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  • Correspondence
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A way forward for diagnosis of patients with extremely rare genetic mutations

Nature Biotechnology volume 41, pages 1190–1192 (2023)Cite this article

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Single-gene mutations resulting in diseases with a prevalence of 1–30 patients with the same mutation worldwide are defined as nano-rare. Most nano-rare mutations occur de novo, and therefore patients are dispersed around the world, which creates unique challenges in diagnosis, identification and treatment of this virtually unserved patient population. With the advent of genomic sequencing, it is now apparent that the overall prevalence of nano-rare mutations is substantial and will grow as more human genomes are sequenced1. Recent progress reported by the Undiagnosed Disease Network (UDN) and the growing number of personalized medicine centers in tertiary care centers has begun to identify more patients with nano-rare mutations. Despite increased identification, the vast majority of patients with nano-rare mutations experience disease progression and succumb to their diseases without achieving a diagnosis. For the fraction of patients who are genetically and phenotypically diagnosed, the journey to diagnosis is long and perilous, replete with inappropriate referrals, misdiagnoses and either no or mistreatments1,2,3,4,5. To meet the therapeutic needs of many patients with nano-rare mutations, the non-profit foundation n-Lorem has taken advantage of the rapidity, efficiency and cost effectiveness of antisense technology to provide personalized experimental antisense oligonucleotide (ASO) treatments free for life to these patients1,2.

The purpose of this Correspondence is to describe the challenges of achieving a diagnosis and treatment in the nano-rare population by presenting the experience of a patient with a particularly well-documented history. Patient 001 is a 13-year-old boy who experiences seizures that are unresponsive to standard antiepileptic agents; choreoathetotic and dystonic movement disorders that limit mobility and functionality; recurrent, often severe, gastrointestinal (GI) disorders; and developmental delays. As he has aged, he has become more anxious and hyper-responsive to various stimuli, and displays variable responses to pain. The patient suffers from severe developmental delays and is reliant on a caregiver to meet all basic needs.

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Author information

Authors and Affiliations

  1. n-Lorem Foundation, Carlsbad, CA, USA

    Stanley T. Crooke

  2. University of California San Diego Department of Neurosciences, Rady Children’s Hospital Division of Pediatric Neurology, La Jolla, CA, USA

    Olivia S. Kim-McManus

  3. Praxis Precision Medicines, Boston, MA, USA

    Kelley Dalby

Authors
  1. Stanley T. Crooke
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  2. Olivia S. Kim-McManus
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  3. Kelley Dalby
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Contributions

S.T.C. was the primary author and reviewed all of the data mentioned. K.D. compiled a natural history of patient 001. O.S.K.-M. reviewed the manuscript and is the treating physician for patient 001.

Corresponding author

Correspondence to Stanley T. Crooke.

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Competing interests

S.C. is the founder, chairman and CEO of n-Lorem Foundation, a non-profit foundation devoted to meeting the needs of nano-rare patients. K.D. is associate director of natural history and diagnostics in epilepsy at Praxis Precision Medicines. O.K.-M. declares no competing interests.

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Crooke, S.T., Kim-McManus, O.S. & Dalby, K. A way forward for diagnosis of patients with extremely rare genetic mutations. Nat Biotechnol 41, 1190–1192 (2023). https://doi.org/10.1038/s41587-023-01879-5

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