A homozygous truncating NALCN variant in two Afro-Caribbean siblings with hypotonia and dolichocephaly.
Caribbean
IHPRF1
NALCN
dolichocephaly
hypotonia
sodium channel
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
19
03
2020
revised:
30
05
2020
accepted:
30
05
2020
pubmed:
4
7
2020
medline:
4
6
2021
entrez:
4
7
2020
Statut:
ppublish
Résumé
NALCN encodes a sodium ion leak channel expressed in the nervous system that conducts a persistent influx of sodium ions to facilitate action potential formation. Homozygous or compound heterozygous loss of function variants in NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1; OMIM 615419). Through exome and Sanger sequencing, we found two siblings of Afro-Caribbean ancestry who are homozygous for a known NALCN pathogenic variant, p.Arg735Ter, leading to failure to thrive, severe hypotonia, and dolichocephaly. The older sibling died suddenly without a known etiology after evaluation but before molecular diagnosis. An international collaboration originating from a resource limited Caribbean island facilitated molecular diagnosis. Due to its small population, geographical isolation, and low socioeconomic status, the island lacks many specialty medical services, including clinical genetics. Descriptions of genetic disorders affecting individuals of Afro-Caribbean ancestry are rarely reported in the medical literature. Diagnosis of IHPRF1 is important, as individuals with biallelic pathogenic NALCN variants are severely affected and potentially are at risk for cardiorespiratory arrest. Additionally, knowing the pathogenic variants allows the possibility of prenatal or preimplantation genetic diagnosis.
Identifiants
pubmed: 32618095
doi: 10.1002/ajmg.a.61744
doi:
Substances chimiques
Ion Channels
0
Membrane Proteins
0
NALCN protein, human
0
Types de publication
Case Reports
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1877-1880Informations de copyright
© 2020 Wiley Periodicals LLC.
Références
Bramswig, N. C., Bertoli-Avella, A. M., Albrecht, B., Al Aqeel, A. I., Alhashem, A., Al-Sannaa, N., … Wieczorek, D. (2018). Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies). Human Genetics, 137(9), 753-768. https://doi.org/10.1007/s00439-018-1929-5
Cochet-Bissuel, M., Lory, P., & Monteil, A. (2014). The sodium leak channel, NALCN, in health and disease. Frontiers in Cellular Neuroscience, 8, 1-17. https://doi.org/10.3389/fncel.2014.00132
Farwell, K. D., Shahmirzadi, L., El-Khechen, D., Powis, Z., Chao, E. C., Tippin Davis, B., … Tang, S. (2015). Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: Results from 500 unselected families with undiagnosed genetic conditions. Genetics in Medicine, 17, 578-586. https://doi.org/10.1038/gim.2014.154
Helbig, K. L., Farwell Hagman, K. D., Shinde, D. N., Mroske, C., Powis, Z., Li, S., … Helbig, I. (2016). Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genetics in Medicine, 18(9), 898-905. https://doi.org/10.1038/gim.2015.186
Li, D., Yuan, H., Ortiz-Gonzalez, X. R., Marsh, E. D., Tian, L., McCormick, E. M., … Falk, M. J. (2016). GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers. American Journal of Human Genetics, 99(4), 802-816. https://doi.org/10.1016/j.ajhg.2016.07.013
Murray, T., Beaty, T. H., Mathias, R. A., Rafaels, N., Grant, A. V., Faruque, M. U., … Barnes, K. C. (2010). African and non-African admixture components in African Americans and an African Caribbean population. Genetic Epidemiology, 34(6), 561-568. https://doi.org/10.1002/gepi.20512
Ren, D. (2011). Sodium leak channels in neuronal excitability and rhythmic behaviors. Neuron, 72(6), 899-911. https://doi.org/10.1016/j.neuron.2011.12.007
Roach, A., Warner, W. A., & Llanos, A. A. M. (2015). Building capacity for human genetics and genomics research in Trinidad and Tobago. Revista Panamericana de Salud Publica/Pan American Journal of Public Health, 38(5), 425-430.