Abstract
Aim: To identify additional genes associated with infantile spasms using a cohort with defined infantile spasms. Method: Whole-exome sequencing (WES) was performed on 21 consented individuals with infantile spasms and their unaffected parents (a trio-based study). Clinical history and imaging were reviewed. Potentially deleterious exonic variants were identified and segregated. To refine potential candidates, variants were further prioritized on the basis of evidence for relevance to disease phenotype or known associations with infantile spasms, epilepsy, or neurological disease. Results: Likely pathogenic de novo variants were identified in NR2F1, GNB1, NEUROD2, GABRA2, and NDUFAF5. Suggestive dominant and recessive candidate variants were identified in PEMT, DYNC1I1, ASXL1, RALGAPB, and STRADA; further confirmation is required to support their relevance to disease etiology. Interpretation: This study supports the utility of WES in uncovering the genetic etiology in undiagnosed individuals with infantile spasms with an overall yield of five out of 21. High-priority candidates were identified in an additional five individuals. WES provides additional support for previously described disease-associated genes and expands their already broad mutational and phenotypic spectrum.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 633-640 |
| Number of pages | 8 |
| Journal | Developmental Medicine and Child Neurology |
| Volume | 64 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2022 |
Funding
Members of the WES Support Group are as follows: Elizabeth A Geiger (Department of Pediatrics, University of Colorado, School of Medicine, Aurora, CO); Jonathan Gunti (Ken and Ruth Davee Department of Neurology, Northwestern University, School of Medicine, Chicago, IL); and Gina Vanderveen (Children's Hospital Colorado, Aurora, CO; and Department of Pediatrics, University of Colorado, School of Medicine, Aurora, CO). This research was supported by an unrestricted research grant from Mallinckrodt Pharmaceuticals (Benke) as well as the Ponzio Family Endowed Chair in Neurology Research (Benke) and National Institutes of Health NINDS R00NS089858 (Carvill). We thank the NUCATS TL1 award for support (TR001423 to JC). Funders did not participate in study design, data collection, or analysis, or manuscript preparation. TAB holds consultancies for AveXis, Ovid, GW Pharmaceuticals, International Rett Syndrome Foundation, Takeda, Taysha, Alcyone, and Marinus; clinical trials with Acadia, Ovid, GW Pharmaceuticals, Marinus, and RSRT; all remuneration has been made to his department. SD holds consultancies for Ovid, Marinus, Biomarin, and Neurogene on unrelated subject matters; all remuneration has been made to his department. GLC holds a collaborative research grant with Stoke Therapeutics for research unrelated to this manuscript; all remuneration has been made to her department. Members of the WES Support Group are as follows: Elizabeth A Geiger (Department of Pediatrics, University of Colorado, School of Medicine, Aurora, CO); Jonathan Gunti (Ken and Ruth Davee Department of Neurology, Northwestern University, School of Medicine, Chicago, IL); and Gina Vanderveen (Children's Hospital Colorado, Aurora, CO; and Department of Pediatrics, University of Colorado, School of Medicine, Aurora, CO). This research was supported by an unrestricted research grant from Mallinckrodt Pharmaceuticals (Benke) as well as the Ponzio Family Endowed Chair in Neurology Research (Benke) and National Institutes of Health NINDS R00NS089858 (Carvill). We thank the NUCATS TL1 award for support (TR001423 to JC). Funders did not participate in study design, data collection, or analysis, or manuscript preparation. TAB holds consultancies for AveXis, Ovid, GW Pharmaceuticals, International Rett Syndrome Foundation, Takeda, Taysha, Alcyone, and Marinus; clinical trials with Acadia, Ovid, GW Pharmaceuticals, Marinus, and RSRT; all remuneration has been made to his department. SD holds consultancies for Ovid, Marinus, Biomarin, and Neurogene on unrelated subject matters; all remuneration has been made to his department. GLC holds a collaborative research grant with Stoke Therapeutics for research unrelated to this manuscript; all remuneration has been made to her department.
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Developmental Neuroscience
- Clinical Neurology