We identified a novel de novo heterozygous missense mutation in the NEDD4L gene (NM_015277: c.2617G>A; p.Glu873Lys) through whole-exome sequencing in a 3-year-old girl showing severe global developmental delay, infantile spasms, cleft palate, periventricular nodular heterotopia and polymicrogyria. Mutations in the HECT domain of NEDD4L have been reported in patients with a neurodevelopmental disorder along with similar brain malformations. All patients reported with NEDD4L HECT domain mutations showed periventricular nodular heterotopia, and most had seizures, cortex anomalies, cleft palate and syndactyly. The unique constellation of clinical features in patients with NEDD4L mutations might help clinically distinguish them from patients with other genetic mutations including FLNA, which is a well-known causative gene of periventricular nodular heterotopia. Although mutations in the HECT domain of NEDD4L that lead to AKT-mTOR pathway deregulation in forced expression system were reported, our western blot analysis did not show an increased level of AKT-mTOR activity in lymphoblastoid cell lines (LCLs) derived from the patient. In contrast to the forced overexpression system, AKT-mTOR pathway deregulation in LCLs derived from our patient seems to be subtle.
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Barkovich, A. J., Guerrini, R., Kuzniecky, R. I., Jackson, G. D. & Dobyns, W. B. A developmental and genetic classification for malformations of cortical development: update 2012. Brain 135, 1348–1369 (2012).
Guerrini, R. & Dobyns, W. B. Malformations of cortical development: clinical and genetic causes. Lancet Neurol. 13, 710–726 (2014).
Mirzaa, G. M., Conti, V., Timms, A. E., Smyser, C. D., Ahmed, S., Carter, M. et al. Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: next-generation sequencing study. Lancet Neurol. 14, 1182–1195 (2015).
Jansen, L. A., Mirzaa, G. M., Ishak, G. E., O’Roak, B. J., Hiatt, J. B., Roden, W. H. et al. PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain 138, 1613–1628 (2015).
Briox, L., Jagline, H., Ivanova, L., Schmucker, S., Drouot, N., Clayton-Smith, J. et al. Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia. Nat. Genet. 48, 1349–1358 (2016).
Benito-Sanz, S., Belinchon-Martinez, A., Aza-Carmona, M., de la Torre, C., Huber, C., Gonzalez-Casado, I. et al. Identification of 15 novel partial SHOX deletions and 13 partial duplications, and a review of the literature reveals intron 3 to be a hotspot region. J. Hum. Genet. 62, 229–234 (2017).
Hori, I., Miya, F., Ohashi, K., Negishi, Y., Hattori, A., Ando, N. et al. Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome. Am. J. Med. Genet. A 170, 1863–1867 (2016).
Negishi, Y., Miya, F., Hattori, A., Jojmura, Y., Nakagawa, M., Ando, N. et al. A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly. BMC Med. Genet. 18, 4 (2017).
Kanda, Y. Investigation of the freely-available easy-to-use software “EZR” (Easy R) for medical statistics. Bone Marrow Transplant. 48, 452–458 (2012).
Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).
Lange, M., Kasper, B., Bohring, A., Rutsch, F., Kluger, G., Hoffjan, S. et al. 47 Patients with FLNA associated periventricular nodular heterotopia. Orphanet J. Rare Dis. 10, 134 (2015).
The authors declare no conflict of interest.
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Kato, K., Miya, F., Hori, I. et al. A novel missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria and cleft palate. J Hum Genet 62, 861–863 (2017) doi:10.1038/jhg.2017.53
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