observed in prenatal ultrasounds.

What is clubfoot? “Clubfoot” is a broad term describing when a person’s feet are rotated inward, hindering their ability to walk. These foot deformities occur in 1 out of 1,000 births and arise from multiple causes. It is usually treated by a combination of physical therapy and surgery. Notably, the foot rotation is often visible in ultrasounds during pregnancy.

The authors performed genetic sequencing on 38 children who had been diagnosed with prenatal clubfoot and found four cases of genetic mutations, including KIF1A. All four genes are involved in musculoskeletal or neural development and likely to cause or contribute to foot deformities.

While these four mutations only comprise 10% of the children observed in this study, the authors assert that genetic testing could be an appropriate step after identifying prenatal foot deformities. These symptoms have been observed in other families with KIF1A mutations, both in individual studies and anecdotally, but we don’t know the prevalence in our community. We need to collect more data to understand foot deformities and KAND, but this study addresses an important point – the earlier we can identify risk factors and perform genetic screening, the better we can identify and help families encountering KIF1A mutations.

Rare Roundup

Personalizing Whole Genome Sequencing Doubles Diagnosis of Rare Diseases

Genetic testing has advanced considerably in a few short decades, but it is still incredibly complex; given their unfiltered whole genome sequence, even most scientists would not know how to interpret the results. This is because there are many factors to consider, each of which requires a level of expertise:

  • In what genes do mutations occur?
  • Is this mutation in a coding or noncoding region of DNA?
  • Is this mutation common in the population?
  • Is this mutation, in this gene, likely to contribute to the symptoms the patient is experiencing?

As a result patients with rare disorders may not always get clear answers from gene sequencing, which stalls their understanding of, and treatment of, their disorder. But as researchers from University College London have shown, a multidisciplinary approach to genome sequencing analysis can help identify causative mutations for more patients. Their team of researchers led personalized assessments of undiagnosed patients that integrated automated bioinformatics, and were able to nearly double their diagnostic rate from 17% to 31%. As the authors of the study stated, this demonstrates that many undiagnosed cases are solvable, but require “adequate workforce planning” to create multidisciplinary teams that can lead such personalized investigations.

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